(No outline received).

(No outline received).

(No outline received).

This project will address the question of health inequalities, by addressing the relationships between measures of socio-economic deprivation and respiratory health, particularly wheezing illnesses, asthma and lung function. The first part of the study will focus on the detailed information on respiratory health and socio-economic factors in the Avon Longitudinal Study of Parents and Children (ALSPAC) to determine the association of socio-economic deprivation and respiratory outcomes during childhood. We will further investigate these associations by attempting to identify explanatory variables, including lifestyle (smoking, diet) and environmental exposures. Observed associations will then be examined using a lifecourse epidemiological approach to investigate whether associations that we observe in a contemporary population of children (ALSPAC) are reproducible across previous generations in the United Kingdom and whether deprivation in childhood is associated with adult respiratory outcomes, independently of adult socio-economic status. In turn, this will allow us to explore the possible effects of social mobility on adult respiratory health. The project brings together expertise on the analysis of inequalities in health from an economics perspective, with a focus on measures of access to resources, and the exploitation of dynamics in data and the use of GIS tools to map local features to individuals (in the Department of Economics), childhood respiratory epidemiology, including assessment of asthma and lung function in a longitudinal birth cohort sample (Department of Community-based Medicine) and the multidisciplinary specialty of lifecourse epidemiology, including access to archived information on other existing cohorts (Department of Social Medicine). Therefore, this is a unique opportunity to build a global, comprehensive picture of the factors associated with socio-economic deprivation in the U.K. and their potential effects on an important aspect of public health.

We wish to use the ALSPAC study to investigate the effects of type 2 diabetes susceptibility variants at the KCNQ1 locus on fetal growth, growth in childhood and intermediate traits related to type 2 diabetes.

Recently, two genome-wide association (GWA) studies of East Asian subjects simultaneously reported a strong association between variants in the KCNQ1 gene and the odds of type 2 diabetes [1, 2]. The effect size estimates were large (OR 1.3-1.4) and the associations were robust, exceeding stringent criteria for statistical significance appropriate to GWA studies (Pless than 5x10-8).

This association had not been identified previously in European GWA studies due to the lower allele frequency (5% vs 40%) and consequently reduced power [3]. However associations were observed in European samples following the East Asian GWA studies, and the effect size estimates were consistent [1-3]. The index SNP, rs2237895, has also shown detectable effects on beta cell function in Europeans [4].

The associations with type 2 diabetes and beta cell function make the KCNQ1 locus an excellent candidate for influencing early growth. A variant that predisposes to reduced insulin secretion and diabetes in adulthood may also influence insulin secretion/action in utero, and thereby reduce birth weight [5]. Our preliminary data on the CDKAL1 and HHEX loci support this (PLoS Med, under review). Maternal diabetes genes may additionally influence birth weight through their effects on the intrauterine environment [6]. We have observed that the maternal risk alleles for fasting glucose and type 2 diabetes at GCK and TCF7L2, respectively, are associated with higher offspring birth weight [7, 8].

The KCNQ1 locus is of additional interest in relation to early growth because the locus is imprinted and may harbour elements that influence the imprinting of neighbouring genes [9, 10]. The region is implicated in Beckwith-Wiedemann syndrome and Silver-Russell syndrome, rare neonatal disorders of fetal overgrowth and growth restriction, respectively.

We therefore propose to analyse the polymorphisms in ALSPAC to test the following hypotheses:

1. Fetal genotype and maternal genotype are associated with fetal growth.

2. Fetal genotype and maternal genotype are associated with growth phenotypes (height, BMI, growth velocity) in childhood

3. Offspring genotype is associated with diabetes-related traits in childhood including fasting insulin, fasting glucose and insulin secretion (in the subset of offspring with OGTT data), triglycerides, HDL, LDL and total cholesterol, anthropometric measures including BMI, lean/fat body mass, WHR, waist circumference, skin folds where available.

4. Due to imprinting, association between the risk allele in the offspring and early growth is dependent upon the parent of origin (we will be able to assess this using informative mother-offspring pairs).

Whether the results are negative or positive they will help our understanding of how the KCNQ1 variants function and, if positive, provide important insights into growth and other diabetes-related phenotypes.

To do this we would like to genotype (at Kbiosciences) all ~20,000 ALSPAC samples. We will need the following phenotypes to test our hypotheses (a detailed list is in the next section):

1. Birth weight, length and head circumference

2. Growth measures in childhood (height, weight and BMI aged 7-11)

3. Covariates of birth weight to check if genotype is acting through them: gestational age, maternal age, maternal BMI, smoking , parity, twin status to exclude non-singletons, ethnicity as genotype frequency may alter with ethnic origin and confound analyses.

4. Type 2 diabetes-related intermediate traits including fasting insulin, fasting glucose and insulin secretion (in the subset of offspring with OGTT data), triglycerides, HDL, LDL and total cholesterol, anthropometric measures including BMI, lean/fat body mass, WHR, waist circumference, skin folds where available.

