Proposal summaries

These are research proposals that have been approved by the ALSPAC exec. The titles include a B number which identifies the proposal and the date on which the proposals received ALSPAC exec approval.

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B819 - Identification of genetic factors determining human head circumference - 06/05/2009

B number: 
B819
Principal applicant name: 
Dr Andrew Jackson (MRC Human Genetics Unit, UK)
Co-applicants: 
Dr Nic Timpson (University of Bristol, UK), Prof Alan Wright (MRC Human Genetics Unit, UK)
Title of project: 
Identification of genetic factors determining human head circumference.
Proposal summary: 

The mammalian brain has undergone significant expansion in its evolution to man, and is over 3 times bigger than our closest primate relatives (1). The longterm research interests of the Jackson laboratory are in brain size. Head circumference is highly correlated with brain size, and is used clinically as a proxy measurement for brain volume. To date our major work has been in the identification and functional analysis of genes causing marked reduction in head circumference/brain size (Primary Microcephaly/Seckel syndrome,ref. 2-6). Several genes have been identified, all of which have centrosomal functions (6-8). Two of these, ASPM and MCPH1 have been found to undergo significant adaptive evolution in primates (9,10). However, to date, variants in these genes have not been found to be associated with normal population variation in head circumference/brain size (11).

Following on from the identification of Mendelian genes for these disorders of extreme reduction in head circumference (-4 to -10sd), it is now of interest to identify the factors responsible for variation in head circumference and brain size in the general population.

Within the Human Genetics Unit, head circumference has been measured as a QTL in ongoing GWAS studies in Croatia and Orkneys. To increase the power of these studies we now plan to perform metaanalyses in conjunction with other cohorts to identify SNPs associated with determining head circumference in the general population. The ALSPAC cohort provides an ideal cohort to combine with our studies, particularly given that genotyping has been performed on the same 317 platform, and the availability of a larger cohort for replication/confirmation, of positive hits. (If required, such validation work through genotyping of candidate SNPs would be performed by Nic Timpson on the ALSPAC cohort for within cohort replication/confirmation)

Once identified, and validated, such genes contributing to variation in head cirucmference, will be functionally characterised at the cellular level and in model organisms, using approaches already established in ongoing work in the lab to characterise the MCPH1 and PCNT genes. Such work, will address whether such variants are acting in developmental pathways already implicated by mendelian genetics in brain size determination.

1. Ponting, C. & Jackson, A.P. Evolution of primary microcephaly genes and the enlargement of primate brains. Curr Opin Genet Dev 15, 241-8 (2005).

2. Griffith, E. et al. Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat Genet 40, 232-6 (2008).

3. Brunk, K. et al. Microcephalin coordinates mitosis in the syncytial Drosophila embryo. J Cell Sci 120, 3578-88 (2007).

4. Alderton, G.K. et al. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Nat Cell Biol 8, 725-33 (2006).

5. Trimborn, M. et al. Mutations in Microcephalin Cause Aberrant Regulation of Chromosome Condensation. Am J Hum Genet 75, 261-266 (2004).

6. Jackson, A.P. et al. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 71, 136-42 (2002).

7. Bond, J. et al. Protein-Truncating Mutations in ASPM Cause Variable Reduction in Brain Size. Am J Hum Genet 73, 1170-7 (2003).

8. Bond, J. et al. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet 37, 353-5 (2005).

9. Evans, P.D. et al. Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum Mol Genet 13, 489-94 (2004).

10. Evans, P.D., Anderson, J.R., Vallender, E.J., Choi, S.S. & Lahn, B.T. Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size. Hum Mol Genet 13, 1139-45 (2004).

11. Timpson, N., Heron, J., Smith, G.D. & Enard, W. Comment on papers by Evans et al. and Mekel-Bobrov et al. on Evidence for Positive Selection of MCPH1 and ASPM. Science 317, 1036; author reply 1036 (2007).

Date proposal received: 
Wednesday, 6 May, 2009
Date proposal approved: 
Wednesday, 6 May, 2009
Keywords: 
Face Shape , Genetics
Primary keyword: 

B820 - Replication of GWAS for Maternal and Fetal Genotype Associations with Birthweight - 05/05/2009

B number: 
B820
Principal applicant name: 
Prof William J Lowe (Northwestern University, USA)
Co-applicants: 
Dr Nic Timpson (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK), Dr Rachel Freathy (Peninsula Medical School, University of Plymouth, UK)
Title of project: 
Replication of GWAS for Maternal and Fetal Genotype Associations with Birthweight.
Proposal summary: 

Fetal growth is determined by interactions between fetal genes and the maternal uterine environment. We are performing a genome wide association study (GWAS) to address the hypothesis that gene-environment interactions in the context of the maternal-fetal unit impact fetal size at birth and maternal metabolism. This is being accomplished using Caucasian, Hispanic, and Afro-Caribbean DNA samples collected from mothers and offspring as part of the NIH-funded Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. HAPO is a multicenter, international study in which high quality phenotypic data related to fetal growth and maternal glucose metabolism was collected from 25,000 pregnant women of varied racial backgrounds using standardized protocols that were uniform across centers. A major strength of HAPO is the large number of subjects available for replication. In addition to the samples analyzed in the initial GWAS, there are additional cohorts of Caucasian, Asian and Israeli Arab/Bedouin and Jewish mothers and babies which are available for replication of the initial GWAS findings. Importantly, phenotype data related to fetal growth and maternal metabolism was collected from these mothers and babies using standardized protocols that were uniform across centers and identical to those used to phenotype subjects in the initial GWAS. In this initial replication study, we intend to focus efforts on a phenotype for which: (i) there are not other ongoing, large GWAS efforts and (ii) there are large replication cohorts from the same ethnic background available. Thus, this study aims to replicate the contribution of maternal SNPs to offspring birth weight and the contribution of fetal SNPs before and after correction for maternal genotype to offspring birth weight. Importantly, our proposal takes advantage of one of the unique strengths of HAPO, access to GWAS data from both mothers and their offspring, and we will be able to consider the contribution of both offspring and maternal genetic variation to the regulation of birth weight. We intend to use a two-stage replication approach by including an additional large cohort of Caucasian subjects from the UK who were recruited under the auspices of the Exeter Family Study of Childhood Health (EFSOCH) and ALSPAC. This project has the following specific aims.

1. To perform a two stage replication of the GWAS results from maternal SNP vs. offspring birth weight associations. We will take 115 SNPs into 2,556 Stage 1 maternal replication samples and a further 15 SNPs into 11,000 Stage 2 maternal replication samples and perform a joint analysis on greater than 15,000 mothers.

2. To perform a two stage replication of the GWAS results from fetal SNPs vs. offspring birth weight associations, including analyses corrected for maternal genotype. We will take 115 SNPs into 2,669 Stage 1 offspring replication samples and a further 15 SNPs into 11,000 Stage 2 offspring replication samples and perform a joint analysis on greater than 15,000 offspring.

The first aim of our study is to investigate, genome-wide, the association between maternal genotype and offspring birth weight. This aim does not overlap with current aims of the EGG consortium.

Since we are also interested in the association between fetal genotype and offspring birth weight, there is some overlap between our proposed analyses and the current GWAS meta-analysis (including 1500 ALSPAC offspring) being carried out by the EGG consortium. However, our proposed analysis is distinct from these efforts because we will adjust for maternal genotype at the genome-wide stage and follow up hits based on those data. To our knowledge, other than in HAPO, there are no existing genome-wide association studies with both maternal and fetal genotype data on large numbers of subjects. It is important to point out that whereas the proposal amendment for B768 asks for the genotyping of top hits from a fetal-only genome-wide study in EGG to test in replication samples whether these top hit are independent of maternal genotype, our proposal is to follow up hits from a genome-wide study that is already adjusted for maternal genotype.

Another feature of HAPO that is distinct from the current EGG collaboration is that genome-wide data are available on different ethnic groups: Afro-Caribbean and Hispanic, in addition to European. This may lead to the prioritisation of different top hits for follow-up, as was seen with the recent discovery of the KCNQ1 gene for type 2 diabetes (Unoki et al and Yasuda st al, 2008 Nat Genet).

Recent successes from genome-wide association studies have highlighted the need for collaboration between centers to provide sufficient power to detect modest effects of common genetic variants. For early growth traits, efforts are already underway in the EGG consortium to ahieve this for fetal genotype vs. birth weight. We acknowledge that the current combined genome-wide fetal genotype sample in EGG exceeds our own fetal genotype sample, and that the contribution of HAPO may be better placed in the wider consortium in regard to this aim. Like ALSPAC, the HAPO group is keen to participate, where possible, in the EGG consortium and the emerging EAGLE consortium once we have examined our own genome-wide data.

In Stage 1 of the planned replication study, we will genotype 115 offspring SNPs for size at birth in 2,669 additional Caucasian subjects from the HAPO study as well as 115 maternal SNPs for size at birth in 2556 Caucasian HAPO mothers. The genotypes from the Stage 1 replication study will be analyzed together with the genotypes from the 1500 mothers and offspring analyzed in the original GWAS. From these analyses, we will identify the 15 most significant offspring SNPs for birth weight and 15 most significant maternal SNPs for offspring birth weight. These will then be typed in the ALSPAC mothers and offspring. Thus, from ALSPAC, we will need offspring birth weight data and additional data that will need to be controlled for in the analyses (gestational age of the neonate at the time of delivery, neonatal gender, parity, maternal age, BMI, and blood pressure). We will also need genotype data. As noted, the SNPs to be genotyped will be determined from analysis of the GWAS and Stage 1 replication study. We are planning that the ALSPAC samples will be genotyped at Kbiosciences. We will pay for the genotyping using the resources of the grant from the NIH.

Date proposal received: 
Tuesday, 5 May, 2009
Date proposal approved: 
Tuesday, 5 May, 2009
Keywords: 
Birth Outcomes, GWAS
Primary keyword: 

B815 - DIUS Shopping List - 28/04/2009

B number: 
B815
Principal applicant name: 
Ms Lynn Molloy (University of Bristol, UK)
Co-applicants: 
Ms Kerry Humphries (University of Bristol, UK)
Title of project: 
DIUS Shopping List.
Proposal summary: 

ALSPAC proposes to use the funding from DCSF (£30,000 in the first year and £55,000 in the second year) towards increasing participation in the ALSPAC study.

In June 2009, ALSPAC executive commissioned the Social Marketing Department at University of West of England to conduct research into how ALSPAC could increase participation in the study. A literature search was carried out which revealed that recruiting and retaining 16-18 year olds in longitudinal cohort studies is a common problem. This is because it is a difficult time for them with hugely conflicting demands over their time and energies. They tend to be very busy and prefer not to adhere to strict timetables or commit to long-term research projects. This has been evident in our recent participation rates for clinic and questionnaires which shows a marked difference from even a year ago. The literature review confirms that although retention is challenging, it can be done, as long as there is an in depth understanding of what moves and motivates young people.

Focus groups were held with participants from the ALSPAC study to try and find out more about what motivates them and what would keep them engaged in the project. Those interviewed were 17 or 18 years old and were from a diverse range of social and study participation backgrounds. Of particular interest were the participants who had completely disengaged from the study. The interviews were analysed and the findings were used to develop strategies that could increase participation. A plan has been devised to implement these strategies over the next two years. This coincides with the remainder of the DCSF funding data collection, Focus at 17 and the 18 year questionnaire.

Findings from these initiatives will be disseminated amongst the research community and hold many benefits for other longitudinal cohort studies, e.g. LSYPE. As previously mentioned, attrition is a major problem in all longitudinal studies, especially amongst young people, and if ALSPAC can show that certain strategies are successful in retaining young people in the study then these techniques can be transferred to LSYPE and other research projects. The DCSF have invested a considerable amount of money into the development of the ALSPAC data set, and through data linkage ALSPAC will continue to collect further education data from the National Pupil Database. The proposed engagement initiatives will enable future data collection to add outcome data to the resource. This significant data set will enable the DCSF to continue to track the young people and their educational achievements and aspirations which could inform their policy making.

ALSPAC intend to fully evaluate each of the initiatives described below with a view to assessing which was the most successful in terms of increasing the participation rate and why. Firstly, we will undertake background research to examine the effectiveness andefficiencyof similar initiatives elsewhere and learn from the most successful of these. Secondly, we will clearly identify the aims and objectives of each initiative and judge the outcome of the activity against these aims and objectives. We will regularly run focus groups and other participatory activities to sound out our participants views on the various activities we are running and if appropriate adapt the activity accordingly.

We believe that the following initiatives are those most likely to improve participation in the study over the next two years.

