Adiposity and ischaemic Heart Disease in the UK Biobank: A prospective cohort study of 450 000 adults.

Background
Ischaemic heart disease (IHD) was the leading cause of death and Daily Adjusted Life Years lost to disability worldwide in 2010. Adiposity is becoming increasingly recognized as a leading risk factor for cardiovascular disease (CVD), including IHD. The mechanism through which adiposity causes CVD is thought to be the result, in part, of its adverse effect on well-established vascular risk factors such as dyslipidemia, hypertension and diabetes mellitus. However, some of the excess risk at high levels of adiposity remains unexplained. Importantly, with the global average BMI increasing by around 1.5kg/m2 each decade and with IHD deaths rising worldwide, it is of fundamental importance to conduct high-quality research delivering detailed estimates of the risk of IHD associated with adiposity in contemporary populations.
Currently, the most robust estimates of the association between adiposity and CVD are derived from pooled analyses of prospective studies, such as the Prospective Studies Collaboration. However, these meta-analyses were restricted to fatal events, and could not conduct as detailed an assessment of confounding compared to a single study. Furthermore, most participants were recruited 30-40 years ago, and the relevance of these findings to the current UK population is unclear.
Importantly, commonly used measures of adiposity such as waist-to-hip ratio (WHR), waist circumference and BMI are useful but imperfect measures of body fat. An advantage of studying UKB participants is the availability of bio-impedance, a potentially more informative measure of adiposity, as it provides an estimate of total and regional body fat relative to body weight. However, the association between bio-impedance and IHD risk has yet to be investigated in large and robust epidemiological studies. A further advantage of UKB is the on-going direct measurement of adiposity in 100 000 participants using highly accurate dual energy X-ray absorptiometry (DEXA) and magnetic resonance imaging (MRI). This will enable the assessment of the reliability of each adiposity measure when estimating general and central adiposity in population sub-groups.
Aims
i) Adiposity and IHD: Prospective associations
- Investigating the association of waist circumference, WHR, BMI and bio-impedance with risk of incident IHD events (both fatal and non-fatal) in 500, 000 UKB participants. Estimates will be adjusted for important potential confounders such as smoking, age and sex. Furthermore, all estimates will be corrected, where appropriate, for regression dilution bias; using resurvey data to assess within-person variability of adiposity measures.
- Identifying the adiposity measure with the most predictive value for incident IHD risk in this population and across important sub-groups of the population.
ii) Cross-sectional associations
- Studying the distribution of adiposity across sub-groups of the UKB cohort population, according to geographical location and various other individual participant characteristics.
- Describing cross-sectional associations between measures of adiposity with known and potential intermediate factors, including diabetes mellitus, blood pressure and lipid levels.
- Investigating correlations between different adiposity measures, with particular emphasis on the relationship between adiposity measures and body fat distribution as assessed by DEXA and MRI scans.
iii) Genetic analysis:
- Using information from genome-wide assays to investigate patterns of SNP's associated with different adiposity measures and body composition estimates. Subsequently generating individual genetic scores for adiposity, and investigating the associated risk of these genetic scores for risk of IHD incidence.