Abstract MP051: A Novel Genetic Locus for Coronary Heart Disease in Type 2 Diabetes

Genetic susceptibility to cardiovascular disease in type 2 diabetes is influenced by abnormal metabolic status in the affected diabetic patients; and the implicated genes may differ from those in the non-diabetic populations. We conducted 3-stage genome-wide association analysis to detect the genetic factors for coronary heart disease (CHD) in existing type 2 diabetes. We analyzed 2.4 million SNPs in 1,249 diabetic women from the Nurses’ Health Study (273 CHD cases and 976 controls) and 984 diabetic men from the Health Professionals’ Follow-up Study (319 CHD cases and 665 controls), all of European ancestry. The first-stage replication was performed in Joslin Heart Study (420 CHD cases and 431 controls); and the second-stage replication was performed in Gargano Heart Study (314 CHD cases and 384 controls), and Catanzaro study (114 CHD cases and 215 controls). All the replication samples were of European ancestry and also affected by type 2 diabetes. We observed associations of genome-wide significance (the best p=2.04 * 10 -8 ) between CHD and SNPs on chromosome 1, between genes ZNF648 ( zinc finger protein 648; 1q25 .3) and GLUL (glutamate-ammonia ligase; 1q31). eQTL analysis indicates suggestive association between the associated SNPs and a potential CHD gene PPAP2B on chromosome 1 with marginal significance (p=1 * 10 -5 ). The identified SNP showed a significant association with the plasma levels of vascular cell adhesion molecule 1 ( VCAM1 ) in patients with type 2 diabetes but not in non-diabetic healthy controls. Our findings indicate that specific genetic predisposition may determine cardiovascular risk in patients with type 2 diabetes. The findings may inform the development of novel therapies for reduction of cardiovascular complications in diabetes.