Year One (November 2009 - March 2010)

  1. New Media techniques

In the first year the focus will be on using marketing and new media techniques in order to 'reach out' to the young people in the cohort. The social marketing report highlighted very strongly that "the internet is a social crutch of huge importance" to the cohort members. They communicate primarily through social networking sites such as Facebook. To maintain contact and credibility with the teenagers, it is essential that ALSPAC fully engages with this online world. In addition to straightforward communication, we need to build online communities which will maintain cohort loyalty, particularly now that the members are dispersing geographically as they get jobs or go to college. ALSPAC already has a presence on Facebook and YouTube, but to make the most of the enormous potential of the internet we need specialist help to develop, execute and monitor a long-term online strategy. This work would include establishing and moderating networks and forums, orchestrating 'viral' and 'buzz' marketing, and creating unique games. Marketing research stressed the importance of these techniques within this age group. It would also include constant monitoring of the ever-changing online world and how the age group inhabits it. Facebook leads the field at the moment - but in a few months it may fall out of fashion. ALSPAC need to stay one step ahead and to keep the cohort members engaged. Specialist youth/digital marketers will ensure that ALSPAC always puts across the right messages in the right media. One idea is to use 'key peers' to engage with the cohort. The key peers will be the 'popular' young people who have lots of influence over a wide range of other young people including those who are disengaged in the study. They will be commissioned to provide content for the ALSPAC facebook site, to comment on ALSPAC on their Facebook page, as well as upload photos of ALSPAC events. Through the use of age appropriate materials and the involvement of influential peers we aim to encourage their 'friends' on Facebook to become interested in what ALSPAC is all about and to get them re-engaged.

  1. Targeted Messages

In order that ALSPAC reaches out to the whole cohort it is important to target the young people as three separate groups; the engaged, recently dropped off, the disengaged. The report made it very clear that involving these three groups in the study would require three different strategies. For example, the young people who were engaged with the study wanted to find out more about the 'Science', whereas the recently dropped off and disengaged could be motivated by incentives. We would like to commission specialist help in assisting us with formulating targeted messages to each of these groups and the way in which this message should be delivered. Funding is also necessary in order to give these incentives; they are likely to range from vouchers for Amazon.co.uk to offering custom 'fitness testing' sessions based on ALSPAC scientific expertise. This would make sure that the three separate groups were catered for.

Year Two (April 2010 - March 2011)

1. Club Membership

The focus for the funding in the second year will be on introducing 'club membership' to all those originally eligible for the study as they turn 18 years of age. This is something that all of the young people taking part in the focus groups were very enthusiastic about. The idea behind this is to keep all of the YPs engaged in the study and to give ALSPAC more of a presence in their everyday lives. It would be similar to an NUS card but will be free to join. The young people will be given a membership card which will entitle them to discounts on various items that could include: nationwide shops/cinemas, a free bus/rail card etc and entry to ALSPAC events (e.g. CV writing, fitness assessment, parties and comedy nights) and competitions. More importantly, it will sustain a link between ALSPAC and them. ALSPAC will be able to keep them updated with what they are doing and what clinics/questionnaires are currently running. For instance, using their membership card, they will be able to use their 'username' to access online questionnaires etc. Evidence has shown that questionnaires are becoming less popular than they were; especially with boys. Short online questionnaires are one way in which to address this problem and if it can be linked in with a membership scheme where there will be incentives to fill out the questionnaire then this will hopefully keep the young people on board with the study. The DCSF funding will go towards setting this up and the ongoing development of the scheme.

Costs

These initiatives will cost £30,000 in Year 1 and £55,000 in Year 2. The costs are broken down below:

Year 1

  • New media techniques - £10,000
  • Specialist expertise - £5,000
  • Incentives - £15,000

Year 2

  • Club membership - £45,000
  • Continuing new media techniques - £10,000

Summary

ALSPAC is at a critical phase of its development. There is serious concern that as the study participants enter young adulthood they will desert the study. We are very encouraged by the findings of this recent work we have undertaken as it shows that attrition is not inevitable and that with further funding there are strategies that can be put in place to increase participation. These initiatives are likely to attract particpants across the social spectrum which has major advantages in terms of representiveness of the study.

Date proposal received: 
Tuesday, 28 April, 2009
Date proposal approved: 
Tuesday, 28 April, 2009
Keywords: 
Cross Cohort Study
Primary keyword: 

B814 - Children born prematurely compared to children born full term in terms of contrast sensitivity contour interaction and circle deformation visual acuity stereoscopic vision and accommodation at age seven data from the ALSP - 23/04/2009

B number: 
B814
Principal applicant name: 
Miss Nicola Jackson (University of Bristol, UK)
Co-applicants: 
Miss Cathy E M Williams (University of Bristol, UK), Dr Kate Northstone (University of Bristol, UK)
Title of project: 
Children born prematurely compared to children born full term in terms of contrast sensitivity, contour interaction and circle deformation, visual acuity, stereoscopic vision and accommodation at age seven: data from the ALSPAC Study.
Proposal summary: 

(No outline received).

Date proposal received: 
Thursday, 23 April, 2009
Date proposal approved: 
Thursday, 23 April, 2009
Keywords: 
Birth Outcomes
Primary keyword: 

B812 - The Geography of Fast Food and Childhood Obesity - 23/04/2009

B number: 
B812
Principal applicant name: 
Dr Lorna Taylor (University of Leeds, UK)
Co-applicants: 
Prof Graham Clarke (University of Leeds, UK), Prof Janet Cade (University of Leeds, UK), Dr Kimberley Edwards (University of Leeds, UK)
Title of project: 
The Geography of Fast Food and Childhood Obesity.
Proposal summary: 

Background

Obesity in children, and adults, is a rapidly growing problem in the UK and worldwide and has been increasing at accelerating rates in more recent years. It is associated with a number of co-morbidities in childhood and with increased risk of adult disease, particularly cardiovascular disease, hypertension and type 2 diabetes. Obesity related diseases account for a substantial proportion of costs of health care resources worldwide (WHO, 2004). The Select Committee Report on Obesity (2004) estimated that the total cost of treating obesity in the UK was £3.3-3.7 billion in 2002, increasing to £7 billion by 2020, and the latest estimates (Foresight report, 2007) put it at £45.5 billion by 2050.

A dietary risk factor for obesity is a high consumption of high fat, salt and sugar (HFSS) foods, and in particular "fast foods" (energy dense, nutrient poor, foods) (Reidpath et al, 2002; Mendoza et al, 2007; Procter, 2007a). The popularity of fast foods has increased over recent years and consumption by children has risen 300% over the last twenty years (St-Onge et al, 2003). It has been shown that on days when children eat fast food, then their energy and fat intake is likely to be higher, and fruit and vegetable intake lower, than normal (Bowman et al, 2004). Also children who eat fast food frequently consume more total energy, more energy per gram of food, more total fat, more total carbohydrate, more added sugars, and less fibre, less milk, fewer fruit and vegetables than children who eat fast food infrequently (Bowman et al, 2004; Speiser et al, 2005). Accordingly, it may not be the consumption of fast food, per se, that leads to obesity (as both lean and obese people consume fast food), but the fact that overweight consumers of fast food are less likely to adjust their daily energy intake to take account of an energy dense fast food meal than their lean counterparts (Ebbeling et al, 2004). This "passive over-consumption" is due to the weak innate ability of humans to identify energy dense foods and thus do not correspondingly reduce the amount of food eaten to achieve energy balance (Prentice & Jebb, 2003).

Household income has been shown to be a significant predictor of obesity (inverse relationship) (Strauss & Knight, 1999; Stamatakis et al, 2005), as has deprivation (Kinra et al, 2000; Kinra et al, 2005) and low socio-economic status (SES) (Parsons et al, 1999; Hardy et al, 2000; Okasha et al, 2003; Monden et al, 2006). The increased prevalence of obesity from more deprived backgrounds could be due to a multitude of factors: dietary differences are often apparent; lack of opportunity / funds for activities, so TV viewing is the primary leisure activity by default; constraints on calories per pound, which focuses purchases on energy dense foods. Also the association between SES and obesity may be due to SES acting as a proxy for the effect of multiple adverse circumstances, which are then manifesting as obesity in the long term (Power & Parsons, 2000). For example, it has been shown that there is a higher density of fast food outlets in poorer areas, which may (partially) explain the phenomenon (Reidpath et al, 2002). Obesity and deprivation may be connected due to the routine consumption of a high energy dense, low cost diet (Drewnoski, 2003). Energy dense diets are associated with lower diet quality and lower costs, and vice versa (Cade et al, 1999; Darmon et al 2004; Andrieu et al, 2006; Drewnoski et al, 2007). Research shows that low income households are associated with a high energy dense diet (Mendoza et al, 2006).

There is a large literature contending that the environment, particularly that of our place of residence or school/work, impacts on health related behaviour and therefore health outcomes (Macintyre et al, 2002; Mohan et al, 2005). This increased interest in the effect of place on health seems to stem from the publication of the Black Report some twenty-five years ago (Black et al, 1980). Since then many authors have shown that deprivation is related to mortality as well as to specific health outcomes. An important debate within health geography is that of whether the environment has compositional or contextual effects on health. That is, the issue of whether individual or area effects on health predominate. Accordingly, the compositional school of thought is that individuals have risks of ill health, therefore an area's ill health is reflective of that of the individuals who live (or work, as appropriate) there. For example, do obese people congregate in similar locations? Conversely, the contextual theory is that living (or working) in an area imposes ill health on that area's residents. For example, do certain attributes of places cause its inhabitants to become obese? This study seeks to address the question of fast food and obesity from both contextual (the physical environment of fast food outlets) and compositional (individual consumption) perspectives

Objectives and hypothesis of project

To describe, measure and map obesity, fast food outlet density and fast food consumption in Bristol, UK(and Leeds,UK)

To investigate the relationship between density of outlets and area measures of deprivation, and to examine whether there is a dose-response relationship between deprivation and outlet density (e.g. as deprivation rises, outlet density rises).

To assess the relationship between obesity and energy dense, low nutrient ("fast") foods: availability and consumption.

To consider the policy implications of the results.

Hypothesis: Fast food outlet density and consumption will be related to the patterns of obesity. Families with the lowest incomes will be more influenced by or susceptible to these factors than higher income households.

Methods

Stage 1 - Describing and mapping obesity

The first stage in the study of spatial variations in obesity will be to build a geographic information system (GIS). The GIS will contain all the census data for Bristol/Avon Region at 'output area' (the new small area census unit), as well as the Index of Deprivation (Communities and Local Government, 2004) at 'super output area' level. This will allow us to identify areas of both low and high social deprivation. The GIS will also contain obesity data from the ALSPAC dataset.

Spatial microsimulation modelling will then be used for estimating or predicting small area levels of obesity. Specifically, we will build on the SimObesity model (a deterministic, re-weighting, spatial microsimulation model developed in the School of Geography, University of Leeds), which combines individual micro-data from national level surveys, such as the Health Survey for England (HSE), which only have location data at the scale of large areas, with census statistics for lower Super Output Areas (SOAs) to create synthetic micro-data estimates for SOAs in Leeds. The new, synthesised, micro dataset includes all the attributes from both the survey and the census datasets. The key benefits of using spatial microsimulation are: to add more attributes to the population under analysis by adding census data to the survey data thereby creating a richer dataset; to get data to a smaller geographical scale in order to identify 'hot spots' of problem areas; and it is cheaper and quicker than commissioning a survey of the local area. There is significant experience of spatial microsimulation modelling in the University of Leeds (Clarke, 1996; Ballas et al, 2005; Procter, 2007b).

Significant clusters of obesity (from both children and adults) will be identified using Spatial Scan Statistics (such as SaTScan, Kulldorff, 1997). Temporal (serial cross sectional) as well as geographic analysis will be undertaken.

Stage 2 - Relationship between fast food and obesity

Once the patterns and spatial/temporal variations of obesity have been understood, the next exercise is to consider the relationship with fast food consumption. There are two components to this analysis.

Firstly we wish to examine the relationship between fast food outlet density and obesity. This stage of the project will involve sourcing (e.g. from the council or yellow pages) the location of fast food restaurants in the study area and transposing this data into a GIS. Ground truthing of the data will also be required (i.e. physically checking the locations exist). Then fast food outlet density for output areas can be calculated and the relationship with obesity considered. The association with an area measure of deprivation will also be considered.

The next stage is to take this further, and to consider the relationship between actual fast food consumption and obesity. This Fast Food consumption data regarding diet is available from the ALSPAC cohort and will be added to the previously described GIS model. This data may be used to simulate fastfood consumption in children in other geographical areas using spatial microsimulation modelling.

Analysis of these data will involve the use of multi-level modelling and geographically weighted regression, in order that the special properties of spatial data (e.g. spatial autocorrelation) can be accounted for.

Stage 3 - Policy implications

The final stage in the project will be to consider how the results from the previous two stages can be utilised to influence policy and to help slow down the rising rates of obesity. The spatial microsimulation model will be used to undertake "what if" scenario analysis to theoretically evaluate the potential impact of policy/intervention suggestions on the prevalence of obesity in say 5, 10 or 20 years time, which is cheaper and much quicker than running a pilot study. Further, we will work with key local stakeholders (from both public and private sector, as both have a responsibility to endorse public health (Stafford et al, 2007)) to enable suggestions to be rated for validity, relevance and potential for change. This is important, as small individual programmes are unlikely to make a difference to the obesity epidemic. For maximum benefit an obesity prevention policy needs to take a coordinated, multi-component, multi-sectoral public health approach and overall policy unity and coherence is required, with buy-in of all stakeholders.

