title: Individual and cumulative effect of type 2 diabetes genetic susceptibility variants on risk of coronary heart disease.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Box 285, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: R
authors.initials: R
authors.lastname: Pfister
authors.forename: D
authors.initials: D
authors.lastname: Barnes
authors.forename: R N
authors.initials: RN
authors.lastname: Luben
authors.forename: K-T
authors.initials: KT
authors.lastname: Khaw
authors.forename: N J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: C
authors.initials: C
authors.lastname: Langenberg
mesh_terms: D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D015994:Incidence; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D059470:Tetraspanins / Q000235:genetics; D006113:United Kingdom
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; C065609:TSPAN8 protein, human; D059470:Tetraspanins