Proposal summaries
B550 - NIH Mercury - 13/09/2007
Fish and seafood are regarded healthy components of a varied diet, particularly important for pregnant women so that they can pass on essential nutrients needed for fetal development of the brain and other organs1. On the other hand, fish may contain environmental pollutants, such as methylmercury, that can put fetal brain development at risk2. A balance has been sought by state and federal agencies in advising the public 3, but certain subpopulations (i.e. pregnant women or women of childbearing age) generally eat less fish than desirable in order to obtain the beneficial effects of fish 1. At the same time, U.S.EPA reports that over 300,000 children born every year exceed the Reference Dose (RfD) for methylmercury and may therefore be at risk at developing adverse effects4.
Tragic pollution episodes have clearly documented that the fetal brain is particularly susceptible to methylmercury toxicity; the adverse effects on the nervous system appear to be irreversible and are much more widespread and serious in children than in adults, especially when exposures have occurred prenatally5,6. While the existence of adverse effects at low exposure levels has been affirmed by national and international regulatory agencies,7-10 certain scientific questions remain unanswered. They relate to the possible occurrence of neurotoxic effects close to the U.S.EPA Reference Dose, the persistence of the cognitive deficits through adolescence, and the possible compensation of adverse effects by essential nutrients present in fish and seafood. The proposed research aims at developing new and more definite information on the benefits and risks associated with seafood intakes at levels relevant to the US general population.
This proposal builds upon the extensive data already collected on a cohort of 14,138 children born between April 1st 1991 and December 31st 1992 in Avon, England, as part of the Avon Longitudinal Study of Parents and Children (ALSPAC) study11. The focus was to identify features of the environment that affect the health and development of children. Detailed information and biological samples were collected at the time of birth and continue to be collected during the course of follow-up11. A10% sample randomly selected was seen at 4, 8 and every 6 months until age 5 years with data including motor and intellectual development. From age 7 years, all children were invited annually for neurobehavioral assessment (including IQ). A pilot project was carried out to measure cord-mercury wet-weight concentrations12, and frozen cords are available from 7,500 subjects to link to the outcome parameters already available.
Because cord tissue has been collected from over half of the children, and because the mercury concentration in the umbilical cord is an excellent biomarker of prenatal exposure levels13, the opportunity exists to assess the developmental mercury exposure level to determine its possible impact on highly relevant neurodevelopmental functions, and the possible interaction with beneficial effects of maternal fish intake.
The specific aims of this project are therefore: to determine if methylmercury-associated cognitive deficits are present at low-level prenatal methylmercury exposures and remain detectable through to adolescence;
- to examine whether intake of fish containing beneficial nutrients affect the same outcomes and counterbalance the methylmercury-associated deficits; and
- to identify other behavioral outcomes that are linked to prenatal methylmercury exposure for possible consideration in future research.
B553 - FAVOUR Fruit and Vegetables for our children FP7 - 11/09/2007
FAVOUR work package 4
Epidemiological investigations of impact of fruit and vegetables introductions at weaning on subsequent intake
Data analysis of existing longitudinal studies - ALSPAC, DONALD
Objectives Statistical analysis of fruit and vegetable eating in childhood in relation to early introduction of fruit and vegetables
Exploration of the relationship of socio-economic background to early feeding and later intake of fruit and vegetables
Description of work
ALSPAC: The Avon Longitudinal Study of Parents and Children (ALSPAC) was devised specifically to determine the ways in which the environment influences the health and development of the child (Golding et al,2001; http://www.alspac.bris.ac.uk/). Detailed information was collected regarding weaning practice and records of the child's food/drink intake were kept at repeated time points. During infancy, mothers completed questionnaires covering the age of introduction and types of weaning and family foods given to the child (at ages 6 and 15 months). Frequency of intake of fruit and vegetables was assessed by questionnaire at age 7 years. Preliminary analysis of this data has shown that children introduced to raw and home-cooked fruit and vegetables by 6 months of age ate fruit and vegetables more often at age 7 years than did those introduced to ready-prepared foods. More detailed food and drink record data were collected using 3d unweighed diaries from 750 to 1000 of the children at 4, 8, 18 months, 3.5, 5, 7 and 10 years. A complete range of foods and drinks consumed at each age is available as well as socio-economic background.