How will the research be useful and to whom

This research will be useful to the PCTs for health planning as it will identify any hot spots of problem areas of obesity. It will also elucidate further on the impact of aspects of the environment and diet on obesity and whether these issues can be addressed using public health policies, and if so, the likely future impact of such changes.

Interdisciplinary nature of the research

This project is clearly interdisciplinary. It combines the quantitative geographic techniques (such as spatial microsimulation, GIS) with those from medical research, using data from local studies as well as national cross sectional surveys. Training will be given for use of the spatial techniques (e.g. SimObesity, ArcGIS, geographically weighted regression). There is extensive experience of using these techniques within the University of Leeds, plus some external courses are available.

Timetable

Year 1/2: Develop literature review; gather information for mapping; learn techniques; carry out stage 1

Year 3/4: Carry out stage 2

Year 5/6: Carry out stage 3 and write up thesis

References

Andrieu, E., N. Darmon, et al. (2006). "Low-cost diets: more energy, fewer nutrients." European Journal of Clinical Nutrition 60(3): 434-6.

Black D, Morris J, Smith C, Townsend P (1980). Inequalities in health: report of a Research Working Group. London: Department of Health and Social Security

Bowman SA, Gortmaker SL, Ebbeling CB, Pereira MA, Ludwig DS (2004). Effects of fast-food consumption on energy intake and diet quality among children in a national household survey. Pediatrics, 113: 112-118

Communities and Local Government. The English Indices of Deprivation 2004. http://www.communities.gov.uk/index.asp?id=1128449 Accessed September 2007

Darmon, N., A. Briend, et al. (2004). "Energy-dense diets are associated with lower diet costs: a community study of French adults." Public Health Nutrition 7(1): 21-7.

Drewnowski, A. (2003). "The role of energy density." Lipids 38(2): 109-15.

Drewnowski, A., P. Monsivais, et al. (2007). "Low-energy-density diets are associated with higher diet quality and higher diet costs in French adults." Journal of the American Dietetic Association 107(6): 1028-32.

Ebbeling CB, Sinclair KB, Pereira MA, Garcia-Lago E, Feldman HA, Ludwig DS (2004). Compensation for energy intake from fast food among overweight and lean adolescents. The Journal of the American Medical Association, 291 (23): 2828-2833

Foresight Report (2007). Tackling Obesities: future choices http://www.foresight.gov.uk/Obesity/obesity_final/20.pdf Accessed October 2007

Hardy R, Wadsworth M, Kuh D (2000). The influence of childhood weight and socioeconomic status on change in adult body mass index in a British national birth cohort. International Journal of Obesity, 24 (6): 725-34

Kinra S, Nelder RP, Lewendon GJ (2000). Deprivation and childhood obesity: a cross sectional study of 20,973 children in Plymouth, United Kingdom. Journal of Epidemiology & Community Health, 54 (6): 456-460

Kinra S, Baumer JH, Davey Smith G (2005). Early growth and childhood obesity: a historical cohort study. Archives of Disease in Childhood, 90 (11): 1122-1127

Kulldorff M (1997). A spatial scan statistic. Communications in Statistics: Theory and Methods, 26: 1481-1496

Macintyre S, Ellaway A, Cummins S (2002). Place effects on health: how can we conceptualise, operationalise and measure them? Social Science and Medicine, 55: 125-39

Mendoza, J. A., A. Drewnowski, et al. (2006). "Dietary energy density is associated with selected predictors of obesity in U.S. Children." Journal of Nutrition 136(5): 1318-22.

Mendoza, J. A., A. Drewnowski, et al. (2007). "Dietary energy density is associated with obesity and the metabolic syndrome in U.S. adults." Diabetes Care 30(4): 974-9.

Mohan J, Twigg L, Barnard S, Jones K (2005). Social capital, geography and health: a small-area analysis for England. Social Science and Medicine, 60: 1267-1283

Monden CWS, van Lenthe FJ, Mackenbach JP (2006). A simultaneous analysis of neighbourhood and childhood socio-economic environment with self-assessed health and health-related behaviours. Health and Place, 12(4): 394-403

Okasha M, McCarron P, McEwen J, Durnin J, Davey Smith G (2003). Childhood social class and adulthood obesity: findings from the Glasgow Alumni Cohort. Journal of Epidemiology and Community Health, 57: 508-9

Parsons TJ, Power C, Logan S, Summerbell CD (1999). Childhood predictors of adult obesity: a systematic review. International Journal of Obesity, 23 (Suppl. 8): S1-107

Prentice AM & Jebb SA (2003). Fast foods, energy density and obesity: a possible mechanistic link. Obesity Reviews, 4 (4): 187-194

Reidpath DD, Burns C, Garrard J, Mahoney M, Townsend M (2002). An ecological study of the relationship between social and environmental determinants of obesity. Health and Place, 8: 141-145

Rudolf MCJ, Cole TJ, Krom AJ, Sahota, P, Walker J (1999). Growth of primary school children: a validation of the 1990 standards and their use in growth monitoring. Archives Disease in Childhood 83: 298-301

Rudolf MCJ, Levine R, Feltbower RG, Connor A, Robinson M (2006). The Trends project: development of a methodology to reliably monitor the obesity epidemic in childhood. Archives of Disease in Childhood; 91: 309-311

Select Committee on Health - Third Report (Obesity) (2004). Health Committee Publications, http://www.parliament.thestationeryoffice.co.uk/pa/cm200304/cmselect/cmh... Accessed December 2005

Speiser PW, Rudolf MC, Anhalt H, Camacho-Hubner C, Chiarelli F, Eliakim A, Freemark M, Gruters A, Hershkovitz E, Iughetti L, Krude H, Latzer Y, Lustig RH, Pescovitz OH, Pinhas-Hamiel O, Rogol AD, Shalitin S, Sultan C, Stein D, Vardi P, Werther GA, Zadik Z, Zuckerman-Levin N, Hochberg Z; Obesity Consensus Working Group (2005). Childhood Obesity, The Journal of Clinical Endocrinology and Metabolism, 90 (3):1871-87

Stamatakis E, Primatesta P, Chinn S, Rona R, Falascheti E (2005). Overweight and obesity trends from 1974 to 2003 in English children: what is the role of socioeconomic factors? Archives of Disease in Childhood, 90: 999-1004

St-Onge MP, Keller KL, Heymsfield SB (2003). Changes in childhood food consumption patterns: a cause for concern in light of increasing body weights. The American Journal of Clinical Nutrition, 78 (6): 1068-1073

Strauss RS & Knight J (1999). Influence of the home environment on the development of obesity in children. Pediatrics, 103 (6): e85

World Health Organisation (2004). Report of a WHO Consultation on Obesity: preventing and managing the global epidemic. WHO Technical Report Series; 894. Geneva. http://www.who.int/nutrition/publications/obesity/en/index.html (accessed Oct 2007).

Date proposal received: 
Thursday, 23 April, 2009
Date proposal approved: 
Thursday, 23 April, 2009
Keywords: 
Diet, Obesity
Primary keyword: 

B816 - Foetal and maternal genetic modifiers of the effects of prenatal tobacco exposure - 20/04/2009

B number: 
B816
Principal applicant name: 
Dr Thomas S Price (King's College London, UK)
Co-applicants: 
Prof Barbara Maughan (King's College London, UK), Sara Jaffee (King's College London, UK), Dr Alina Rodriguez (King's College London, UK)
Title of project: 
Foetal and maternal genetic modifiers of the effects of prenatal tobacco exposure.
Proposal summary: 

1. SUMMARY

Maternal smoking during pregnancy is a well-established and preventable risk factor for low birthweight and its sequelae of poor physical, cognitive and behavioural development, excess morbidity, and increased rates of both perinatal and adult mortality. Preliminary findings from genetic epidemiology studies suggest that the degree to which prenatal tobacco exposure depresses birthweight may be moderated by foetal and maternal genotype. The advent of affordable genomewide genotyping presents an opportunity for systematic investigation of this phenomenon. We propose to prioritize candidate polymorphisms using genomewide genotype data from three studies for which data is available on prenatal tobacco exposure and perinatal outcomes. We will use this information to prioritize approximately 50 single nucleotide polymorphisms (SNPs) to be genotyped in 3,500 mother-child dyads participating in ALSPAC. We will use these data to test hypotheses about the moderating effects of maternal and foetal genotype on the effects of prenatal tobacco exposure to reduce birthweight, shorten gestation, and alter postnatal physical, cognitive, and behavioural development.

2. BACKGROUND

Maternal smoking during pregnancy is a well-established and preventable risk factor for low birthweight (less than 2,500g) and its sequelae of poor physical, cognitive and behavioral development, excess morbidity, and increased rates of both perinatal and adult mortality (Kramer, 2003). The primary causes of low birthweight are preterm birth and intrauterine growth restriction (IUGR). The consequences of IUGR include both short-term and long-term morbidity and permanent deficits in growth and neurocognitive development (Kramer, 2003). Epidemiological studies have shown that maternal smoking is associated with both short gestation and IUGR (Kramer, 2003). Mothers who quit smoking while pregnant have longer gestations and heavier newborns than those who continue to smoke (Lumley, Oliver, Chamberlain, & Oakley, 1998). This fact is recognized in public policy: in the UK, formal smoking cessation programs are recommended as part of antenatal care to prevent low birthweight (Health Development Agency, 2004).

Preliminary findings from studies in genetic epidemiology, including my own research, suggest that the degree to which prenatal tobacco exposure depresses birthweight may be moderated by foetal and maternal genotype (e.g. Infante-Rivard, Weinberg, & Guiguet, 2006, T. S. Price, Grosser, Plomin, & Jaffee, 2008). The combination of affordable experimental methods for high-throughput genotyping and the availability of richly phenotyped birth cohorts for whom information is available on prenatal environmental exposures and perinatal outcomes provides an opportunity for systematic investigation of this phenomenon. I propose to study the issue using a two-phase experimental design. Phase 1 will address the issue broadly, in three large cohorts, by studying the impact on intrauterine growth of all common genetic variation. Phase 2 will address the issue deeply, in an independent sample, by looking at the downstream effects of selected polymorphisms on long-term features of postnatal development.

3. METHODS

3.1 Overview

Phase 1. Genomewide association studies to detect interactions between maternal and child genotype and maternal smoking during pregnancy on intrauterine growth. I have negotiated access to three studies with genomewide genotype data and information on prenatal environmental exposures and perinatal outcomes. Two of these studies are birth cohorts with genomewide genotype information on the children: the Twins Early Development Study (TEDS, PI R. Plomin; Trouton, Spinath, & Plomin, 2002) and the 1966 North Finnish Birth Cohort (NFBC, PI: M.-R. Jarvelin; Rantakallio, 1969). The third has genotype data from parent-child trios and siblings (IMAGE, PI: P. Asherson; Kuntsi, Neale, Chen, Faraone, & Asherson, 2006). In total, these samples comprise more than 9,000 families for whom information will be available on genomewide genotype, environmental risk exposure and perinatal outcomes. Hypotheses of genotype*environment interaction and haplotype*environment interaction will be tested genomewide in each study population. Untyped polymorphisms will be imputed using standard techniques (Marchini, Howie, Myers, McVean, & Donnelly, 2007) to ensure that the genotype set is consistent across studies and facilitate meta-analysis.

Phase 2. Replication and extension. Approximately 50 single nucleotide polymorphisms (SNPs) prioritized in the initial stage - located in the 5 genomic regions providing the best evidence of genotype-environment interaction - will be typed in an independent sample of approximately 3,500 mother-child dyads participating in the Avon Longitudinal Study of Parents and Children (ALSPAC, PI: G. Davey-Smith; Golding, Pembrey, & Jones, 2001). These data will be used to test hypotheses of genotype-environment interaction and haplotype-environment interaction on intrauterine growth and on postnatal phenotypes associated with maternal smoking during pregnancy including Attention-Deficit Hyperactivity Disorder (ADHD), cognitive ability, and height. The availability of prospective information on environmental exposure in this sample will allow hypotheses to be tested about dose-related effects and the impact of timing for mothers who quit smoking during pregnancy.

3.2 Data collection.

We propose to genotype approximately 3,500 mothers and their children participating in the ALSPAC study for approximately 50 single nucleotide polymorphisms prioritized in the first phase of the study. We will choose the 1,500 or so families in which the mother reported smoking throughout the pregnancy, an equal number of families in which the mother reported not smoking at any time during the pregnancy, plus the 500 or so families in which the mother reported smoking early in the pregnancy and subsequently quitting. The intention is to select the five regions providing the best evidence of genotype-environment interaction in phase 1, and fine map the immediate regions of linkage disequilibrium (as defined using resequencing data for Caucasian populations) in ALSPAC so as to be able to test hypotheses of haplotype-environment interaction in phase 2. Although haplotype block length is enormously variable, we anticipate an average of 10 non-redundant SNPs per region will suffice based on estimates of haplotype block length in Caucasian populations (Li & Chen, 2008).

3.3 Existing data required

Concept

Specific Measure

Person

Source

Time Point(s)

Demographic variables (age, sex, ethnicity, marital status, family structure, SES, education, employment, income etc.)

Family

Questionnaire

Antenatal

Pregnancy health variables (nulliparity, pre-eclampsia, IUGR, gestational diabetes etc.)

