Background. 1) Current research has shown that atherosclerosis starts early in life. The social patterning of coronary heart disease (CHD) in adulthood is also likely to start early in life. However, knowledge of the social patterning of the pre-clinical phases of CHD (endothelial function) and its early life determinants in childhood is scarce. 2) The role of passive smoking, a potential exposure linked to the early social patterning of disease, on CHD aetiology is controversial. Applying the principle of Mendelian randomisation will allow me to investigate whether there is a link between exposure to passive smoking in childhood and measures of early-life atherosclerosis.

Objectives.

1. To systematically review the current evidence regarding social patterning of CHD exposures and pre-clinical disease indicators occurring in early life.

2. To describe the social patterning of endothelial function in childhood.

3. To describe the social patterning of CHD risk factors in early life.

4. To investigate how the social patterning of potential CHD early-life risk factors contributes to the social patterning of endothelial function in childhood.

5. To investigate whether candidate genetic polymorphisms associated with slower detoxification of tobacco smoke are associated with endothelial dysfunction among children exposed to environmental tobacco smoke.

Methods.

Systematic reviews will establish the strongest candidate factors in early life contributing to the development of atherosclerosis and social inequalities in adulthood (Objective 1).

TheAvon Longitudinal Study of Parents and Children (ALSPAC) is a unique prospective cohort study set up to investigate the health and development of children. Vascular function measures are available from at least 6,000 children and include flow mediated dilation, arterial distensibility and pulse wave velocity. DNA for genotyping was obtained from 10,232 children. Early life CHD risk factors and detailed childhood socioeconomic circumstances data are available.This will allow establishing which exposures are likely to initiate and contribute to the social patterning of CHD risk (Objectives 2 to 4).

Polymorphisms in candidate genes related to detoxification of tobacco smoke and their association with endothelial dysfunction will be assessed in the ALSPAC cohort (Objective 5).

Scientific opportunity. The ALSPAC cohort offers a unique opportunity to answer scientific questions regarding the early life determinants of disease andseveral funders have given program support to this cohort. The analyses, proposed here for the first time, will enhance the scientific return from this investment.

Public health importance This proposal will inform interventions for public health policy by identifying the early life factors that may contribute to the adult social patterning of CHD risk. In addition, it will provide evidence regarding a potential link between passive smoking and vascular dysfunction.

Severe intrapartum hypoxia is associated with neurodevelopmental disability, however little is known about the possible long-term effects of mild hypoxia during birth on subsequent neurodevelopment. Around one in 30 neonates have an initially low Apgar Score (less than 7) but recover by 5-10 minutes and the accepted view is such hypoxia can only cause later disability if the infant develops encephalopathy. There is evidence that perinatal hypoxia can injure areas of the brain which are more concerned with cognitive function, only becoming apparent later in life when cognitive function becomes possible to assess.

The aim of the proposed fellowship is the study the association of initially low Apgar Scores, a measure of fetal compromise, with measures of neurodevelopment age 8-10 years and in early adulthood (age 18) in two complimentary datasets. The first dataset is based on a linkage of the Swedish birth register (including 1, 5 and 10 minute Apgar Scores) with the conscription intelligence test records (age 18) of around 110,000 Swedish men. The second complementary dataset , the Bristol-based Avon Longitudinal Study of Parents and Children (ALSPAC) is a birth cohort of 14,000 intants containing more detailed measures of neurodevelopment up to age of 10 years.

The study aimed to determine the cognitive effect of the Val108/158Met polymorphism in the catechol-O-methyltransferase (COMT) gene in children before and during puberty. This polymorphism affects cognitive function in healthy adults and may contribute to risk for schizophrenia. METHOD: COMT genotype was determined for 8,707 children from the Avon Longitudinal Study of Parents and Children (ALSPAC), a geographically defined general population cohort of children born between April 1, 1991, and Dec. 31, 1992, in the southwest of England.