DONALD: The DONALD study is an ongoing open cohort study with about 40 new infants recruited every year. Currently there are 750 children and adolescents taking part. Dietary assessment has been conducted in the DONALD study as 3d weighed dietary records at ages 3, 6, 9, 12, 18, 24, 36 months. Food consumption is broken down to single food items including those from composite foods such as baby jars, and it is possible to distinguish between home prepared meals and commercial products at each age.For both studies, the diet records have been coded and analysed and information about food/drink and nutrient intakes including details of actual fruits and vegetables eaten is available. Children will be grouped according to fruit and vegetable weaning practice. Intakes of fruits, vegetables and other foods at each age up to 10 years will be investigated to determine the likely influence of these weaning behaviours. The socio-economic position of the families will be taken into consideration to determine the influence of these external factors on weaning practice. At each of the two cohorts a research nutritionist will be employed to carry out this work. The work will complement the results of the intervention study in work package 3.
Task 4.1 Assembly of dietary dataset covering weaning and later childhood diet Incorporate data from diet records from various timepoints covering nutrients and foods/drinks consumed. Create groups of subjects according to their fruit and vegetable weaning practice at 6 months.
Task 4.2. Linking of dietary dataset to socio-economic background variables. Compile socio-economic background data including educational level and age of mother, housing tenure, marital status and incorporate into dietary dataset
Task 4.3. Establishment of protocol for statistical analysis. Provide descriptive statistics of fruit and vegetable intakes at various ages and discuss with partners to establish protocol for the statistical analysis
Task 4.4. Statistical analysis. Determine amount of fruit eaten at each age in relation to eating raw fruit, home cooked, and ready-prepared fruit. Determine amount of vegetables at each age in relation to eating raw vegetables, home-cooked vegetables, and ready-prepared vegetables by 6 months.Investigate differences in nutrient intakes at each age according to type of fruit and vegetables introduced by 6 monthsInvestigate differences in other food/drinks consumed at each age according to type of fruit and vegetables introduced by 6 months
Task 4.5 Adjustment for socio-economic influences. Investigate the influence of socio-economic position on fruit and of vegetable eating at each age in relation to weaning practice.
B548 - Outcomes of moderately premature infants born at 33-36 weeks of gestation - 10/09/2007
No outline received
B549 - Birthweight and subsquent levels of glucose and insulin a quantitative systematic review of published evidence - 06/09/2007
Background:
Early life exposures have been hypothesised to affect subsequent levels of glucose and insulin. We aim to draw together all of the research done to date looking at this possible relationship in all normal populations in both children and adults.
Scientific hypothesis:
That there is an association between birthweight and subsequent levels of glucose and insulin.
Objectives:
To establish the difference in mean levels of fasting and post load glucose and insulin per one Kg increase in birthweight. We also wish to examine the effect of potential modifiers and confounders.
Methodology and planned statistical analyses:
The first stage is to identify all studies with published reports on the relationship between birthweight and subsequent levels of glucose and insulin in general populations of both children and adults. Investigators will be asked to provide data (preferably) or to carry out pre-defined analyses. Individual study data will be analysed with multiple logistic regression to obtain estimates for the differences in glucose and insulin that are associated with a 1 kg increase in birthweight, based on the full range of birthweights for each study. Models will be fitted without adjustment and then with additional adjustments for
* age and (if appropriate) gender
* for social class
* current body mass index
Analyses will also examine the effect of excluding subjects with
* birthweights greater than 4kg
* maternal diabetes.