Mother

Questionnaire, medical records

Antenatal

Parental anthropometrics (height weight)

Mother, Father

Questionnaire

Antenatal

Pregnancy exposure variables (tobacco, alcohol and drug use; chemical exposure; diet; nutrient supplementation; stress; life events; partner cruelty; lack of social support)

Mother

Questionnaire

Antenatal

Birth/delivery variables (weight/length, placental weight, gestational age, Caesarian), perinatal health

Child

Questionnaire, medical records

Birth/perinatal period

Childhood head injury

Child

Questionnaire

Birth - 4 years

Childhood temperament

Carey

Child

Questionnaire

6-24 months

Childhood behaviour

SDQ

Child

Questionnaire

42 - 157 months

ADHD

Child

Questionnaire

166 months

Antisocial behaviour

Child

Questionnaire

169 months - 198 months

Psychotic symptoms

Child

Questionnaire

140 months - 198 months

Adolescent substance use (tobacco, alcohol, drugs)

Child

Questionnaire

157 months - 198 months

Language development

McCarthy

Child

Questionnaire

24 months

Cognitive ability

WISC

Child

Clinic test

8-10 years

Scholastic achievement

Child

Questionnaire

166 months

Anthropometrics (Height, weight)

Child

Questionnaire

Birth - 157 months

Parental antisocial behaviour (antisocial behaviour as children or adults; contact with police; criminal convictions)

Mother, father

Questionnaire

Antenatal - 145 months

Childhood postnatal experiences (maternal depression and anxiety, parental discipline)

Mother

Questionnaire

Birth - 145 months

Parental postnatal substance use (tobacco, alcohol, drugs)

Mother, father

Questionnaire

Birth - 145 months

3.4 Data Analysis.

Phase 1. Missing genotype data (including polymorphisms genotyped in at least one but less than three of the datasets) will be imputed using published methods (Marchini et al., 2007). Hypotheses about effects on birthweight (corrected for gestational age) will be tested using linear models incorporating terms for prenatal tobacco exposure, foetal genotype, interaction between foetal genotype and prenatal tobacco exposure plus relevant covariates (including significant principal components of the genetic data to guard against spurious associations due to population admixture (A. L. Price et al., 2006), demographics, pregnancy and antenatal health variables, and parental physical and behavioural characteristics). Meta-analysis will be performed to synthesize the results from the three studies. SNPs to be genotyped in phase 2 will be chosen based on the regions that show the greatest evidence of association in phase 1. Where significant results are found for foetal genotype, post hoc analyses of the influence of maternal genotype and parent-of-origin effects will be tested in the IMAGE sample.

Phase 2. Hypotheses about effects on birthweight, head circumference, and crownheel length (all corrected for gestational age) will be tested using linear models incorporating terms for prenatal tobacco exposure, maternal genotype, foetal genotype, interaction between maternal genotype and prenatal tobacco exposure, interaction between foetal genotype and prenatal tobacco exposure, and the three-way interaction between foetal and maternal genotype and prenatal tobacco exposure, plus relevant covariates (including demographics, pregnancy and antenatal health variables, and parental physical and behavioural characteristics). Analyses will be stratified by ethnicity to guard against spurious associations due to population admixture. Should statistically significant results be found, post hoc hypotheses about trajectories of postnatal physical, behavioural, and cognitive development will be tested using growth curve models and growth mixture models; in addition, mediation analyses will be conducted to test whether postnatal development is conditionally independent of genotype and prenatal tobacco exposure after controlling for any effects on birthweight and gestational age. Hypotheses about the effects of prenatal tobacco exposure will test for heterogeneity of the effects with respect to mode of exposure (maternal smoking/maternal exposure to second hand smoke), dose, and timing of smoking cessation. A parallel set of analyses will be conducted using paternal tobacco exposure as the environment of interest in order to validate the inference of intrauterine effects. Analyses will be conducted to assess the possible influence of attrition in the sample on the outcomes of interest. If necessary, informative missingness will be explicitly modelled.

3.5 Statistical Power

Phase 1. Based on the most accurate information available, we anticipate that information on genomewide genotype, prenatal environmental exposures, and perinatal outcomes will be available for children from 4,000 families enrolled in TEDS, 4,763 families participating in NFBC, and 304 families from IMAGE. We expect that the numbers of children born to mothers who reported smoking during pregnancy in these three samples will be, respectively, 568, 700, and 63. For the purposes of the power analysis let us assume a total population of N = 9,067, exposure prevalence of 14.7%, population SD of birthweight = 400g, marginal effect of maternal smoking -200g, and no marginal effect of genotype. We will use alpha = 10-6 so that if we test 2-sided hypotheses of GxE in relation to 10-6 SNPs we expect on average 1 false positive by chance. Under these assumptions we will have 80% power to detect GxE accounting for 0.356% of the variance in birthweight and 50% power to detect GxE accounting for 0.261% of the variance.

Under an additive model of inheritance, 0.261%-0.356% of the variance corresponds to GxE accounting for a difference of 102-119 g between groups differing by an allele count of 1 and with different smoking status, assuming a minor allele frequency of 20%, or 136-159 g assuming a minor allele frequency of 10%. Under a dominant model of inheritance, 0.380%-0.521% of the variance corresponds to GxE accounting for a difference of 120-141 g between groups differing in whether or not they carry a risk allele and with different smoking status, assuming a minor allele frequency of 20%, or 147-172 g assuming a minor allele frequency of 10%.In other words, for common SNPs there is good power to detect a GxE whose coefficient is similar in magnitude to the marginal environmental effect. Effect sizes of this magnitude are by no means implausible, as recent candidate gene studies have demonstrated (e.g. Sasaki et al., 2008, T. S. Price et al., 2008), but there are likely to be relatively few variants in the genome that could account for interactive effects of this size. It is for this reason that we intend to follow up only a handful of the best hits.

Phase 2. Assuming that genotype data is available for 3,000 individuals, with 50% exposure to prenatal smoking throughout pregnancy, a population SD for birthweight of 400g, a marginal effect of maternal smoking of -200g, and using 2-tailed hypotheses for each of the three phenotypes of birthweight, head circumference, and crownheel length and a conservative significance threshold of alpha = 3.3e-4 (0.05 after Bonferroni correction for 50 x3 = 150 hypothesis tests), we estimate that for the effect sizes giving 50% power in the phase 1 we expect 69% power to replicate in phase 2, and for the kinds of effect size giving 80% power in phase 1 we expect at least 88% power to replicate in phase 2.

3.6 Work already completed

We recently investigated the relations between maternal smoking, foetal genotype, and foetal growth in a dizygotic twin pairs participating in TEDS (T. S. Price et al., 2008). Maternal smoking retarded growth by 118g in twins born to mothers who reported smoking less than 10 cigarettes per day and by 185g in twins born to heavier smokers, allowing for the effects of twin sex, birth order, gestational age, and maternal and familial characteristics. We selected 497 twin pairs, whose mothers smoked, for a molecular genetic study. In this subsample, a functional SNP in the NQO1 gene (Pro187Ser; rs1800566) was significantly associated with foetal growth within families assuming a dose-related model of effects (p=0.0028). These results provide the first demonstration that foetal genotype for a xenobiotic metabolizing enzyme influences intrauterine growth under conditions of smoke exposure independently of maternal genotype.

4. REFERENCES

Golding, J., Pembrey, M., & Jones, R. (2001). ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology. Paediatr Perinat Epidemiol, 15(1), 74-87.

Health Development Agency. (2004). The evidence of effectiveness of public health interventions - and the implications.

Infante-Rivard, C., Weinberg, C. R., & Guiguet, M. (2006). Xenobiotic-metabolizing genes and small-for-gestational-age births - Interaction with maternal smoking. Epidemiology, 17(1), 38-46.

Kramer, M. S. (2003). The epidemiology of adverse pregnancy outcomes: An overview. Journal of Nutrition, 133(5), 1592S-1596S.

Kuntsi, J., Neale, B. M., Chen, W., Faraone, S. V., & Asherson, P. (2006). The IMAGE project: methodological issues for the molecular genetic analysis of ADHD. Behav Brain Funct, 2, 27-27.

Li, J., & Chen, Y. (2008). Generating samples for association studies based on HapMap data. BMC Bioinformatics, 9, 44-44.

Lumley, J., Oliver, S., Chamberlain, C., & Oakley, L. (1998). Interventions for promoting smoking cessation during pregnancy. Cochrane Database of Systematic Reviews(3), Art. No.: CD001055. DOI: 001010.001002/14651858.CD14001055.pub14651852.

Marchini, J., Howie, B., Myers, S., McVean, G., & Donnelly, P. (2007). A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet, 39(7), 906-913.

Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006). Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet, 38(8), 904-909.

Price, T. S., Grosser, T., Plomin, R., & Jaffee, S. R. (2008, Nov 11-15). Fetal genotype for the xenobiotic metabolizing enzyme NQO1 influences intrauterine growth among infants whose mothers smoked during pregnancy. Paper presented at the American Society for Human Genetics, Philadelphia, PA.

Rantakallio, P. (1969). Groups at risk in low birth weight infants and perinatal mortality. Acta Paediatr Scand, 193.

Sasaki, S., Sata, F., Katoh, S., Saijo, Y., Nakajima, S., Washino, N., et al. (2008). Adverse birth outcomes associated with maternal smoking and polymorphisms in the N-nitrosamine-metabolizing enzyme genes NQO1 and CYP2E1. American Journal of Epidemiology, 167(6), 6.

Trouton, A., Spinath, F. M., & Plomin, R. (2002). Twins Early Development Study (TEDS): A multivariate, longitudinal genetic investigation of language, cognition and behavior problems in childhood. Twin Research, 5(5), 444-448.

Date proposal received: 
Monday, 20 April, 2009
Date proposal approved: 
Monday, 20 April, 2009
Keywords: 
Smoking
Primary keyword: 

B813 - The assessment of loci associated with varying levels of IL6 through the use of Genome Wide Association Studies - 20/04/2009

B number: 
B813
Principal applicant name: 
Prof Tim Frayling (Peninsula Medical School, University of Plymouth, UK)
Co-applicants: 
Dr Andrew R Wood (Peninsula Medical School, University of Plymouth, UK), Dr Michael N Weedon (Peninsula Medical School, University of Plymouth, UK), Dr Nic Timpson (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK), Dr Luigi Ferrucci (National Institute on Ageing, USA), Dr Stefania Bandinelli (National Institute on Ageing, USA)
Title of project: 
The assessment of loci associated with varying levels of IL6 through the use of Genome Wide Association Studies.
Proposal summary: 

Interleukin-6 (IL6) is a key pro-inflammatory cytokine involved in the acute-phase response and is associated with a number of diseases, including Type 2 Diabetes.

We plan to do an IL6 genome-wide association study meta-analysis of 1410 ALSPAC individuals with 1210 individuals from the InCHIANTI study. We will require IL6 levels, age and gender adjusted results and combine using an inverse variance approach. We will perform genome-wide analyses and also cis-effect analyses for variants in or near (+/- 300kb) the genes coding for IL6 or IL6R - encoding for the IL6 receptor. IL6R SNPs have been previously associated with IL6 levels and can act as positive controls (Melzer et. al 2008).

Having meta-analysed this data, we then plan to replicate our initial findings using ~5000 additional children with IL6 measured from the ALSPAC study in order to determine loci that are robustly associated with varying levels of IL6. Potentially, this may involve ~10 top hits (or candidate hits) from the meta-analysis, although the exact number of SNPs we will follow up will depend on the false discovery rate/QQ plot statistics.

Note also that the InCHIANTI study has been approached by another GWAS consortium looking at IL6 levels (based around the Sardinia study) with a view to replicating their results. In the event that the GWAS meta-analysis of ALSPAC and InCHIANTI does not produce any stand out results, we would suggest that the best next step will be to join ALSPAC and InCHIANTI into an expanded IL6 GWAS consortium. Although making the relative contribution of ALSPAC and INCHIANTI smaller, it will increase power substantially and help identify variants that influence IL6 levels, something that could be useful for Mendelian Randomisation studies.

Date proposal received: 
Monday, 20 April, 2009
Date proposal approved: 
Monday, 20 April, 2009
Keywords: 
Mendelian Randomisation
Primary keyword: 

B810 - Interactions between birth weight and BDNF on IQ - 16/04/2009

B number: 
B810
Principal applicant name: 
Dr Birit Broekman (National University of Singapore, Singapore)
Co-applicants: 
Prof Michael Meaney (McGill University, ROW), Dr Seang Mei Saw (National University of Singapore, Singapore), Asst. Prof Liang Kee Goh (Duke-NUS Graduate Medical School, ROW), Dr Yi-Ju Li (Duke University, USA), Prof Terri Young (Duke University, USA), Dr Yen Ling Low (Singapore Institute for Clinical Sciences (SICS), ROW), Prof Sir Peter Gluckman (Singapore Institute for Clinical Sciences (SICS), ROW)
Title of project: 
Interactions between birth weight and BDNF on IQ.
Proposal summary: 

The aim of this study is to understand how fetal growth influences neurocognitive function. We hypothesize that the outcome on IQ is mediated by birth weight in interaction with polymorphisms of certain SNPs of the BDNF gene.

