Aims:

1) To assess the how alcohol consumption affects metabalomic profile

2) To identify a genetic instrument for metabolites that are associated with alcohol consumption

Title: analyse the evolution of fruit and vegetable intake frequency of children from infancy to 15 years, segmenting by household socioeconomic status (SES) and parental attitudes.

Specific objective: the aim of the analysis is to explore trends in intake (amount and frequency) across children's ages in years to evaluate the possibility of tracking of food habits (specifically fruit and vegetable intake), and any trends in changes in intake along the child's lifecycle (e.g. frequency of intake tends to drop/rise at the age of X). The idea is to construct different series of average intake by socioeconomic groups, and by mothers' attitudes to fruits and vegetables and eating in general. The analysis of segmentation by socioeconomic group and attitudinal variables will be helpful not only in illustrating any difference in starting points in fruit and vegetable intake when children are categorised according to these variables, but also any persistence and/or broadening of inequality as children grow older.

Broader objective: secondary data analysis of trends in children's fruit and vegetable intake by socioeconomic grades and mothers' attitudes as part of the research agenda for a PhD project on Consumer Behaviour and Associated Change Drivers and Barriers in the Consumption of Fruits and Vegetables by Children.

Methods: graph plotting average and median intake (y axis) against age (x axis) for categories by SES (quintiles or tertiles of SES) and mothers' attitudinal characteristics. Statistical analyses (paired t tests and correlations) to test for tracking of food habits (Skinner et al. 2002).

With regards to children with cerebral palsy, very little information about attainment of urinary continence is available. The long-term physical, psychosocial and financial burden of incontinence in the cerebral palsy patient is considerable and in order for the paediatrician to begin addressing these important issues further information regarding the normal attainment of bladder control in children with cerebral palsy has to be established. This is the aim of this study.

METHODS

The original study:

The data in this study originate from a previously published population based study (Scrutton and Baird 1997) which established a cohort of children with bilateral cerebral palsy born from 1989 to 1992 (inclusive) to mothers resident at the time of birth within the geographically defined area of the South East Thames Regional Health Authority (SETRHA) in south east England in order to monitor the children's hip development up to the age of 5 years using serial hip X-rays. It is for this reason that children with hemiplegic cerebral palsy are not included. The South East Thames Health Region at the time had a population of 3.65 million with 205 958 live births during the study period. A comparison of epidemiological data between SETRHA and England and Wales showed similarities between the two. For original methods of recruitment, details of ethical permission and consent, and diagnosis of cerebral palsy the reader is referred to the original paper (Scrutton and Baird 1997).

Present study:

For the purposes of this study, a questionnaire containing details of the child's attainment of bowel and bladder control by day and night, as well as parental concerns or presence of abnormal bladder and bowel symptoms, was used. This questionnaire was administered by physiotherapists to the parents of the children sometime after their third birthdays together with other information required for the original study at that time. The parents/carers were asked to post the questionnaire back to the investigators in a self-addressed envelope. Almost all were returned between the third and fourth birthdays, although one was returned at 5 years. After 5 years of age, a visit was carried out by the original authors, mostly in the child's home together with the parents. A number of parameters were obtained during this visit including confirmation of the diagnosis of cerebral palsy, the nature of the motor disorder including distribution (quadriplegia, diplegia, double hemiplegia and paraplegia) and type (hypertonia, ataxia, involuntary movements, hypotonia and ataxic diplegia after Hagberg 1985), learning level (as ascertained from other medical or educational sources), severity of disability and the age of attainment of bladder and bowel control by day and night. For funding and practical reasons these visits were carried out between 7 to 9 years of age. A closing visit questionnaire, including further continence data was completed some time after the age of 14 years (up to age 19 years) in this cohort, in a similar manner to the above. Whilst the stated aim of this study is to establish the age of attainment of bladder control in subjects with cerebral palsy, data on bowel control have been analysed simultaneously for two reasons: availability and therefore ease of analysis together with bladder data, and the fact that bowel and bladder control are physiologically and developmentally linked, and have been shown by previous authors to follow each other sequentially (Stein and Susser 1967, Largo and Stutzle 1977, Crawford 1989).

Definitions:

Cerebral palsy has been taken to mean all non-progressive disorders of movement and posture caused by a defect or lesion in the brain by 15 months chronological age, and not part of another syndrome which has a motor component. Those with syndromes including a high risk of skeletal or joint anomalies and children whose disorder had no clinical trunk or lower-limb involvement were also excluded. Each child's paediatrician provided written confirmation of the diagnosis at 5 years of age.

Bladder and bowel control was defined as being reliably continent with socially acceptable toileting even if help was required.

Definitions of learning level, severity of disability and type (Hagberg 1989)/distribution of motor disorder are defined and classified according to the Gross Motor Function Classification System (GMFCS).

RESULTS

The results of bladder and bowel continence attainment will be presented in a longitudinal manner together with details of any abnormal patterns which will be discussed. The data collected at three years and eight years of age have already been analysed and analysis of the data available at 16-19 years of age is currently awaited. The only available control comparison group is a series of international studies which are for the large part retrospective, cross-sectional and not population based and neither are they collected from a British population with a similar birth date.

Recent advances in high-throughput genotyping technologies, coupled with the development of massive databases such as the International HapMap Project that catalogues millions of SNPs (single nucleotide polymorphisms), have set the stage for genome-wide association studies. Genome-wide association (GWA) studies are designed as two- or three phased studies. The first phase requires a dense set of hundreds of thousands of SNPs across the human genome, genotyped in a large sample of well-characterised individuals. The second and third phases aim to replicate and fine-map the most significant findings of the first phase in other large cohorts. Eventually, genome-wide association studies will identify new gene variants, previously unanticipated, that will contribute to a better understanding of the etiology of common disease and complex traits.