The estimates will then be included in meta-analyses, carried out using fixed-effects modelling if there is not appreciable evidence of heterogeneity.
B544 - The lifecourse determinants of oral health in a contemporary birth cohort - 31/08/2007
No outline received
B542 - A study of psychosis-like symptoms PLIKS in 17-year old adolescents in ALSPAC - 30/08/2007
AIMS The aim of this proposal is to examine risk factors for developing psychosis-like symptoms (PLIKS) during late adolescence within a population-based birth cohort. Furthermore, we will examine factors affecting persistence of PLIKS throughout adolescence, and the pathways from developing PLIKS in early adolescence through to disorder (PLIKS with concurrent functional impairment) in late adolescence, focusing on both risk and protective factors that are likely to be operating along this trajectory. More specifically, the aims of this proposal are:
1) To carry out an interview-based assessment of PLIKS, along with measures of functional impairment, in order to determine the prevalence and distribution of sub-clinical PLIKS, and of PLIKS related disorder (PLIKS and concurrent functional impairment) in 17-year olds.
2) To investigate whether established risk factors for adult onset psychotic illness (maternal exposures during pregnancy, pregnancy and birth complications, social relationships during childhood and adolescence, social cognition, emotional experiences, cognitive ability, substance use, and genetic variation) alter risk of developing PLIKS at age 17, or impact upon persistence of symptoms (from assessment at age 12 through to age 17 assessment) or transition into PLIKS related disorder.
3) To further refine and increase the validity and positive predictive value of a self-rated questionnaire-based assessment of PLIKS by comparing self-reported responses to structured questions with observer ratings of PLIKS from a semi-structured interview
B541 - Role of PHLDA2 in fetal growth - 29/08/2007
The Objective
Understanding the basic molecular mechanisms for growth in utero will eventually lead to prevention or therapy for intrauterine growth restriction (IUGR). Our group and others have shown that imprinted genes have an important role in fetal growth both in mouse and man (1). Some of these genes are imprinted in the placenta and their role appears to be linked to successful nutrient transfer, which is vital for normal fetal growth (2). The objective of this proposal is to follow up our study on the maternally expressed PHLDA2 imprinted gene and its promoter region. The expression of PHLDA2 in the placenta has been negatively correlated with growth (3). Recently we have found a deletion polymorphism in the PHLDA2 promoter region that exhibits a trend implicating a role in its growth suppressing function.
B545 - Prediction of Drinking Outcomes in ALSPAC An Update - 28/08/2007
?SEQ CHAPTER h
1Our overall goal is to add a limited number of additional variables to our current data analyses using the ALSPAC data. We currently have information on the level of response to alcohol and demography at age 12-13, know the outcome regarding a limited number of alcohol-related variables at age 14-15, and have models of how the level of response to alcohol relates to alcoholic outcomes in teenagers and adults from several additional studies (the Collaborative Study on Genetics of Alcoholism, the San Diego Prospective Study adults, and the San Diego Prospective Study adolescents). However, to date none of these structural equation models have been tested in subjects in their early teens. Therefore, if several additional areas of data can be made available to us within the next week or so, we will be able to test whether aspects of the structural equation models generated in late teenagers and adults apply to the ALSPAC population using predictors from age 12-13. The published structural equation models have utilized both the MPlus approach and the AMOS programs as described in the references offered below. To carry out these analyses, we would be grateful for any of the following variables as an update to the data already supplied to us in June 2007.
B536 - When to have another baby An event history analysis of the reproductive decisions of contemporary British mothers MERGED WITH B535 - 20/08/2007
Aim:
Using existing ALSPAC data this project will model social, economic and demographic measures as risk factors for having another baby over the following decade. ALSPAC provides an unusually detailed dataset to consider these questions, providing regular time varying data on a range of relevant variables. Accordingly, multilevel event history models will be utilised to gain a uniquely sophisticated longitudinal analysis of the determinants of fertility. The project aims to appraise current theories of reproductive decision making grounded in evolutionary and economic theories of fertility (e.g. Kaplan et al., 2002; Mace, 2007) and further promote integration between these two frameworks.