Methods: In the large Asian cohort study of SCORM we have analysed six hundred fifty three children aged 7-9 years old, recruited from 3 schools in Singapore, who were followed yearly from 1999 onwards. Birth parameters were recorded by health personnel. Childhood IQ was measured with the Raven's Standard Progressive Matrices at ages 8 to 12. Buccal DNA was collected and single nucleotide polymorphisms for BDNF were obtained from the Illumina 550K beadchip.

Results: In SCORM we found that the BDNF gene show significant interactions between rs6265 (p=0.000) and rs11030104 (p=0.000) and birth weight (corrected for gestational age) on IQ. In children with TC (p=0.033) and TT (0.045) alleles of BNDF rs6265 and CC (0.054) and TC (0.029) alleles of the BNDF 11030104 a lower birth weight is associated with a lower IQ, while a higher birth weight is associated with a higher IQ.

These findings could implicate that improved fetal growth reduces the risk for lower IQ and improved developmental outcomes in children with certain alleles of BDNF genotypes. We would like to replicate these findings in the large Western cohort of ALSPAC.

Satistical Analysis:

Categorical data will be analyzed using the chi-square test. Differences between gender in age, birth weight and IQ are measured with t-tests. Genotype differences for continuous variables are evaluated using one-way analysis of variance. Birth weight will be corrected for gestational age. The interaction effects of SNP * Birth weight (corrected for gestational age) on IQ are examined with lineair regression. Posthoc analyses are performed if the relationship was found to be significant by subgroup analyses. All p values are two-tailed and considered statistically significant when the values were below 0.05. All statistical procedures used SPSS version 16.0 (SPSS Inc, Chicago, USA).

Date proposal received: 
Thursday, 16 April, 2009
Date proposal approved: 
Thursday, 16 April, 2009
Keywords: 
Weight
Primary keyword: 

B809 - Follow-up and meta-analysis of signals associated with intelligence maths scores and memory in ALSPAC - 16/04/2009

B number: 
B809
Principal applicant name: 
Dr Beate St. Pourcain (University of Bristol, UK)
Co-applicants: 
Title of project: 
Follow-up and meta-analysis of signals associated with intelligence, maths scores and memory in ALSPAC.
Proposal summary: 

(No outline received).

Date proposal received: 
Thursday, 16 April, 2009
Date proposal approved: 
Thursday, 16 April, 2009
Keywords: 
Intelligence
Primary keyword: 

B811 - In-utero lead exposure and timing of puberty in the United Kingdom - 13/04/2009

B number: 
B811
Principal applicant name: 
Dr Mildred Maisonet (Centers for Disease Control and Prevention, USA)
Co-applicants: 
Prof Jean Golding (University of Bristol, UK), Ms Adrianne Holmes (Not used 0, Not used 0), Dr Michele Marcus (Emory University, USA)
Title of project: 
In-utero lead exposure and timing of puberty in the United Kingdom.
Proposal summary: 

Specific Aim - To conduct analyses of existing data to assess the effects of in-utero lead exposure on timing of puberty in children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC).

Background and Significance - Recent literature suggests that lead appears to have endocrine disrupting potential in humans. Cross-sectional analyses of the United States Third National Health Examination and Nutrition Survey showed associations of blood lead levels with delayed breast and pubic hair development and menarche in girls 1 2 A cross-sectional study from Russia reported a delayed onset of genital development among boys with blood lead levels >= 5 micro-g/dL 3. Overall, the literature of the impact of lead on pubertal timing is sparse and the mechanisms leading to these associations are not known.

The Centers for Disease Control and Prevention (CDC) is currently conducting a study in ALSPAC participants to assess effects of exposure to substances with endocrine-disrupting potential in pubertal onset and progression. Analytes being tested in maternal serum and urine and children urine samples originate mainly from pesticides or plasticizers. The analytes are: organochlorine pesticides, polychlorinated biphenyls (PCBs), brominated flame retardants (PBB and PBDE), polyfluoroalkyl chemicals (PFCs), triazine herbicides (atrazine), environmental phenols, phthalates, and phytoestrogens.Data on pubertal development have been collected via self-administered questionnaires beginning at age 8 up to age 14.

In our study we are not testing samples for lead levels. However, ALSPAC have tested maternal blood samples for lead levels to study the effect of this exposure on other health outcomes. Because of the evidence that lead may impact the pace of pubertal development we want to obtain from ALSPAC the data on maternal blood lead levels to assess the effects of in-utero lead exposure on timing of puberty onset.

Due to the sparse, yet suggestive, reports on the association of lead with delayed pubertal development in boys and girls the proposed analysis of existing data would be an important contribution to the literature on the effects of environmental contaminants on endocrine function.

Research Design and Methods - As indicated previously outcome and exposure data has already been collected for other purposes. Among 8-14 year old singletons who responded to the puberty questionnaire, there were 3945 girls with valid data on breast and pubic hair Tanner stage and menarche; 3938 boys with valid data on pubic hair Tanner stage; and 2877 boys with valid data on genital Tanner stage.

We will construct survival models to assess the effect of lead on puberty. For girls, we will estimate the difference in timing of menarche attainment and of transition into stage 2 of breast and pubic hair development in exposure groups after adjustment for confounders. For boys, we will estimate the same for transition into stage 2 of genital and pubic hair development. We found inconsistencies in genital stage reporting in a large proportion of boys. Because of the reported association between delayed genital development and lead exposure we believe that it is important to assess this association in our study group. We have included the analyses of this association in the proposal as a possibility whose validity would be explored further.

Lead levels were tested on samples taken at time of enrollment in approximately 4000 mothers whohad whole blood stored in an acid washed vaccutainers. Data collection on parents and children enrolled in the ALSPAC cohort was conducted by the University of Bristol. The University of Bristol assigned a unique identification number to the puberty data they sent to CDC. We will provide the identification numbers of children with valid puberty data to ALSPAC staff to obtain their mother's lead levels and the gestational age when the blood sample was obtained. They will not be sending blood samples to CDC for lead testing. They will use the CDC assigned IDs to know for which children we want to obtain results of the blood lead testing they conducted. What we expect from them is an updated de-identified dataset of children with valid puberty data that will include results of their blood lead testing and the age the child was tested. Only the University of Bristol has access to information on personal identifiers. Data transfer will be conducted according to the confidentiality assurances and procedures that the University of Bristol have implemented as part of their study to prevent any breach in confidentiality.

The final number of children with both exposure and outcome values is not yet known. The number of maternal samples tested is large and may yield sufficient children to detect statistically significant differences among exposure groups. As a comparison, of the 1127 children from the Children in Focus Cohort seen at 25 months, 368 girls responded to at least one puberty questionnaire. If we apply this ratio (368/1127) to the number of mothers with lead data (~4000) we may have about 1300 girls with both lead and puberty data for analyses.

We conducted power calculations for different sample size scenarios of the study outcomes. For menarche attainment we obtained power estimates for sample sizes ranging from 250 to 1500 in increments of 250 at a level of significance of 0.05, a proportion of lost to follow-up of 13%, and a prevalence of delayed menarche of 3.2 2 for unequal sample sizes in comparison groups. Estimates were obtained using the PASS software.

Power calculations

Sample

size

Difference in proportion of girls with

menarche in comparisons groups

3.0

5.0

7.0

9.0

250

0.29

0.52

0.71

0.84

500

0.50

0.81

0.95

0.99

750

0.67

0.94

0.99

1.00

1000

0.80

0.98

1.00

1.00

1250

0.88

0.99

1.00

1.00

1500

0.93

0.99

1.00

1.00

With a sample size of 500 we will be able to attain a power of 80% to find a difference in the proportion of menarche attainment >= 5.0. It is likely that effects of lead in puberty are of a smaller magnitude; however, it seems reasonable to expect that the number of girls with lead and puberty data will be larger. We will address the potential for selection bias by exploring differences between those children with and without lead data. The proposed analyses of existing data seem feasible and will make an important contribution to current knowledge on effects of lead on endocrine function.

References

1. Selevan SG, Rice DC, Hogan KA, Euling SY, Pfahles-Hutchens A, Bethel J. Blood lead concentration and delayed puberty in girls. N Engl J Med 2003;348(16):1527-36.

2. Wu T, Buck GM, Mendola P. Blood lead levels and sexual maturation in U.S. girls: the Third National Health and Nutrition Examination Survey, 1988-1994. Environ Health Perspect 2003;111(5):737-41.

3. Hauser R, Sergeyev O, Korrick S, Lee MM, Revich B, Gitin E, et al. Association of blood lead levels with onset of puberty in Russian boys. Environ Health Perspect 2008;116(7):976-80.

Date proposal received: 
Monday, 13 April, 2009
Date proposal approved: 
Monday, 13 April, 2009
Keywords: 
Environmental Exposure, Puberty
Primary keyword: 

B807 - The measurement of polybrominated diphenylether flame retardants in samples of umbilical cord - 01/04/2009

B number: 
B807
Principal applicant name: 
Prof John Gordon Bell (University of Sterling, UK)
Co-applicants: 
Prof Jean Golding (University of Bristol, UK), Prof Anne O'Hare (University of Edinburgh, UK)
Title of project: 
The measurement of polybrominated diphenylether flame retardants in samples of umbilical cord.
Proposal summary: 

The hypothesis we would like to test is that children with autism, and perhaps those with other forms of developmental delay (DD), may have elevated body polybrominatd diphenylether (PBDE) concentrations, compared to typically developing (TD) controls. Using samples of umbilical cord tissue to measure PBDE leadings is highly relevant to what the foetus would have received from the mother via the placenta. In the first instance we would like to obtain 3 samples of cord tissue of varying mass, between 0.3 and 1.5g, so that we can find out what PBDEs we can measure in samples of this size. Hopefully we will be able to meaure most of the important PBDEs in these samples so that we could proceed with a funding application to measure samples from the different study groups described above.

PBDEs have been used as flame retardants in textiles, including carpets, curtains and household furnishings, as well as in plastics and computer components, since the mid-1980s, around the time that autism prevalence began to increase globally. While the causative factors involved in an individual becoming autistic are likely to be multi-factorial, the timing of PBDE introduction in homes and workplaces, their rapid rise in the environment since the 1980s and a parallel rise of PBDE concentrations in human tissues and fluids along with their known affects on metabolism makes them environmental factors that are very worthy of further investigation. Unlike many of the other neuroendocrine and elemental toxins such as dioxins, PCBs, Hg and Pb, that are all decreasing in the environment, PBDEs have risen rapidly over the same time frame as the recorded increased prevalence of autism. While around 43 PBDE congeners have been identified the contribution to overall tissue concentrations in humans is largely represented by 10 congeners namely PBDEs 28, 47, 49, 66, 99, 100, 153, 154,183 and 209. The measurement of tissue PBDE concentrations will be conducted using state-of-the-art analytical equipment including automated solvent extraction (ASE(tm)) and gas-chromatography/mass spectrometry (GC/MS). PBDEs have known endocrine disrupting activity including alteration of thyroid hormone concentrations [they deplete T4 levels and function, as well as reducing vitamin A (retinol)]. In addition, PBDEs stimulate pro-oxidant activity resulting in an increase in the oxidised/reduced glutathione ratio (GSSG/GSH). Increased GSSG/GSH ratio and antioxidant dysfunction have been reported in patients with autism. PBDEs induce hepatic cytochrome P450 IIB1 and 1A1 hepatic detoxifying systems. Possible impairments in this metabolic detoxification in individuals with autism and/or developmental delay might make these individuals more susceptible to elevated tissue levels of PBDEs. Perhaps the greatest concern of damaging effects of PBDEs relate to developmental neurotoxicity in mice and rats. These effects include disruption of spontaneous behaviour, impaired learning and memory, hearing and memory impairments and behavioural changes. The mechanisms for these affects on behaviour and cognition are unknown but may be associated with alterations to cholinergic receptors (Viberg et al., 2002).

