Genome-wide association analysis on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a novel risk locus

Genome-wide association analysis on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a novel risk Diabetes is a known risk factor for coronary artery disease. There is accumulating evidence 3 that coronary artery disease pathogenesis differs for individuals with type 1 diabetes. However, 4 the genetic background has not been extensively studied. We aimed to discover genetic loci 5 increasing coronary artery disease susceptibility especially in type 1 diabetes, to examine the 6 function of these discoveries and to study the role of the known risk loci in type 1 diabetes. We performed the largest genome-wide association study to date for coronary artery disease in 9 type 1 diabetes, comprising 4869 individuals with type 1 diabetes (cases/controls: 941/3928). 10 Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 (OR=1.32, 11 p =1.50×10 −8 ), and rs6055069 on DEFB127 promoter (OR=4.17, p =2.35×10 −9 ), with consistent 12 results in survival analysis. The CDKN2B-AS1 variant replicated ( p =0.04) when adjusted for 13 diabetic kidney disease in three additional type 1 diabetes cohorts (cases/controls: 434/3123). 14 Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide 15 analysis. Among the eight suggestive loci ( p <1×10 -6 ), rs70962766 near B3GNT2 associated 16 with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and 17 rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated 18 genetic risk scores for individuals with type 1 diabetes with the known susceptibility loci. General population risk variants were modestly but significantly associated with coronary 20 artery disease also in type 1 diabetes ( p =4.21×10 -7 ).

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