Abstract P230: Individual and Cumulative Effect of Type 2 Diabetes Associated Genetic Variants on the Risk Of Cardiovascular Disease
Hypothesis Since type 2 diabetes is a major risk factor for cardiovascular disease (CVD) we hypothesised that diabetes associated single nucleotide polymorphisms (SNP) might be associated with increased risk of CVD. Aim To asses the individual and combined effect of 46 type 2 diabetes associated SNPs on the risk of incident CVD independently of diabetic status. Methods Data from the first Danish MONICA study was used (N=3753) and results were reproduced using the Inter99 study (N=6169). Using Cox proportional hazard regression adjusted for sex and with age as the underlying time-scale the individual effect of each SNP on incident CVD was analyzed. Risk was presented as hazard ratios (HR) per risk allele. Furthermore, the cumulative effect of the 46 SNPs was assessed by adding the number of diabetes risk increasing alleles to a genetic sum score. Both the single and cumulative effect was adjusted for diabetic status in order to see if any possible association with CVD persisted or if the effect was mediated through diabetes. Results During 74,386 person years 1411 incident cases of CVD (fatal and non-fatal) was registered in the MONICA study. In Inter99 729 events was registered during 51,976 person years. In the Danish MONICA study seven genetic variants were significantly associated with incident CVD independently of known diabetic status; SLC2A2 (HR 1.12, 95% CI 1.001-1.26), DGKB (1.11, 1.02-1.2), C2CD4A (1.11, 1.02-1.20), GCKR (1.10, 1.01-1.20), KLF14 (1.12, 1.03-1.21), NOTCH2 (1.16, 1.02-1.32) and JAZF1 (1.10, 1.02-1.20). The genetic score was significantly associated with increased risk of CVD (1.03, 1.02-1.05) per risk increasing allele. In Inter99 three genetic variants were found to be associated with risk of CVD independently of diabetes; SLC2A2 (1.24, 1.07-1.43), CDC123 (0.84, 0.73-0.97) and HNF1B (1.16, 1.03-1.29). The genetic score was not significantly associated with CVD. The results persisted after further adjusting for possible mediating factors like BMI, total cholesterol, HDL cholesterol and blood pressure. Conclusions We found in both studies several diabetes associated genetic variants significantly associated with an increased risk of incident CVD. The SLC2A2 (rs11920090) genetic variant was the only variant that was found to be significantly associated in both studies. This association persisted after adjusting for diabetic status suggesting an effect on CVD beyond the increased risk of diabetes. This potential pathway needs further exploration.
- © 2012 by American Heart Association, Inc.