The genetic determinants of cardiovascular disease in patients with type 2 diabetes

Abstract

The aim of this thesis was to identify genetic determinants associated with cardiovascular disease. We developed and verified algorithms to identify Coronary artery disease (CAD) , ischaemic stroke (IS) and lower extremity arterial disease (LEAD) cases and controls from electronic medical record data linked to Genetics of Diabetes and Audit Research Tayside Scotland cohort. We showed that these could be used in the discovery of novel genetic variants by replicating known signals in the LPA and the 9p21 region. We also identified unique associations of genetic scores for type 1 diabetes and triglycerides with the derived cardiovascular phenotypes. We used the derived CAD phenotype to contribute towards a large scale meta-analysis of CAD that led to the discovery of 15 new loci for CAD. A genetic score, that combined all the SNPs that passed a false discovery rate of 0.5% in the CAD meta-analysis, was not more predictive of CAD low density lipoprotein and high-density lipoprotein cholesterol. We found that a genetic score for decreasing 25-hydroxy vitamin D was associated with an increased risk of CAD. The effects of the genetic score suggested that there is a causal relationship between low 25OHD levels and increased CAD risk. A meta-analysis of CAD in patients with type 2 diabetes identified two independent signals in ADAMTS7 associated with CAD at genome wide significance. Tests for heterogeneity of allelic effects for known CAD loci showed significant heterogeneity for signals in the 9p21 region, ADAMTS7, ABO, and VEGFA. A meta-analysis of LEAD replicated known associations in the 9p21 region and a known locus for nicotine dependence CHRNA3. A smoking interaction analysis identified signals in ADAMTS17 that interact with smoking status to increase the risk of LEAD in non-smokers. We identified novel loci for CAD and putative loci for CAD in patients with T2D and LEAD with further analysis and replication required to establish these loci.

Date of Award	2013
Original language	English
Sponsors	Tenovus Scotland & IMI SUMMIT study
Supervisor	Colin Palmer (Supervisor) & Andrew Morris (Supervisor)