AIMS/HYPOTHESIS: Type 2 diabetes is a major risk factor for CHD. We hypothesised that diabetes genetic susceptibility variants might be associated with increased CHD risk. METHODS: We examined the individual and cumulative effect of 38 common genetic variants previously reported to be associated with type 2 diabetes on risk of incident CHD in 20,467 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk Study who had been free of CHD at baseline. RESULTS: During a mean follow-up of 10.7 years, 2,190 participants had a CHD event. Two individual variants next to the TSPAN8 (HR 1.07, 95% CI 1.00-1.14) and the CDKN2A/B region (1.11, 1.04-1.17) were significantly associated with increased CHD risk. A genetic score based on the 38 diabetes variants was significantly associated with an increased risk of CHD (1.08, 1.01-1.14 per score tertile). Adjustment for prevalent and incident diabetes attenuated the association of the TSPAN8 variant (1.06, 0.99-1.13) and the genetic score (1.05, 0.99-1.12 per score tertile) with CHD risk, but not that of the CDKN2A/B variant (1.11, 1.05-1.18). Addition of the genetic score did not improve risk discrimination based on clinical risk factors. CONCLUSIONS/ INTERPRETATION: The increased risk of CHD observed with genetic susceptibility to type 2 diabetes was at least partly mediated by its diabetes-predisposing effect and was not useful for clinical risk discrimination. The potential role of pathways associated with the variant CDKN2A/B in linking diabetes and CHD needs further exploration.
AIMS/HYPOTHESIS: Type 2 diabetes is a major risk factor for CHD. We hypothesised that diabetes genetic susceptibility variants might be associated with increased CHD risk. METHODS: We examined the individual and cumulative effect of 38 common genetic variants previously reported to be associated with type 2 diabetes on risk of incident CHD in 20,467 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk Study who had been free of CHD at baseline. RESULTS: During a mean follow-up of 10.7 years, 2,190 participants had a CHD event. Two individual variants next to the TSPAN8 (HR 1.07, 95% CI 1.00-1.14) and the CDKN2A/B region (1.11, 1.04-1.17) were significantly associated with increased CHD risk. A genetic score based on the 38 diabetes variants was significantly associated with an increased risk of CHD (1.08, 1.01-1.14 per score tertile). Adjustment for prevalent and incident diabetes attenuated the association of the TSPAN8 variant (1.06, 0.99-1.13) and the genetic score (1.05, 0.99-1.12 per score tertile) with CHD risk, but not that of the CDKN2A/B variant (1.11, 1.05-1.18). Addition of the genetic score did not improve risk discrimination based on clinical risk factors. CONCLUSIONS/ INTERPRETATION: The increased risk of CHD observed with genetic susceptibility to type 2 diabetes was at least partly mediated by its diabetes-predisposing effect and was not useful for clinical risk discrimination. The potential role of pathways associated with the variant CDKN2A/B in linking diabetes and CHD needs further exploration.
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