B535 - Contact with kin childhood development trajectories in contemporary Bristish families MERGED WITH B536 - 20/08/2007
Aims:
Grounded in evolutionary life history theory (Mace and Sear, 2005), the proposed research will examine the wider rearing environment of British children as a determinant of social and physical development trajectories, using the Avon Longitudinal Study of Parents and Children cohort (ALSPAC - children born in 1991/92). A previous study on this cohort has already identified a distinction in the impact of informal friend or kin-based care vs. paid care in determining cognitive outcomes by age 7 (Gregg et al., 2005) The proposed research takes a broader focus considering a wider range of development outcomes, over a longer period, and crucially will involve a more precise categorisation of contact with kin and investments by kin, informed by evolutionary demography. Outcome variables will include childhood malaise, growth, cognitive development and pubertal timing. ALSPAC provides an unusually detailed dataset to consider these questions, providing regular time-varying data on a wide range of relevant variables. Accordingly, multivariate multilevel models for change (Singer and Willet, 2003) will be utilised to gain a uniquely sophisticated longitudinal analysis of the role of contact with kin in childhood well-being.
B538 - Effects of BDNF and ACE genes on normal variation in cognitive function - 14/08/2007
The project would be two genetic association studies assessing the effects of variations in two genes (BDNF and ACE) on normal variation in cognitive function in ALSPAC. This would be an extension of our previous, successful collaboration in which we have investigated the effects of SNPs in the COMT, 5HTTP and MAOA genes (Barnett et al 2007). Analyses are hypothesis-driven (see below). Outcome measures would be cognitive scores from ages 8 (attention and IQ) and ten years (working memory). Genotype data would be required for the ACE and BDNF genes, which we understand has already been completed in the cohort.
Brain-derived neurotrophic factor (BDNF) is one of the group of neurotrophins which affect cell survival, axonal and dendritic growth and synaptic plasticity among dopaminergic and other neurons (Bath and Lee 2006). The BDNF gene on 11p13 contains a common Val-Met substitution at codon 66. The Met allele is associated with smaller hippocampal volume (Pezawas et al 2004; Szeszko et al 2005) and better memory (Egan et al 2003; Hariri et al 2003; Dempster et al 2005; Tan et al 2005; Ho et al 2006) but not attention, processing speed, language or planning abilities (Ho et al 2006). The relative rarity of Met/Met homozygotes (about 4% of the US population, (Shimizu et al 2004)) means that the cognitive status of Met/Met individuals is effectively unknown. There have been no studies, to our knowledge, of the effect of BDNF genotype on children's cognitive function, despite the obvious importance of BDNF in neurodevelopment.
Angiotension-converting enzyme (ACE) is a central enzyme of the renin-angiotensin system (RAS) and is primarily involved in blood pressure regulation. It is widely distributed throughout the brain, and particularly associated with cerebral blood vessels, and astrocytes of the periventricular nuclei. Raised RAS activity through elevated ACE is thought to impair cellular metabolism (Williams et al 2000) and amplify free radical and pro-inflammatory responses (Harding et al 2005). ACE may therefore play a role in neurodevelopmental progress and subsequent cognitive development (Harding et al 2005) as well as late-life cognitive decline (Amouyel et al 1996). This hypothesis is supported by demonstrations that ACE inhibitors improve cognitive function (Amenta et al 2002; Tzourio et al 2003).
