Obstetric, lifestyle and genetic determinants of vascular and metabolic traits in women in early middle-age

The aim of this study is to identify the risk factors, including changes during pregnancy (such as changes in weight and blood pressure), different patterns of change in lifestyle factors such as smoking habits and physical activity, and genetic factors, that determine the variations in atherosclerosis and other vascular and metabolic traits in women in their mid-40s. Cardiovascular disease (CVD) is the commonest cause of death among women in the UK, with 113,140 women (37% of the total number of deaths in all women in the UK) dying of CVD and 11% living with either coronary heart disease or stroke in 2004. Study participants will be mothers from the Avon Longitudinal Study of Parents and Children. For these women we already have over 15 years of prospectively collected genetic, lifestyle and obstetric data collected repeatedly since their index pregnancy in the early 1990s. 7,000 women (average age 44) will be recruited to participate in a clinical examination. This will include fasting blood samples for insulin, glucose and lipid measurements, DXA determined fat mass and carotid intima media thickness (a measure of atherosclerosis). This work will provide the necessary evidence base for developing effective interventions aimed at preventing CVD in women.

Aim
To identify the obstetric, lifestyle, and genetic determinants, of variations in vascular and metabolic traits in women in their mid-40s, an age at which few will have died or been on treatment for cardiovascular disease (CVD).

Objectives
1. To determine the association of obstetric factors (BMI and blood pressure at the start of pregnancy, different patterns of changes in weight, blood pressure and glycosuria throughout the antenatal period, gestational diabetes and pregnancy induced hypertension) with variations in vascular and metabolic traits (fat mass, fat distribution, fasting insulin, glucose and lipids, and blood pressure), in women in their mid-40s, and to use this information to determine whether routinely collected antenatal data can predict variations in metabolic and vascular traits in women in their mid-40s.
2. To use genetic variants with established associations with adiposity as instrumental variables to estimate the magnitude of the causal association of variations in average fat mass over the life course with metabolic and vascular traits in women.
3. To determine the different ways in which obstetric, lifestyle (different patterns of cigarette smoking, physical activity, and dietary intake including alcohol consumption) and genetic factors relate to each other to affect variations in vascular and metabolic traits in women in their 40s.
4. To contribute to determining the association of novel genetic variants (that will be identified by bioinformatics and genome wide association studies) with fat mass, fasting insulin, glucose and lipids, blood pressure and smoking, physical activity and alcohol patterns, and replicate these findings in independent studies; and to examine whether there are genetic variants that are related specifically to adverse metabolic profile in pregnancy.

Design & methodology
Study participants are mothers from the Avon Longitudinal Study of Parents And Children. For these women there is an established DNA bank, immortalised cell-lines, and data on obstetric, socio-demographic and lifestyle factors collected repeatedly, since their index pregnancy in the early 1990s. Fat mass, fat distribution and blood pressure measurements (N=5000), and fasting glucose, insulin and lipids (N=2000) will be collected for women attending their offspring‘s 15 year follow-up clinic (mean age: 44). Relevant statistical methods - generalised linear regression models, multilevel models, instrumental variables analysis - will be used as appropriate.

Medical opportunities
This study will provide the necessary evidence base for developing programmes aimed at preventing CVD in women. Identifying women at risk of future adverse metabolic and vascular risk profiles during their pregnancy is likely to be advantageous as over 85% of women experience a pregnancy and antenatal care, and they may be particularly receptive to preventive interventions at this stage in their life course.