Date proposal received: 
Wednesday, 1 April, 2009
Date proposal approved: 
Wednesday, 1 April, 2009
Keywords: 
Biological Samples
Primary keyword: 

B801 - Determination of the affect of a complex CNV region on Chr 12 on various psychological variables of the ALSPAC cohort - 30/03/2009

B number: 
B801
Principal applicant name: 
Prof Anthony J Brookes (University of Leicester, UK)
Co-applicants: 
Title of project: 
Determination of the affect of a complex CNV region on Chr 12 on various psychological variables of the ALSPAC cohort.
Proposal summary: 

Copy number variation (CNV) represents a significant proportion of human genomic variation and it is increasingly becoming clear that CNV is involved in phenotypic variation and disease (Itsara et al, 2009). We are interested in understanding the relationship between copy number variation at loci critical to development, growth and disease. Our current region of interest focuses on a genomic domain spanning genes important for pluripotency, energy utilisation and the immune response. Our analysis of the current genome build reveals part of this region to exist mainly as an ancient (pre-simian) tandem duplication, with corresponding gene duplications. SNP genotyping across this interval in a case control study demonstrated association with rheumatoid arthritis and also revealed hints for CNV (Lorentzen et al, 2007). Due to its complexity and limited LD with surrounding DNA the region is not detected using current genome wide SNP technologies, and therefore targetted CNV analysis is required. Assays for CNV within the tandem duplication were developed based on an adaption to the paralogous ratio test (PRT)(Armour et al, 2007). In these assays the relative number of copies between the tandem repeats is assessed using oligonucleotide primers that amplify simultaneously from both repeats. During this analysis we discovered that either repeat can be duplicated or deleted, thereby representing a complex CNV. From these investigations we have developed an accurate copy number counting assay and demonstrated a significant association between rheumatoid arthritis and copy number of this tandem duplication. This region is of substantial interest as, in addition to the association with RA, it has been implicated in a number of disorders through the data from the rat genome database including QTLs related to insulin resistance and heart disease. Mouse models determine that homozygous nulls for this gene are lethal whereas heterozygous null are related to insulin resistance and increased body mass. Furthermore, changes in protein levels of one of the genes within the CNV in humans has been linked to cancer, insulin resistance and Alzheimer's disease. Given the wide range of disease associations and the role pluripotency, energy transfer and immune response plays in growth and development it is likely that changes in copy number at this region will have an impact on various underlying biochemical measures. Therefore it would be prudent, in addition to traditional case control studies that we are planning, to examine the role of copy number in relation to various endophenotypes. For this the highly characterised ALSPAC cohort is ideal.

For this purpose we have designed and assessed a number of assays based on the paralog ratio test (PRT). These assays allow the assessment of copy number between the repeats, and thereby can indicate which of the two repeats are changing in copy number. The PRT is relatively unique among copy number counting methods in that it requires very little DNA to produce accurate counting. It would therefore be feasible to rapidly genotype the entire ALSPAC cohort with multiple assays using 100 ng DNA, including repeats.

The results of these assays would then be analysed in relation to various biochemical and physiological measures listed below.

Date proposal received: 
Monday, 30 March, 2009
Date proposal approved: 
Monday, 30 March, 2009
Keywords: 
Genetics, Psychology
Primary keyword: 

B805 - Exploring and understanding the food practices of working families with younger children - 30/03/2009

B number: 
B805
Principal applicant name: 
Dr Rebecca O'Connell (University of London, UK)
Co-applicants: 
Prof Julia Brannen (University of London, UK), Dr Ann Mooney (University of London, UK), Dr Charlie Owen (University of London, UK)
Title of project: 
Exploring and understanding the food practices of working families with younger children.
Proposal summary: 

N.B. This research proposal is a response to a specific call from the ESRC/Food Standards Agency relating to the NDNS

Recent research suggests that the nation's diet will be more likely to improve if healthy eating policies take into account changing patterns of family life (Jackson & Pickering, 2009). This study aims to map and understand the effects of a major social change that research indicates affects the quality of children's diets, namely the rise of maternal/dual parental employment in the UK. The study will take as its starting point that children's nutrition and food practices take place not only in their homes but in a range of contexts. The study will interrogate the 2009 National Diet and Nutrition Survey (NDNS), the Health Survey for England (HSE) and the Avon Longitudinal Study of Parents and Children (ALSPAC) to examine in relation to diet the associations found in other studies between childhood overweight and parental employment. This secondary analysis will be followed by an intensive study of 48 working families sampled from the NDNS and selected according to (high and low) income level and the quality of children's diets. This part of the study will seek to provide explanations for statistical associations found (or not found) in the NDNS survey data. It will employ ethnographic methods, including interviews and photo elicitation, in order to understand the social processes which influence healthy and unhealthy diets of children both within and outside the home. The quantitative analysis of secondary data will hypothesise and examine associations between diet and parental employment status while the qualitative part of the study will inductively explore the contextual meanings of 'food use' in working families, the embodiment of food practices, and their embeddedness in different social contexts (inside and outside the home). The implications of the research for policy and practice include informing the design and evaluation of health interventions so that they may be tailored more effectively to the needs of employed families. Through its use of a variety of research tools the study will inform the methodology of future studies.

Background

Between 1995 and 2003, the prevalence of obesity among children aged 2 to 10 rose from 9.9% to 13.7% (Health Survey for England, 2006). As UK studies suggest, early childhood overweight is associated with the propensity for overweight and obesity in adulthood (Gardner et al., 2009). Given the lack of robust evidence concerning the effectiveness of interventions later in the life course (Summerbell et al., 2003), public policy is concerned with children's health (DH/DCFS, 2008a). Research has shown that some groups of children are at greater risk of being overweight and obese than others (Waldman, 2008): those from lower social economic groups (e.g. Kinra et al., 2000; Armstrong et al., 2003; Power et al., 2003; Stamatakis et al., 2005); and some ethnic minority groups (Health Survey for England, 2004; Rennie & Jebb, 2005; Law et al., 2007).

In addition, research evidence suggests an association between maternal employment and children's overweight status (Scholder, 2007; Hawkins et al., 2008). Analysing the Millennium Cohort Study, Hawkins et al. (2008) found associations between maternal employment and overweight among preschool children, a finding supported by some US research (e.g. Anderson et al. 2003; Crepinsek & Burstein, 2004). Specifically, Hawkins et al. found that children's likelihood of being overweight increased with the number of hours their mother worked per week. However, this finding was only significant among higher income families (annual income in excess of £33,000) (Hawkins et al., 2008). These results mirror US studies showing links between childhood overweight and maternal employment in highly educated, well off, white families (Fertig et al., 2003). These findings thus serve to complicate the general picture of a positive association between household income and children's weight (see e.g. Health Survey for England, 2006). Hawkins et al. (2008) hypothesise a link with diet, suggesting that longer maternal working hours may impede young children's access to physical activity and healthy foods. Analyses of ALSPAC suggest that the dietary patterns of children aged three (North & Emmet 2000) and seven (Northstone & Emmet, 2005) whose mothers were in paid employment were significantly associated with a 'junk' dietary component, although these studies do not explore diets in relation to working hours. In apparent contradiction, a survey by Sweeting & West (2005) of older children and their working parents (N=2,146) suggests a link between non-working mothers and poor diets : 63% of 11 year old children whose mothers were at home full-time were classed as eating "less healthily", compared to 52% of those whose mothers worked full-time. However, this latter analysis did not control for income and maternal education which are known to affect children's diets (Gregory et al., 1995; Northstone & Emmett, 2005).

Early nutritional experiences have both immediate and long term consequences not only for younger children's weight but also for their educational attainment and mental, social and economic wellbeing (NHS/HDA 2004; DfES, 2006; FHF, 2007; Feinstein et al., 2008; Golley et al., 2008). A possible link between parental employment and children's diet is important since the rise of maternal employment is one of the key recent social changes which has impacted upon children's lives in the UK (Layard & Dunn, 2009); the economic activity rate for women aged 16-59 rose from 59% in 1971 to 74% in 2007 (ONS, 2007; Walling, 2005). The most striking change in employment rates has occurred among mothers of young children (Berthoud 2007). In 2004, 57 per cent of women with a child of pre-school age were economically active compared with 55 per cent in 1997 (Aston et al., 2005); more than two thirds of working-age women with dependent children (68%) were in employment in the second quarter of 2008 (ONS, 2008).

However, these rises in parental employment have not been accompanied by any significant increase in public policy or workplace support for employed parents. Within the household, although recent studies have highlighted increases in men's care contribution to family life (e.g. Gershuny, 2001; O'Brien & Shemilt, 2003), including food provisioning (e.g. Drydon et al., 2009), gendered sociocultural expectations around carework have not kept pace with changes in parental employment patterns. Women remain disproportionately responsible for food work (Murcott, 2000; DeVault, 1997): the UK Time Use Survey suggests that in 2000 females spent roughly twice as much time as males on the activities of shopping, preparing food and washing up (ONS, 2000). Some US literature suggests that 'time poor' working families may face significant challenges in meeting the demands of feeding their families (e.g. Jabs et al., 2007). Parents' feeding decisions may represent attempts to reconcile competing symbolic and practical tasks. For example, whilst they recognise that some 'convenience' food is not 'healthy', mothers may find it helps them 'meet their priority of feeding their families in a time-scarce environment' (Jabs et al., 2007:24; Warde, 1999).

Theoretical approaches and methodologies

Research suggests that because parents play such a critical role in determining the diets of their children, as meal providers and role models (e.g.Wardle and Cooke, 2008), 'pressures on parents' food choices have great importance for the nutrition and health status of their children' (Devine et al., 2006: 2592). However, children exert their own pressures on parents (Norgaard et al., 2007), form their own preferences and practices and use food to forge (and reject) connection with others. Food is an important way in which people construct identities through consumption (Valentine, 1999), especially for children (e.g. James, 1998; Wills et al., 2008; James, 2008; James et al., forthcoming). In short, food practices are negotiated (DeVault, 1997; Jackson & Pickering, 2009:4). This study will be guided by such ideas and by a practice-based theory of family life (Morgan, 1996) in which children's agency is given due weight (Christensen, 2004). While home and family are of central importance in terms of feeding younger children and establishing eating patterns (Birch, 1998), they also interact with other environments (Bronfenbrenner, 1979) which provide food and influence food practices (NICE, 2006:149). School is a key eating environment for older children and when mothers or both parents work, for younger children nurseries, childminders, after school clubs, and the homes of friends and relatives are environments where a large proportion of the daily diet is consumed. Much of the limited supply of childcare in the UK is provided in the private sector by large companies or small businesses (private nurseries and childminding) where regulations around food consumption are limited (More, 2008), in contrast with the tighter regulations in schools (cf. Belot & James, 2009). A holistic view of children's nutrition and food practices is needed to understand the range of intersecting contexts in which children are nourished and their food practices nurtured.

A focus in some public health policy on individual consumer 'choice' has tended to confound food selection with preference, obscure the socio structural conditions in which food practices evolve and neglect the cultural and emotional factors that influence nutrition (Attree, 2006:67). Food plays important roles beyond providing sustenance, fulfilling non material cultural goals (de Garine, 2004:19) for adults and children (Alcock, 2007). It is an expression of care and identity (Kaplan, 2000). It is also political (Lien, 2004); food mediates power relations, including those based on age and gender (Murcott,1982,1983a; Charles & Kerr 1988). Understanding food practices requires approaches that go beyond rational-choice paradigms to confront 'habitus' (Bourdieu, 1977) - the situatedness of practices in everyday routines and social relations. Providing empirical data concerning the relationship between parental employment and children's diets and the embedded practices and processes which shape them, the proposed study will fill a clear gap in knowledge.

The main aims of the study are to address these key research questions:

* How does parental employment influence and shape family food practices in particular the diets of children (aged 1.5 to 10 years)?

* How do parents' experiences of negotiating the demands of 'work' and 'home' affect domestic food provisioning in families?

* What foods do children of working parents eat in different contexts - home, childcare and school - and how do children negotiate food practices?

The specific objectives of the study are:

1. To examine the relationship between parental employment status and the diets of younger children via secondary analysis of the 2009 NDNS Survey, the Health Survey for England (HSE) and the Avon Longitudinal Study of Parents and Children (ALSPAC)

2. To seek understandings of the food practices of children in working families, including families with high and low incomes and those whose children are classified on the NDNS as having 'healthy' and 'unhealthy' diets, by applying a range of in-depth qualitative methods

3. To develop the methodology in this area through the use of a multi-method research approach

4. To inform healthy eating advice for employed families, by presenting to policymakers and practitioners issues to consider for bringing about improvements in children's diets

Research design: A mixed methods approach

Hawkins et al., (2008:37) have suggested that '[f]urther research is needed to examine factors along the causal pathway between maternal employment patterns and childhood overweight, which can help inform policy and interventions. For example, little is known about differences in children's diet or physical activity levels by maternal employment status. Focussing on diet, this study will employ the different logics which underpin different methods (cf. Murcott, 1995:734; Brannen, 1992, 2005; Bryman, 1988; Greene et al., 1989). Through secondary analysis of survey data it will hypothesise and examine associations between diet and parental employment status. Through an anthropological and sociological approach it will inductively explore the contextual meanings of food use in working families, the embodiment of food practices, and their situatedness in different social contexts and practices. Together these approaches will help to provide a fuller picture (Brannen 2004; Mason, 2006).

Exploiting the knowledge and capacities of the multidisciplinary research team, the study will draw on a mix of disciplines (anthropology, sociology and social statistics) and research fields including the 'new social studies of childhood', family studies, childcare research and the study of food practices to achieve these objectives and complement the FSA's existing work in nutrition, dietetics and physiology. Its sample will aim to focus on families with at least one young child aged 1.5-10 years. The study will have four main phases. The timetable below is proposed based upon NDNS data becoming available in December 2009:

Phase 1: October - December 2009 Access to large scale data sets (NDNS, HSE, ALSPAC), identification of relevant variables, preparation of data set for analysis in Phase 2, design and piloting of qualitative research instruments for use in Phase 3.