The ACE gene on 17p23 contains a 287bp insertion/deletion polymorphism in intron 16. Both tissue and circulating ACE levels are higher in individuals with two copies of the deletion allele (Tiret et al 1992). The insertion allele appears to confer a slightly increased risk for Alzheimer's disease (Narain et al 2000) while the deletion allele has been repeatedly associated with increased risk for age-related cognitive impairment and dementia (Amouyel et al 1996; Palumbo et al 1999; Bartres-Faz et al 2000; Richard et al 2000; Stewart et al 2004). Deletion allele carriers are reported to show greater cognitive impairment in moderate and severe traumatic brain injury (Ariza et al 2006), less improvement after shunt surgery in normal pressure hydrocephalus (del Mar Matarin et al 2005), and reduced cognitive impairment in alcoholism (Bartres-Faz et al 2002). However three epidemiological studies have found no associations between ACE genotype and normal cognitive ageing (Visscher et al 2003, Frederiksen et al 2003, Yip et al 2002). Two studies have investigated the effects of ACE genotype on cognitive function in children (Gao et al 2006, Harding et al 2005). Both studies were negative, however both were limited by sample size and by the relatively crude cognitive measure they employed.
B537 - HOPE Project - 14/08/2007
HOPE Project (http://www.hopeproject.eu/)
Work Package 3 (WP3): Early Childhood Obesity Prevention.
Objectives:
1. To describe differences in prevalence and trends in overweight and obesity across Europe in infants and preschool children.
2. To identify specific obesogenic nutrition and physical activity patterns in infants and preschool children across Europe.
3. To identify family-environmental determinants of overweight and obesity including types of feeding, weaning practices, optimum activity learning techniques in infants and preschool children across Europe.
4. To produce a checklist for good quality interventions, as a means of strengthening the evidence base regarding effectiveness of interventions.
B543 - The communicating teenagerInvestigating the role of language and literacy in the employability and social success of the young people of ALSPAC - 10/08/2007
The overall aim is to investigate the role that language and literacy play in the educational and social functioning of young people as they enter adulthood and to identify factors and processes that are associated with positive and negative outcomes. Four work streams will focus on particular objectives as follows: 1. To identify risk and protective factors associated with language and literacy outcomes. In particular we will identify: how speech, language, literacy and cognitive variables cluster and change during childhood; to what extent do language learning and literacy difficulties persist to school leaving age predictors of language and literacy performance at school leaving age; mechanisms and characteristics by which social class impacts upon children's language and literacy during preschool, primary school and at school leaving. 2. To identify the relationship between young people's current and past performance in language and literacy and their decisions about social activities, further education and future employment as they leave school. We aim to identify the patterns of social, educational and employment outcomes at school leaving age that are related to different language learning and literacy trajectories; social conditions that predict young people's perceptions of their own functional language and literacy performance and outcomes. 3. To identify the prevalence of conduct and behaviour disorders, risk taking and criminal offending behaviours in relation to young people's current and past performance in language and literacy. In particular we will identify any subgroups of speech, language and literacy deficits that are associated with raised occurrence of psychopathology and /or conduct disorders and at what age the mental health impact become apparent. 4. To identify the current and predicted social costs and return on investment to society as a whole from support of children's language and literacy skills development through professional involvement of speech and language services. Particular objectives include: What is the relationship between GCSE performance outcomes and the level of support in childhood for language and literacy skills development and how does this translate to economic resource savings in the UK economy? To identify whether children with language and literacy difficulties who have received support in childhood through the professional involvement of speech and language services choose higher skill occupation destinations than who have not received such support and, if so, what are the social costs incurred? To identify the economic benefits in monetary terms of professional involvement in language and literacy skills support for emotionally and socially vulnerable young people. Finally it is also an objective of the project to create an archive of the language samples from 5, 8 and from the young people at 17+.
B531 - Combined depression and head injury at 17 - 10/08/2007
B484 - Physical activity and depression in mothers from a community ALSPAC sample - 24/07/2007
This study aims to use the ALSPAC data to examine the association between risk of a 'high depressive symptom score' and levels of physical activity during pregnancy. The ALSPAC data is ideally suited to address this question as it has an appropriate measure of exposure, at more than one time point, an outcome measure that has been accepted in previous publications and a longitudinal, prospective design.
