Hypothisis

1. Changes in exposures over the period 17-25y will be associated with change in cardiometabolic

phenotype over the period 17-25y.

2. These associations will be reflected in changes in intermediate molecular phenotypes (epigenetics and

metabolomic measures).

3. Changes in intermediate molecular phenotypes will act as markers of exposure, and, in some cases,

highlight possible causal pathways

4. Exposures over the entire life course to 25y will act via accumulative or sensitive period models to

determine outcomes at age 25y

Outline of the proposed study

ALSPAC commenced in 1990-92 and recruited children from 15 247 pregnancies.73 Follow-up data includes 59 questionnaires (4 weeks-18 years of age) and 9 clinical assessment visits (7-17 years of age). The resource comprises a wide range of phenotypic and environmental measures in addition to biological samples, genetic (DNA on 11,343 children, genome-wide data on 8,365 children, complete genome sequencing on 2000 children) and epigenetic (methylation sampling on 1000 children) information and linkage to health and administrative records.

Young adults participating in the ALSPAC study will be invited to re-attend clinic for detailed assessment of exposures, risk factors and phenotype. Based on previous experience and pilot studies, we anticipate approximately 4000-5000 young adults will attend the 25+ clinic. We will undertake a range of investigations including: cardiac structure and function by 3-dimensional (3D) echocardiography, including strain rate using a EPIQ 7 ultrasound (3D echo offers significant advantages over 2D/M-mode in the assessment of LV mass and remodelling[74]); carotid ultrasound for cIMT and carotid distensibility will be performed using a Panasonic CardioHealth station; carotid-femoral PWV will be measured using a Vicorder device; peripheral and central BP including waveform analysis (pressure separation75, reservoir/excess pressure) will be measured using a BP+ validated cuff-based device. BP and HR reactivity in response to a step exercise and handgrip will also be performed as done in ALSPAC 17+ clinic. Resting heart rate variability will be measured from a 5 minute resting ECG. Anthropometry, questionnaires (including dietary questionnaires), fasting bloods, urine, 3D body scans, metabolomics and DXA will be performed as part of the core clinic (supported by existing core-grant). Blood samples will also be collected for analysis of insulin (all participants), DNA methylation (in 1000 participants), chromatin preparation and storage. Urine will also be collected and stored.