Plans for meta-analysis:

ALSPAC will provide the largest European-ethnicity dataset for association studies with fetal growth. However, we have access, through our own studies and extensive collaborations to samples from the Exeter family study (950 population based parent-newborn trios), the Northern Finland 1966 Birth Cohort (4600 individuals with own birth measures) and the Hyperglycemia and Adverse Pregnancy Outcomes study (4000 European mother-offspring pairs; 2000 Thai/Chinese mother-offspring pairs; 1250 African-Caribbean mother-offspring pairs; 2500 other ethnicity). We hypothesize that real genetic associations will be consistent across all of these studies - i.e. even if individually studies show only nominal significance, a meta-analysis of all studies will provide highly significant results.

Infant malnutrition is a major problem on the South Asian subcontinent. Rates of malnutrition and stunting are very high in South Asian societies. Interestingly, some evidence suggests that this phenomenon may be influenced by cultural factors. These include infant feeding practices such as a use of the supine position, feeding while sleeping, the prolonged use of the bottle, delay of protein and adult food. Other cultural factors that may influence this phenomenon have to do with the low status of women in South Asian societies. Maternal depression has been strongly linked to infant malnutrition; furthermore, female infants and children are far more likely than males to experience malnutrition and related diseases and problems, and to die before reaching the age of five. The problem of childhood malnutrition, while grave in itself, may also increase vulnerability in the South Asian population to the later development of obesity and metabolic-related problems such as diabetes.

There has been very little study of this phenomenon in communities of the South Asian diaspora, including immigrants from India, Pakistan, and Bangladesh. Such research is important. Comparative research is especially crucial in this regard, since it could permit the identification of culture-specific practices and behaviors that might be amenable to modification. Our research team has considerable experience working in the New York City South Asian community (and, mention your stuff). We would like to develop a research intervention to assist South Asian families in this regard. However, to develop and fund pilot work, we would like to present preliminary data indicating the features, correlates, and prevalence, of infant and child malnutrition in South Asians. Comparative research which shows that some practices and behaviors are especially common or uncommon among South Asian families, will be particularly helpful in this regard.

We propose to conduct a secondary analysis of ALSPAC data. The 82 families of South Asian origin will be compared to 82 families of white-European background. We will select a comparison group matched on factors such as: housing status, parity, maternal and paternal education, gestational age at birth, and birth length.

We will compare the South Asian and control groups with regard to the primary outcome variables related to growth, e.g.,: BMI, height- Z scores, and head circumference Z scores. Secondary outcomes will include the longitudinal parent-reported feeding measures of: difficulty feeding, being choosy with food, not intaking a sufficient amount of food. Co-variates will include measures of; matenral depression, sociodemogrphics, child gender, parenting scores (i.e. HOME), etc.

Note, no new data are requested. We will conduct analyses with the dataset we already have, and will not require ALSPAC assistance.

AIMS

To test this hypothesis we propose to assess the sensitivity, specificity, positive predictive value, and negative predictive value of DCDC2 allelic variations for reading performance in all 10,000 DNA samples of the ALSPAC epidemiologic collection. These children have been phenotyped with an array of age-appropriate neurocognitive and reading assessments. At a minimum we will attempt to correlate genotypes with quantitative tests of basic word reading (Wechsler Objective Reading Dimension: WORD subtests49), phoneme deletion (Auditory Analysis Test of Rosner and Simon50), and spelling (regular and irregular words). These tests are administered to the ALSPAC cohort at age 7. We will also include IQ assessments at age 8 through the Wechsler Intelligence Scale for Children III51, and other cognitive measures such as language and verbal short-term memory, and Key Stage 1 School Assessments, if available. Furthermore, our on-going lab studies of the developmental biology of DCDC2 and it's role in neuronal migration, and physiology studies through functional imaging studies at the Yale Center for the Study of Learning and Attention, will suggest correlating additional age-appropriate neurocognitive and language measures that are extant in the ALSPAC cohort.

These studies will lead to the development of a sensitive and cost-effective population screening tool that will identify children at-risk for RD before entering school and help to guide strategies for effective early intervention.Moreover, when considered in the context of our parallel studies of gene function and cognitive imaging profiles, they will lead to a comprehensive understanding of the neurodevelopmental processes subserving language, which should further guide the remediation of RD and other learning disorders.

(No outline received).

Blood pressure (BP) is a key determinant of cardiovascular health, but the pathways that underlie the regulation of human BP are incompletely understood. Key to the ultimate development of fully effective preventive and management strategies for high blood pressure, both at an individual and population level, will be a comprehensive understanding of the relevant biological pathways. Studies of environmental and genetic risk factors can inform this understanding, and current approaches recognise the importance of both. Recognised environmental determinants of BP include obesity, salt intake and excessive alcohol consumption. Familial aggregation of BP has long been recognised, and estimates of the heritability of systolic and diastolic BP have exceeded 50%. The identification of genes involved in BP regulation, by improving knowledge of the relevant biology, should facilitate advances in treatment and control of BP. The study designs employed in such studies need to account for the fact that BP is a complex trait. That is, it is caused by multiple genetic and environmental determinants that may interact in complex ways.