B527 - Depression at 17 - 17/07/2007
Depression in adolescence is important for a number of reasons. First, there is a high risk of recurrence in adulthood. Evidence from both clinical1 and community2 studies finds that adolescents with depression are more likely to have depression as adults. For example in Lewinsohn's Oregon study2 45% of 16 year olds with depression had a recurrence before the age of 23 (odds ratio 3.2 compared to no disorder). Second, once a person has had an episode of depression, it seems that future episodes are easier to provoke.3 In other words, successfully preventing the first episode of depression in adolescence might have much greater public health benefit than preventing recurrent episodes in adulthood. Third, adolescence is a critical period of life and can interfere with educational attainment and have detrimental effects on future occupation and the stability of future relationships4. Finally, self-harm is common in young people with depression5 and is associated with a substantial risk of suicide.
We propose to study depression at age 17 years in the Avon Longitudinal Study of Parents and Children (ALSPAC), a large birth cohort based in Bristol. Results from the ONS Longitudinal study suggest that the peak incidence of depression and anxiety occurs in young people6 in contrast to the prevalence that is higher in middle age. Depression has been measured before in ALSPAC, and the last occasion was at 15. However, the rates of depression are increasing rapidly at this age and the current proposal will allow investigation of a number of hypotheses by carrying out an assessment of depression at 17 years. It will also allow us to investigate psychological vulnerability factors for depression.
B522 - Does the FTO genotype interact with dietary energy density in the causation of obesity in children - 17/07/2007
Appetite is tightly controlled by internal physiological mechanisms in younger children but a decline in the degree of innate appetite control is observed with age 1-3. It has been postulated that external factors, such as palatability of food, begin to influence internal controls and ultimately override satiety signals 4. The energy density of food has been shown to increase energy intake and short term weight gain in experimental studies 5. Energy density is closely related to the palatability of a food and may disrupt appetite control by over stimulating sensory centres in the brain, which process information on texture and taste of food. An association between fat mass and the FTO gene has recently been identified 6. No functional information about the FTO gene is currently available. Human tissue panel expression studies showed that the FTO gene was most highly expressed in the brain, specifically the cerebral cortex, which may implicate a role in the sensory centres, located in the prefrontal cortex.
I hypothesise that the relationship between dietary energy density and obesity, which we have shown to vary by age in the ALSPAC sample 7, may also vary by the FTO genotype, such that children carrying the high-risk allele A will have a stronger relationship between energy density and obesity than those without. Since the relationship between the FTO gene and BMI z score also appeared to get stronger with age this may be explained by age related changes in appetite control in response to energy dense foods. So I would hypothesise further that the interaction between FTO and energy density on obesity may also get stronger with age.
Data requirements:
This analysis would require access to existing data at ALSPAC from direct assessment and biological samples including:
- Dietary energy density from diet diaries at age 10 years
- Genotype for FTO gene
- Fat mass from DXA at age 13 years
- Height measured at age 13 years (In order to adjust fat mass for height)
The proposed work would be split between MRC HNR and ALSPAC. Laura Johnson, at MRC HNR, would generate the dietary energy density variable from the dietary data at age 10 years. This variable would be checked and cleaned by Laura and sent to ALSPAC. Nick Timpson, at ALSPAC, would perform the analysis of association between the FTO genotype, dietary energy density and fat mass. Laura Johnson would then write up the results of the analysis in a paper.
The plan of analysis to test the hypothesis would be to initially inspect the data for potential associations using cross tabs. If there is evidence for an association then a linear regression should be performed with fat mass (adjusted for height) as the dependent variable and the FTO gene, dietary energy density (DED) and FTO*DED interaction term as independent variables.
If there is evidence for an interaction then a linear regression analysis of fat mass and DED stratified by genotype would be done in order to test the hypothesis that the relationship between DED and obesity is stronger in children with the A allele. Further analysis could include a logistic regression with obesity (the top quintile of fat mass adjusted for height) as the dependent variable and the FTO gene, dietary energy density (DED) and FTO*DED interaction term as independent variables. Followed by stratification by genotype if evidence of an interaction is found.
