Identifying genetic determinants of coronary heart disease in individuals with diabetes
Principal Investigator: Dr Brent Richards
Approved Research ID: 24281
Approval date: April 14th 2016
The aim of this research program is to identify genetic variants predisposing to coronary heart disease (CHD) in type 2 diabetes (T2D). We propose to combine UKBiobank genome-wide association (GWAS) data with other large studies to understand the common genetic determinants of CHD amongst type 2 diabetics. The rationale for this study is that while T2D and hyperglycemia are strong predictors of CHD, lowering glucose in T2D has no clear effect upon risk of CHD in several recent large-scale RCTs. Using a human genetics approach we hope to understand the biologic mechanisms that lead to CHD amongst diabetics. Our project meets the UK Biobank?s aim of improving the prevention, diagnosis and treatment of serious and life threatening illnesses. T2D costs approximately £8.8B in direct costs per year in the UK and there are 150,000 annual incident cases diagnosed, while another 850,000 are estimated to have T2D, but are not yet diagnosed. T2D independently increases the risk of CHD between 2- to 4-fold. The proposed study therefore aims to better understand the biologic mechanisms leading to CHD amongst T2D that may eventually lead to better prevention of CHD amongst diabetics. We propose a meta-analysis of GWASs from the ORIGIN Trial, the UKBiobank and the T2DCx cohort. We have secured DNA from the ORIGIN Trial (N = 5,433), an RCT of individuals with CHD risk factors and diabetes or ?pre-diabetes? followed for 6.2 years for CHD outcomes. The T2DCx cohort is a case/control study recruiting 1,000 diabetics with CHD. We propose to also identify cases as those with T2D from UKBiobank who have experienced the same CHD outcomes and controls as type 2 diabetics, matched for relevant factors, who have not experienced these same CHD outcomes. We will identify cases and controls from 15,550 UKBiobank subjects with diabetes admission pre- and post-recruitment by position of diagnosis in HES (ICD-10 E10-E14, O24, R73.0), with (N = 25,100) and without ischaemic heart disease (ICD-10 I20-I25,). Subjects will be matched for relevant variables. We request genome-wide association genotypes for all individuals meeting our case/control definitions (see section 2). We estimate that this will include approximately 8-10,000 individuals. We have previous experience and computational capacity to analyze genome-wide association data arising from tens of thousands of subjects.