Fourteen measures of cognitive function--including working memory, verbal and motor inhibition, attentional control, and IQ--were assessed at ages 8 and 10 years. Any pubertal development at age 9 years was reported by parents. Effects of COMT genotype on cognition and interactions with gender and puberty were assessed using general linear models. RESULTS: In boys, genotype significantly affected executive function and explained up to 10 points normal variation in verbal IQ. The effects on IQ were significantly greater in pubertal than in prepubertal boys. In girls, there were no significant effects of genotype on cognition. CONCLUSIONS: This common polymorphism may be one of the genes of small effect that contribute to normal variation in IQ. The gender-specific nature of the effect and its possible interaction with puberty may be relevant to both normal cognitive and brain development and to abnormal development in disorders such as schizophrenia.

Asthma is common in childhood and, while many causes for its occurrence and increasing prevalence are known, much remains unanswered in terms of causes. In adults, 10-15% of newly diagnosed asthma is due to an occupational exposure to either low (e.g. isocyanates) or high (e.g. proteins in animal urine) molecular weight asthmagens. Lung disease in the spouses and children of workers exposed to asbestos at work is accepted and recognized. There is a report of children being sensitized to occupational sensitizers, to which their parents have been exposed at work, there is also a report of a child exposed to occupational sensitizers in the workplace developing 'occupational' asthma. In addition there are reports of asthma related to spousal occupation. The magnitude of this potential problem has not been investigated.

We wish to test the hypothesis that children are more likely to develop asthma if their parents work in occupations known to be associated with a risk of occupational asthma because parents may bring asthmagens home on their clothing, resulting in their children being exposed. In addition, we will take the opportunity to determine whether the partner of a worker exposed to occupational sensitizers is more likely to develop asthma. The hypothesis will concentrate on high molecular weight causes although potential exposure to low molecular weight agents will be analysed.

We will use existing data from the ALSPAC cohort of children to relate childhood wheezing, diagnosed asthma, and rhinitis, to parental occupation. In addition, parental occupation will also be related to objective parameters such as ventilatory function and bronchial responsiveness in later childhood (8 1/2 years) to determine if early life and/or cumulative exposure to parents in high-risk occupations are associated with physiological changes. Maternal wheeze, diagnosed asthma, and rhinitis will also be related to her partner's occupation.

Data on occupation have been obtained for both mother and father prospectively and will be coded using the CASCOT system developed by the University of Warwick. Parental occupations will be classified according to recognized associations with occupational asthma. We will also explore whether there is any relationship between the timing of childhood exposure to potential parental occupational asthmagens at 21 months of age and the likelihood of developing asthma. Risk modification by atopy and environmental tobacco smoke exposure will be investigated. The dataset will also provide the opportunity to consider parental self reported asthma or rhinitis in relation to occupation, adding to the limited population data in this area. Finally we will be able to assess the level of agreement between maternal and direct report of spouse's occupation and compare these with the codes generated by automatic and semi-automatic coding software (i.e. SOC 1990 and SOC 2000 codes from CASCOT).

If occupation is shown to increase the risk of asthma in children and partners, help and advice will need to be given to workers in at risk occupations to reduce carriage of asthmagens home on their clothes, in order to reduce the risk of their children and partner developing 'bystander occupational' asthma.

(No outline received).

The project will establish a resource of detailed asthma phenotypes from birth to 8.5 years based on available questionnaire and objective data. The resource will be linked to a wide range of information on environmental exposures before and after birth to address the following general hypotheses:

1. Different environmental exposures in early life are associated with different phenotypic outcomes of asthma.

2. Outcomes are determined by the timing and the magnitude of exposures and by their interactions with (a) other environmental risk/protective factors and (b) family history of asthma/atopy.

3. Exposures at different stages of development (prenatal, perinatal, postnatal) have differential effects on asthma outcomes.

The outcomes will generate new hypotheses about the origins of asthma in early childhood that will be used as the basis for targeted proposal to examine interactions between genetic predisposition and environment in the development and phenotypic expression of asthma in childhood.

(No outline received).

From around six months onwards breast milk alone no longer provides enough iron to sustain adequate blood haemoglobin and ferritin levels in infants. It is important to introduce suitable weaning foods from this age and incorporate feeding practices that enhance absorption of iron from the diet (eg Vit C containing foods or drinks with meals).

This study will be nested within ALSPAC a unique, ongoing research project which enrolled 14,541 mothers during pregnancy in 1991-2 and has followed the children and parents in minute detail ever since. It is a world resource with unrivalled data - with the potential to find ways in which common diseases in childhood and adult life can be prevented or treated.

(No outline received).