Phase 2: November 2009 - Feb 2010 Secondary analysis of large scale surveys. To examine how parent employment relates to children's diets, secondary analysis will be carried out on the 2009 NDNS, the Health Survey for England (HSE) and the Avon Longitudinal Study of Parents and Children (ALSPAC), as all of these collect data on children's diet and mothers' employment. The NDNS is the only rolling UK survey to collect nationally representative and detailed dietary information on children and adults. So far, different waves have concentrated on specific age groups. A key advantage is that NDNS contains linked data on food, nutrient intake, nutritional status and contextual information on individuals. The first NDNS (1992/93) collected data on the diets of 1,340 children aged 1.5 to 4.5 and collected detailed data on the mother's hours of work. The third survey (1997) collected data for children aged 4 to18, with a full dietary record for 1,701 children; the survey asked about mother's employment, but only classified hours of work as full or part time. Some data have been analysed by social class (Gregory & Hinds, 1995), but not by mother's employment. Unfortunately, the sample sizes are quite small, especially for analysing sub-groups (Scientific Advisory Committee on Nutrition, 2008:21), such as employed mothers. Parental employment appears to have been asked in NDNS 2009.

HSE is an annual survey carried out on behalf of the NHS. The survey includes data on diet and nutrition for children and hours of work for mothers (although only full or part time). In 2007 there was a boost sample of children, so that a total of 7,504 children were included (Craig & Shelton, 2008b). The relation between diet and maternal employment has not been analysed. However, even a sample this size has limitations: as the survey report noted, while 'exploratory analysis indicated that there may be associations between a child's perception of how healthy they perceive their diet to be and how healthy their parents perceive their own diet to be... numbers of parent and child pairs ... are too small to produce reliable conclusions' (Craig & Shelton, 2008a: 292).

From the early 1990s ALSPAC followed approximately 14,000 children from birth into their teenage years. It collected detailed data at different age points on children and their families, including data on parental employment and on diet and nutrition (Emmett, 2009). This unique dataset provides opportunities to explore associations between employment and children's diets in a large sample across the childhood years. The level of detail on mothers' hours of employment varies at different points in time: at 47 months mothers were asked about employment, but not about hours of work; at 61 and 85 months mothers were asked about hours of work. However at 73 months mothers were not asked any questions about their employment. This study would look in detail at the effect of hours of work at different ages. Other studies have related diet and nutritional information for children and socio-economic data for adults: diet in 3-year olds (North & Emmett, 2000) and 4-year olds and 7-year olds (Northstone & Emmett, 2005) was analysed in relation to socio-economic factors, including mother's employment, although diets in relation to working hours was not examined.

These three datasets each has some information to contribute, but each has its limitations - in terms of sample size or in terms of details on hours of work. By analysing the data in combination, it should be possible to explore the relation between mother's hours of work and children's diet in more detail than has been done before. To identify a composite measure of diet quality using variables from the NDNS, HSE and ALSPAC datasets the advice of a public health nutritionist will be sought. The nutrition literature contains a wide variety of diet quality indices (Emmett, 2009; Kant, 1996) which have different advantages and disadvantages. The aim is to derive and interpret children's dietary patterns and assess their association with parental employment status using appropriate multivariate analysis techniques. The viability of the NDNS 2009 sample we wish to select will also be tested - single and dual parent earner households with children aged 1.5-10 years. Given the possible small sample size of the latter age group in the NDNS 2009 it may be necessary to carry out the analysis on all children in the survey who are under 18 years.

Phase 3: January - December 2010 Selection of participants, fieldwork and preliminary analysis of the qualitative study of employed parents and children's diet. The 2009 NDNS offers the most up to date analysis of children's diets and will provide the sampling frame for working families. This part of the project will seek to understand the relationship between parental employment and the food practices in which parents and their children aged 1.5-10 engage both in the home and in contexts outside the home. Forty eight dual and lone parent households and high and low income groups will be selected from the NDNS 2009 survey. The sample of households will be drawn from a number of urban and suburban areas in which these data are clustered in several different parts of England. To assist recruitment and thank participants for their time commitment, vouchers will be given to each household. Whilst we would hope to secure all 48 households in this way, we may need to be pragmatic if this is not possible. Further families will be found through snowballing from the selected NDNS participants. These participants will be screened for household employment and age of children, income and broad dietary indicators through completion of a short telephone interview (Casey et al., 1999). The diet data will be collected in the same format as in the NDNS to make the additional sample comparable. Four groups of working families divided by income level and by the quality of children's diets as assessed by the NDNS data will be selected:

(a) 12 households (one child aged 1.5-10) in which the child scores high on a composite measure of diet quality and where the parent /s they live with are employed and in low status jobs;

(b) 12 households (one child aged 1.5-10) in which the child scores low on a composite measure of diet quality where the parent/s they live with are employed and in low status jobs;

(c)12 households (one child aged 1.5-10) in which the child scores high on a composite measure of diet quality where the parent/s they live with are employed and in high status jobs;

(d) 12 households (one child aged 1.5-10) in which the child scores low on a composite measure of diet quality where the parent/s they live with are employed and in high status jobs.

Since the home is at the centre of family food practices the study will necessarily focus on food in the domestic domain. However, because other environments (workplaces, preschools, schools, after school clubs) interact with the home (e.g. Brannen & Storey, 1998; Burgess & Morrison, 1998), supplementing and influencing food practices within it (and vice versa), data will be collected from parents and children about food consumption in these contexts. Further, because food practices are embedded in social relations and social processes, they are not necessarily easily accessible to reflection (Eisner, 2008). The use of creative and visual methods facilitates investigating layers of experience that cannot easily be put into words (Gauntlett, 2007; Bagnoli, 2009). A flexible range of research tools (e.g. Mooney & Blackburn, 2003; Edwards et al., 2005) will be employed as appropriate to bring practices to the level of discourse and to address the contexts in which food is consumed. These will include 4 approaches: (a) in-depth semi-structured interviews with parents and children aged 1.5-10 that includes story telling with children; (b) drawing methods with children (e.g. Backett & Alexander, 1991; Backett-Milburn & McKie, 1999; Hill et al., 1996; Morrow, 2001); (c) a task based exercise in which family members will be asked to suggest working-family-friendly meal ideas for inclusion in a cookbook; (d) photo elicitation interview methods (PEI's) (Collier, 1967; Radley & Taylor, 2005) carried out by parents and children (Punch, 2002) in which they will photograph foods and meals (consumed in and outside the home) for discussion in the interview. Adopting this range of qualitative tools will enable choices to be made about the most appropriate methods for eliciting children's perspectives based on their maturity, competencies and preferences (Hill, 2006; Christensen & James 2000). Rather than only serving as 'records' of food eaten (as in a realist approach), photographs, drawings and storytelling will be employed to aid reflection (Harper, 1998, 2002; Pink, 2001) upon the meaning of food events to participants and the relevance and importance of different social, environmental and temporal contexts. Photography is a particularly appropriate method for achieving our objectives, not only because it may bring the public into the private (and vice versa; cf. Moss, 2001) but also because food is a material substance which appeals to several senses and is amenable to visual representation. Households will be visited twice. At the first visit, the PEI and other exercises will be explained to parent(s) and children; at the second visit, parent(s) and children will be interviewed, employing photographs, drawing, storytelling and the cookbook task as appropriate. Analysis of photographs is a collaborative process between participants and the researcher. As in qualitative research more generally, analysis is an iterative process in which emergent questions guide the collection of future data (Pink, 2004; Jenkings et al., 2008). Qualitative data analysis software (e.g. NVivo/NUD*IST/Atlas.ti) will be employed to assist in the inductive development of key themes, patterns and categories (Hammersley & Atkinson, 2007) specifically relating to the negotiation of domestic food provisioning and the experiences of participants relating to food practices across different sites.

Phase 4: Jan 2011-September 2011. Analysis, writing up and raising methodological questions for future research including the NDNS survey. The fourth phase will involve integrating the data and results generated from the secondary analysis of NDNS, HSE and ALSPAC and from the qualitative study. The ways in which the different data sets will be integrated will be considered from the outset of the study (Greene et al 1989; Brannen 1992, 2005; Bryman, 2006). Mixed methods can provide for an articulation between different layers and types of explanation - macro and micro - each of which cannot be fully explained without reference to the other (Kelle, 2001). However, it is recognised that translation of research questions across different methods of data collection changes their significance and is likely to affect responses and create problems of interpretation. The two layers do not map on to each other readily; they are different forms of explanation albeit they may complement one another (Bryman, 2007; Murcott 1995). We may expect to find some dissonance (Perlesz & Lindsay, 2003) between findings generated by different methods, e.g. reports of the nature of diets in the survey and what is said in the interviews. On the other hand, we may expect the two analyses to complement each other, e.g. explanations for dietary habits may not be viewed in relation to health or quality issues. The analysis of the NDNS and the qualitative study will provide guidance for future research about the value of a mixed method approach for this area of research, which methods and which survey/interview questions are useful and for which purposes.

Date proposal received: 
Monday, 30 March, 2009
Date proposal approved: 
Monday, 30 March, 2009
Keywords: 
Social Conditions
Primary keyword: 

B804 - Contribution of ALSPAC lung function data to international consortium on lung function reference values - 24/03/2009

B number: 
B804
Principal applicant name: 
Prof John Henderson (University of Bristol, UK)
Co-applicants: 
Title of project: 
Contribution of ALSPAC lung function data to international consortium on lung function reference values.
Proposal summary: 

An international concortium led by Janet Stocks, UCL and funded initiallly by Asthma UK, has produced reference equations for spirmoetry from childhood through to adult life (www.growing lungs.org). This project is an extension of this work utilising large collections of lung function data from cohort and cross-sectional studies to refine the current reference equations. ALSPAC has greater than 7000 measurements fo spirmoetry in 8 year olds and a further 4000 from 15 year olds that will be a valuable addition to the resource and wil be appropriately credited in publicatiosn arising from this work.

Data required are spirometry measurements form Focus@8: FEV1, FVC and mid expiratory flows (FEF 25-75) and child's sex, height and weight on day of measurement. No other identifying information will be sent.

Date proposal received: 
Tuesday, 24 March, 2009
Date proposal approved: 
Tuesday, 24 March, 2009
Keywords: 
Respiratory
Primary keyword: 

B803 - Evaluation of a novel atopic dermatitis susceptibility variant in the ALSPAC cohort - 24/03/2009

B number: 
B803
Principal applicant name: 
Dr Young-Ae Lee (Masaryk University, Europe)
Co-applicants: 
Prof John Henderson (University of Bristol, UK)
Title of project: 
Evaluation of a novel atopic dermatitis susceptibility variant in the ALSPAC cohort.
Proposal summary: 

Atopic dermatitis (AD or eczema) is a chronic inflammatory skin disorder and a major manifestation of allergic disease. In the industrialized countries, the prevalence of AD is approximately 15 % with a steady increase over the past decades1. Genetic and environmental factors interact to determine disease susceptibility2, and family and twin studies indicate that the genetic contribution is substantial3. The molecular mechanisms underlying eczema are not fully understood. Skin barrier defect as well as systemic and cutaneous immune dysfunction in response to allergens or bacterial products are thought to play an important role4.

We conducted a genome-wide association study in 939 individuals with AD and 975 controls as well as 270 complete nuclear families with 2 affected siblings. SNPs consistently associated with AD in both discovery sets were then investigated in two additional independent replication sets totalling 2637 cases and 3957 controls. Highly significant association was found with rs7927894 on chromosome 11q13.5 (Pcombined = 3.1 x 10-10). Approximately 13% of individuals of European origin are homozygous for the risk allele, and their risk of developing AD is 1.47 times that of noncarriers5.

The objective of this study is to evaluate this novel eczema susceptibility variant at the at the general population level in the ALSPAC cohort in order to

1) replicate the initially reported association with eczema.

The ALSPAC cohort (n=7000) carries sufficient power to replicate the original finding:

Under the assumption of a moderate odds ratio of 1.3 and a disease prevalence of 10%, the power to detect an association is 94%.

2) assess the population-attibutable risk of this variant for eczema.

in contrast to the affected families and cases/controls used in the GWAS, the ALSPAC cohort will enable us to estimate the population attributable risk fraction (PARF) which indicates the proportion of cases in the population attributable to the rs7927894 risk allele.

3) evaluate this variant for association with other atopic disorders.

Interestingly, this variant has also been reported to be a risk factor for Crohn's Disease6, extending the number of overlapping risk variants for different chronic inflammatory diseases and highlighting the importance of shared molecular pathogenic pathways. The ALSPAC cohort will allow us to test this variant for association with other atopic disorders including asthma, and hayfever. An association analysis with Crohn's Disease may be attempted. However, due to the expected low prevalence of Crohn's disease, the ALSPAC cohort may not carry sufficient power to yield conclusive results.

4) evaluate epistatic effects between this variant and Filaggrin loss-of-function mutations.

Loss-of-function mutations in the filaggrin gene are strongly associated with eczema7,8. We have detected an epistatic effect between rs7927894 and the filaggrin loss-of-function mutations in the German Multicenter Allergy Study (MAS 90). However, only 871 of the original 1300 MAS children were available for genetic studies. The ALSPAC cohort is significantly larger than the MAS cohort and will allow us to replicate this finding and to estimate the effect size more accurately.