Calculations in Quanto (http://hydra.usc.edu/gxe/) indicate that using a sample of 5000 children there is a power of 0.99 to detect a true positive effect, using the following parameters to estimate power:
For the continuous outcome fat mass index (kg/m5.8);
Risk allele (A) frequency = 0.39
Mode of inheritance = additive
Dietary energy density standard deviation = 1.5 kJ/g
Fat Mass Index mean = 1.21 kg/m5.8, standard deviation = 0.63
Main effect sizes
Gene B = 0.1 kg/m5.8 per A allele
Diet B = 0.05 kg/m5.8 per 1kJ/g
Gene*Diet B = 0.05 to 0.15
N = 5000
Power for all G*E effect sizes between 0.05 and 1.5 was 0.99, meaning that it should be possible to detect an interaction effect as small as 0.05 kg/m5.8
B521 - Diagnosing Autistic Spectrum Disorders Health and Social Implications - 10/07/2007
It has been argued that diagnosis of learning disorders including those associated with ASD involves stigmatisation and is therefore not desirable.1,2, 3 Parents have claimed that the social factors involved in identification, interpretation and remediation determine what it means to be autistic.4 On the other hand many clinicians, health practitioners, educators and parents have argued that ASD is partly genetically determined and diagnosis is essential as young as possible to treat and manage the condition.5,6 In order to address this debate we examine whether diagnosing ASD in children leads to a deterioration or improvement of the condition over time as compared to an undiagnosed group with similar social awareness skills, using ALSPAC data.
How parents perceive diagnosis of ASD at the point of diagnosis has not been studied. To address this, a qualitative study will examine what triggers parents to ask for diagnosis, and how parents, who receive or do not receive a diagnosis, view the diagnosis of the condition and construct their own explanations and causes for it. These views will be mapped on to the views of experts to examine any differences of perspective that may exist to highlight how parents and professionals can best work together to help the children.
B525 - Determining the causal effect of vitamin D on perinatal metabolic vascular and bone health - 08/07/2007
This grant will be submitted as DA Lawlor's main MRC programme grant for 2008 as part of the MRC Centre for Causal Analyses in Translational Research. It is concerned with determining the causal effect of vitamin D on perinatal outcomes (gestational diabetes, pre-eclampsia, variations in blood pressure during the antenatal period, intrauterine growth retardation, preterm delivery), vascular outcomes (variations in blood pressure, endothelial function, carotid intima media thickness), metabolic outcomes (variations in fasting glucose, insulin, pro-insulin, lipids) and skeletal health (variations inpeak bone mass and fracture risk in later lifeassessed by DXA scan andcortical bone geometry, and hence bone strength assessed bypQCT). Data from ALSPAC offspring and mothers other relevant studies that are linked to the MRC Centre for Causal Analyses in Translational Epidemiology (CAiTE) will contribute to the programme. Our specific objectives are:
1. To use bioinformatics and genome wide association studies to identify genetic variants that are associated with vitamin D levels.
2. To replicate the association of these variants with vitamin D levels in ALSPAC mothers and offspring.
3. To use the genetic variants, identified in 1 and tested in 2 above, as instrumental variables to determine the causal effect of vitamin D on perinatal outcomes (gestational diabetes, pre-eclampsia, variations in blood pressure during the antenatal period, intrauterine growth retardation, preterm delivery)using data from ALSPAC, Danish National Birth Cohort, the Norwegian Birth Cohort and the Born in Bradford Cohort.
4. To use the genetic variants, identified in 1 and tested in 2 above, as instrumental variables to determine the causal effect of vitamin D on vascular outcomes (variations in blood pressure, endothelial function, carotid intima media thickness)using data from ALSPAC (offspring and mothers), the Cardiovascular Risk in Young Finns study, the 1958 UK birth cohort and other CAiTE based adult cohort studies with these measurements.