Our GWA study is designed for the identification of new, unanticipated gene variants that contribute to variation in obesity as well as BMI, and related traits, including age at menarche. This GWA study is undertaken as a collaboration between the MRC Epidemiology Unit and the WT Sanger Institute (Dr Ines Barroso) using a case-cohort design. The 1713 cases (defined as those with a BMI greater than 30kg/m2) and a random control cohort of 2200 individuals have been selected from the EPIC-Norfolk prospective cohort study, a population-based cohort of 25.663 men and women aged 40-79 years recruited in Norfolk, UK between 1993 and 1997. All 3913 individuals have been genotyped for two dense SNP-chips; i.e. the 500K GeneChip Mapping Sets of Affymetrix and the Sentrix HumanHap300 BeadChip of Illumina. We are currently analysing associations of this genome-wide data with obesity as a dichotomous outcome in the case-cohort study and with BMI, age at menarche and various metabolic variables as quantitative traits within the cohort study.

In order to increase the power to detect true positive signals Phase 1 will be expanded by performing a meta-analysis of two other cohorts with similar GWA phenotypic and data. We have recently established a long term collaboration with Vincent Mooser (GSK) and colleagues, who have performed a GWA study in the GSK-Lausanne cohort. The GSK-Lausanne population is comparable to the EPIC data as it is a cohort study of 6,205 Europid men and women from Lausanne, aged 35-75 years. This collaboration has a general aim to identify genes that contribute to various metabolic traits. The summary statistics from these GWA studies on these traits will be shared and meta-analysed at the MRC Epidemiology Unit.

Key to genomewide association studies is replication of the initial findings in more populations with similar characteristics. New genes identified by GWA will be taken forward for rapid confirmation studies in several large cohort studies. In addition to ALSPAC, these include a second equal sized case-cohort study within the EPIC cohort (n=3,900), the MRC-Ely study (n = 1,700), the MRC-Fenland study (currently n = 2,000), the Hertfordshire study (n = Outline 3,000), and the European Youth Heart study (n = 2,700).

Variation in fasting glucose concentration (FPG) is important for human health. In the normal range FPG is associated with risk of type 2 diabetes and ischaemic heart disease independently of obesity. In pregnancy maternal FPG concentration is an important independent determinant of birth weight in non-diabetic mothers. There is evidence that the regulation of FPG has a strong genetic component.

The main regulator of FPG concentration is the enzyme glucokinase. Our preliminary data shows that common variants in the promoter region of the glucokinase gene are associated with FPG and fetal growth. The minor allele at GCK-30, present in 30% of the UK population raises FPG by0.06 mmol/l (0.04-0.11), p = 0.003; and, when present in the mother, birth weight by 64g (25-102), p = 0.001. We have next shown that variation, further upstream (rs3757840) of the gene, and with no obvious functional role, has a similar, but independent effect on FPG.

In this project we propose to test comprehensively the hypothesis that common genetic variation in GCK alters FPG and birth weight. We will use the latest approaches for capturing the important variation across a gene together with DNA resources from 28,799 mother-child pairs. This approach will establish, if our hypothesis is true, a definitive genetic component to the aetiology of normal variation in FPG and birth weight.

Fetal growth is an important indicator of fetal well-being. The timely detection of pathologically impaired fetal growth is a prerequisite for the quality of antenal care, because of its apparent links to perinatal morbidity and mortality1, as well as adverse effects in childhood and later life2.

The prevalence of impaired fetal growth depends on the definition used. Population-based birth weight standards define 'small for gestational age' as the lowest tenth or fifth percentile, or as two standard deviations below the main birth weight for gestational age. This definition, however, includes 'natural' smallness. Therefore, it is essential to adjust for this normal variation in order to identify those infants who are pathologically small. Maternal weight, height, ethnic origin, parity and the infant's gender have all been found to be significantly associated with physiological variation in birth weight3. Professor J Gardosi developed the so-called customised growth charts, which are based on a new definition of fetal growth, thereby focussing on fetal growth potential, which takes in account the aforementioned variables (www.gestation.net).

Customised birth weight percentiles allow distinction between small, healthy newborns and those who are pathologically small3. Individually adjusted birth weight percentiles are more clearly associated with Apgar scores, perinatal outcome and neonatal morphometry indices than the unadjusted birth weight percentiles4. In this context, however, the association with long-term morbidity, such as cognitive and physical development, has never been examined.

ALSPAC is a longitudinal population-based cohort study, which includes all variables needed to analyse the long-term effects of intrauterine growth restriction on physical and cognitive health of schoolchildren.

We are writing to all the birth cohorts in Europethat we know have an interest in environment and health to ask them to participate in this coordinating action (list attached). We have already contacted quite a number of them and leaders in various projects such as GA2LEN, ESCAPE, HIWATE and they have agreed to participate. We would like you to read the text below and let us know if you are interested in taking part in this proposal. We need an answer very soon since the deadline for submission is 25 February. Besides extracting currently available information, we also hope to generate new information (but are limited to what can be done within a coordinating action and available funding) and we have proposed a number of ideas, but other ideas are welcome. Please indicate if you are interested in any asap (and correct any incorrect information), and whether you are willing to take the lead of any of the ideas/WPs.

Aims

(i) Whether changes in bone size relative to body size contribute to the increased risk of fracture during puberty will be established, by examining the relationship between longitudinal changes in these parameters across puberty.

(ii) Whether the higher risk of fracture in pubertal boys compared to girls is related to gender differences in bone size relative to body size will be determined.

(iii) Whether small bone size relative to body size represents a stable trait that once established in childhood persists following puberty will be investigated.