Reference List

1. Taylor, B., Wadsworth, J., Wadsworth, M., & Peckham, C. Changes in the reported prevalence of childhood eczema since the 1939-45 war. Lancet 2, 1255-1257 (1984).

2. Cookson, W. The alliance of genes and environment in asthma and allergy. Nature 402, B5-11 (1999).

3. Schultz, L. F. Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J.Am.Acad.Dermatol. 28, 719-723 (1993).

4. Bieber, T. Atopic dermatitis. N.Engl.J.Med. 358, 1483-1494 (2008).

5. Esparza-Gordillo, J. et al.A common variant on chromosome 11q13 is associated with atopic dermatitis. Nature Genetics in press (2009).

6. Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat.Genet. 40, 955-962 (2008).

7. Palmer, C. N. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat.Genet. 38, 441-446 (2006).

8. Brown, S. J. & McLean, W. H. Eczema genetics: current state of knowledge and future goals. J Invest Dermatol 129, 543-552 (2009).

Concept Specific measure Person Source Time point(s)

eczema Doctor's diagnosis of eczema child questionnaire Age 0-5 years

Age 6-10 years

Age greater than 10 years

eczema eczema child Physical exam Age 0-5 years

Age 6-10 years

Age greater than 10 years

asthma Doctor's diagnosis of asthma child questionnaire Age 0-5 years

Age 6-10 years

Age greater than 10 years

asthma asthma child Physical exam Age 0-5 years

Age 6-10 years

Age greater than 10 years

hayfever Doctor's diagnosis of hayfever child questionnaire Age 0-5 years

Age 6-10 years

Age greater than 10 years

hayfever hayfever child Physical exam Age 0-5 years

Age 6-10 years

Age greater than 10 years

atopy Elevated spec. IgE or Skin Prick test child evaluation Age 0-5 years

Age 6-10 years

Age greater than 10 years

Chronic inflamm. bowel disease (IBD) Doctor's diagnosis of IBD child questionnaire ever

Date proposal received: 
Tuesday, 24 March, 2009
Date proposal approved: 
Tuesday, 24 March, 2009
Keywords: 
Skin
Primary keyword: 

B802 - Investigating the relationship between IL-6 and bone mass accrual in childhood - 24/03/2009

B number: 
B802
Principal applicant name: 
Dr Jon Tobias (University of Bristol, UK)
Co-applicants: 
Title of project: 
Investigating the relationship between IL-6 and bone mass accrual in childhood.
Proposal summary: 

(No proposal received).

Date proposal received: 
Tuesday, 24 March, 2009
Date proposal approved: 
Tuesday, 24 March, 2009
Keywords: 
Bones
Primary keyword: 

B799 - Parallel longitudinal model of childhood depression and BMI LINKED TO B0659 - 23/03/2009

B number: 
B799
Principal applicant name: 
Dr Jon Heron (University of Bristol, UK)
Co-applicants: 
Title of project: 
Parallel longitudinal model of childhood depression and BMI (LINKED TO B0659).
Proposal summary: 

(No outline received).

Date proposal received: 
Monday, 23 March, 2009
Date proposal approved: 
Monday, 23 March, 2009
Keywords: 
Depression
Primary keyword: 

B800 - The Impact of Prolonged Infertility on Parenting - 20/03/2009

B number: 
B800
Principal applicant name: 
Dr Catherine Pearlman (Yeshiva University, USA)
Co-applicants: 
Title of project: 
The Impact of Prolonged Infertility on Parenting.
Proposal summary: 

Previous studies have small samples with small or no control groups. ALSPAC's vast data will allow for a larger sample of women who have experienced prolonged infertility. The data also provides for control groups. Due to the large numbers of variables present in the data, it will be possible to screen out for a variety of variables that might skew the data. For example, age of mother, ethnicity, socioeconomic status, and other variables. To date I have not found other studies that use the length of time of being infertile as a variable. Using the ALSPAC data, this will be possible. Instead of focusing on the type of technology used to become pregnant, I will focus on how the length of time trying to conceive influences subsequent parenting.

Date proposal received: 
Friday, 20 March, 2009
Date proposal approved: 
Friday, 20 March, 2009
Keywords: 
Parenting, Fertility/Infertility
Primary keyword: 

B798 - Understanding the lifestyle molecular and genetic pathways that link womens reproductive function to healthy ageing LINKED TO B1193 - 15/03/2009

B number: 
B798
Principal applicant name: 
Prof Debbie A Lawlor (University of Bristol, UK)
Co-applicants: 
Prof Naveed Sattar (University of Bristol, UK), Prof Scott Nelson (University of Glasgow, UK), Prof Kate Tilling (University of Bristol, UK), Dr Caroline Relton (Newcastle University, UK), Dr Jon Tobias (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK)
Title of project: 
Understanding the lifestyle, molecular and genetic pathways that link women?s reproductive function to healthy ageing (LINKED TO B1193).
Proposal summary: 

Aims and objectives of the programme

Broad aims of programme

The aims of the programme are to (i) understand the mechanisms that underlie the associations of women's reproductive characteristics (age at menarche, menstrual patterns, follicular activity, fertility, pregnancy and age of menopause and menopausal changes) with later risk for chronic complex diseases and their risk factors (obesity, hypertension, dyslipidaemia, hyperglyaceamia, insulin resistance, type 2 diabetes, coronary heart disease, stroke, osteoporosis, depression, breast density and breast cancer); (ii) to understand the role of women's reproductive health in healthy ageing and (iii) to determine the mechanisms for the intergenerational transmission of patterns of women's reproductive, cardiovascular, metabolic, skeletal and mental health.

The programme will bring together existing funded work of the PI and co-applicants that is concerned with pregnancy related changes and future cardiovascular, metabolic and bone health in offspring and mothers (project grants from US NIH, MRC, Wellcome Trust & BHF). In the first phase we will focus primarily on consolidating the work from these different projects (objective 1 of the first 5 years) in order to obtain a comprehensive picture of how pregnancy related changes affect a wide range of future health related outcomes in mother and offspring. In addition in the first 5 years we will obtain detailed repeatedly assessed phenotypic data (hormonal, vascular, metabolic, bone and DNA methylation changes) on a cohort of women (the mothers) as they go through the menopausal transition (from age 47-52 years). These new data will be used to address objectives 2-7 below and will provide the evidence based for understanding how oestrogen deficiency and menopausal changes influence ageing in general and specifically vascular, metabolic and muscular-skeletal ageing. With subsequent renewal of the programme , after the first 5 years, we would focus on the daughter's menstrual pattern, follicular activity and emerging fertility, as well as linking data on the mother's breast density from routine mammography and mental health outcomes to the main dataset.

Specific objectives of the first 5 years

We will:

1. Determine the extent to which pregnancy related weight gain, vascular and metabolic changes are related to the mother's and her offspring's future reproductive, vascular, metabolic and muscular-skeletal health.

2. Determine the pattern of changes in glucose, insulin, lipids, blood pressure, total and truncal fat and bone mineral density as women go through the menopausal transition and distinguish whether there is a specific menopausal effect over and above age related changes in these phenotypes.

3. Determine the hormonal, genetic, molecular and lifestyle pathways that underlie variation in age at menopause and variation in changes in vascular, metabolic and bone phenotypes over the menopausal transition.

4. Determine the association of different patterns of change in glucose, insulin, lipids, blood pressure and total and truncal fat over the menopausal transition with variation in postmenopausal carotid intima media thickness.

5. Establish the role of DNA methylation in determining the timing and magnitude of menopausal changes.

6. Determine the pattern of global and gene-specific (e.g. ESR1) DNA methylation patterns as women go through the menopausal transition.

7. Determine the consequences of menopause- related DNA methylation changes with respect to subsequent changes in vascular, metabolic and muscular-skeletal health.

Data requirements and new data collection

Objective 1 above will use existing data or data currently being collected (e.g. mums clinic and 17+ clinic fasting blood samples and assays) and brings together agreed work of the PIs in ALSPAC as funded by existing grants (NIH; MRC; BHF).

The remaining objectives will be addressed by collection of new data from a subgroup (~3000) of the ALSPAC mothers who fulfil the following criteria:

Age 47-49 years at start of new clinics (September 2010)

No previous history of hysterectomy or bilateral oophorectomy

Not known to have undergone natural menopause

Mothers fulfilling these criteria will be invited to attend annual clinics over a 4 year period (4 clinics in total) at which the following will be completed:

1. Completion of menstrual cycle & hormonal use questionnaire

2. Taking of a fasting blood sample

3. Measurement of weight, height, waist circumference and blood pressure

4. DXA scan - total & hip

The grant will request funds to complete the following on the blood samples:

1. Repeat assessment (at each clinic) of sex hormones, glucose, insulin and lipids

2. Global and gene specific DNA methylation patterns.

Date proposal received: 
Sunday, 15 March, 2009
Date proposal approved: 
Sunday, 15 March, 2009
Keywords: 
Epigenetics
Primary keyword: 

B796 - Metabolic syndrome in adolescents Associations with dietary intakes circulating 25-hyrdroxyvitamin D and IGF-1 - 05/03/2009

B number: 
B796
Principal applicant name: 
Dr Kirstin Newby (Boston University, USA)
Co-applicants: 
Title of project: 
Metabolic syndrome in adolescents: Associations with dietary intakes, circulating 25-hyrdroxyvitamin D and IGF-1.
Proposal summary: 

The prevalence of metabolic syndrome (MetS) has been estimated anywhere from 2% to 9.4% for US

adolescents and varies depending on the definition used (1-3). A more recent report based on the National

Health and Nutrition Examination Survey (NHANES 1999-2002) estimated the prevalence of MetS as

high as 23% for overweight/obese children aged 12-18 years (4). MetS components in childhood are

carried into adulthood (5, 6). With the growing obesity epidemic and the positive relationship between

obesity and MetS (7), research aimed at understanding the risk factors for MetS in children is needed and

is likely to have important public health implications.

Diet is a known risk factor for MetS, although contributions of individual dietary components to MetS

remain relatively ambiguous for children and adolescents. In particular, associations between dairy intake

and MetS remain unclear, although several studies, mainly in adults, suggest a protective effect crosssectionally

(8-10) and prospectively (11, 12). The Coronary Artery Risk Development in Young Adults

(CARDIA) study, a 10-year prospective study, reported a lower incidence of MetS (OR: 0.28; 0.14-0.58)

among overweight individuals consuming the highest compared with the lowest dairy category (12).

Little information exists regarding this relationship in children and adolescents. A recent cross-sectional

study observed a decreased likelihood of MetS with higher frequency of dairy, fruit, and vegetable

consumption in children aged 6-18 years living in Iran (13).

Calcium and vitamin D are two major nutrients found in dairy products that may play a protective role

against MetS (10, 14-16). Serum 25-hydroxyvitamin D is used to assess overall vitamin D status. A few

population-based studies have found inverse associations between 25(OH) D and MetS (17, 18). Data

regarding the relationship between calcium, vitamin D, and MetS are limited for children. However, a

cross-sectional study of 217 obese children aged 7-18 years found that vitamin D insufficiency was

associated with several MetS risk factors including higher BMI and systolic blood pressure and lower

HDL-cholesterol concentrations (19). Therefore, examining the potential relationship between dietary

calcium, serum vitamin D and MetS may be important in understanding the associations.

Higher circulating levels of IGF-1 have been associated with risk of certain types of cancer such as

prostate cancer (20, 21), whereas lower levels have been related to other chronic conditions such as

obesity and MetS (22, 23). In several studies, IGF-1 has been positively associated with dairy and milk

intake (24-26). Rich-Edwards et al (27) reported results from two pilot studies examining associations

between milk intake and IGF-1 as follows: 1) Mongolian children showed significant increases in IGF-1

and other factors with whole milk intake over 1 month, and 2) girls living in Boston showed small

increases in IGF-1 when consuming lowfat milk compared with a vegetable-based milk substitute over a

1 week period; these findings were not statistically significant. Rogers et al (26) found that milk and

dairy intakes were associated with IGF-1 and its binding protein (IGFBP-3) concentrations for all

children and for boys after adjustment. These associations were no longer statistically significant after

additional adjustment for protein intake, suggesting that protein may be an important mediator in this

relationship. In that study, dairy intake was positively associated with leg length in boys but not in girls,

and it appeared that IGF-1 played a role in this relationship as the association was attenuated after

adjustment. The mechanism by which IGF-1 is related to milk consumption is not fully understood.

Possible explanations include the high protein content of milk and dairy (26, 28) and/or constituents in

milk that may not be degraded/deactivated during digestion, such as growth hormones used in milk

production (27). More research is needed to identify the exact mechanism by which milk intake increases

IGF-1 and other growth factors. A recent population-based study of 6,810 British subjects found that

serum 25(OH)D and IGF-1 concentrations were inversely associated with MetS. However, associations

with IGF-1 were not statistically significant for participants with the lowest vitamin D concentrations,

indicating that both need to be considered in future research studies (22). Research projects that consider

all of the nutrients and factors discussed above are needed, especially in child and adolescent populations.

Date proposal received: 
Thursday, 5 March, 2009
Date proposal approved: 
Thursday, 5 March, 2009
Keywords: 
Diet, Metabolic, Nutrition
Primary keyword: 

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