5. To use the genetic variants, identified in 1 and tested in 2 above, as instrumental variables to determine the causal effect of vitamin D on metabolic outcomes (variations in fasting glucose, insulin, pro-insulin, lipids)using data from ALSPAC (offspring and mothers), the Cardiovascular Risk in Young Finns study, the 1958 UK birth cohort and other CAiTE based adult cohort studies with these measurements.
6. To use the genetic variants, identified in 1 and tested in 2 above, as instrumental variables to determine the causal effect of vitamin D on skeletal outcomes(variations inpeak bone mass and fracture risk in later lifeassessed by DXA scan andcortical bone geometry, and hence bone strength assessed bypQCT). Data from ALSPAC mothers and offspring will be used for this objective.
B524 - Linkage of polymorphisms of PMCH with asthma and obesity - 08/07/2007
Th1 and Th2 cells are the two main subsets of CD4+ T helper cell and are defined by their cytokine expression patterns. The subsets have different roles in the clearance of pathogens, and their unregulated activation leads to distinct immune pathologies. Th1 cells express IFNgamma and are crucial for the phagocytic immune response against intracellular pathogens such as M. tuberculosis, but their aberrant activation is implicated in autoimmunity. Human Th2 cells express IL-4, IL-5 and IL-13 and orchestrate an immune response characterized by eosinophilia and IgE class-switching, in order to fight extracellular pathogens. Th2 cell activation is also central to the pathogenesis of allergic diseases such as asthma, in which the Th2 cytokines play important roles.
PMCH encodes a pro-hormone, pro-melanin concentrating hormone (PMCH) of 165 amino acids which is proteolytically processed to form several peptides including the orexigenic peptide melanin concentrating hormone (MCH). PMCH was first implicated in the regulation of appetite by the finding that the gene is upregulated in obese, leptin deficient mice. Further studies demonstrated that intracerebroventricular administration of MCH into rats increases feeding, and weight gain occurs after chronic infusion of the peptide into the lateral ventricle, strongly suggesting that the peptide stimulates appetite. In addition, mice deficient in MCH are lean and hypophagic, and animals overexpressing the gene are obese. Several groups cloned the G-protein coupled receptor for MCH termed MCHR1, and MCHR1 deficient mice are resistant to diet induced obesity. A second receptor, MCHR2, was later identified in humans by its homology to MCHR1. MCHR2 is not present in the rodent genomes, but orthologues have been identified in ferret, dog and rhesus monkey, in addition to the human gene. PMCH therefore has an important role in increasing appetite, and a small molecule antagonist of MCHR1 has been shown to reduce feeding and weight gain in rats fed a high fat diet ad libitum.
The prevalence of both asthma and obesity are increasing in the western world, and a link between the two conditions has been proposed and debated. Epidemiological evidence from several studies suggests a positive association between body mass index (BMI) and asthma, especially in females (1). Mechanisms to explain the association are unknown.
Utilizing microarray analysis of in vitro differentiated Th1 and Th2 cells to identify secreted proteins selectively expressed by human Th2 cells, we found for the first time that activated Th2 cells expressed the gene PMCH. Activated Th2 cells secreted MCH-containing proteins, and ex vivo Th2 but not Th1 cells also expressed the gene.
PMCH gene is located on chromosome 12q23.1, a region consistently shown to have linkage to asthma. We hypothesize that expression of PMCH by Th2 cells in vivo in the asthmatic lung may provide a mechanistic link between allergic inflammation, asthma and obesity. Asthmatic individuals are not necessarily obese, however, therefore we wish to test whether there are genetic polymorphisms of PMCH that are associated with both asthma and obesity. As expected, a positive association between BMI and asthma in girls at 7 years of age has been confirmed in ALSPAC (AJ Henderson, unpublished data).