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

AIMS: Diabetes is a known risk factor for coronary artery disease. There is accumulating evidence that coronary artery disease pathogenesis differs for individuals with type 1 diabetes. However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing coronary artery disease susceptibility especially in type 1 diabetes, to examine the function of these discoveries and to study the role of the known risk loci in type 1 diabetes.

METHODS AND RESULTS: We performed the largest genome-wide association study to date for coronary artery disease in type 1 diabetes, comprising 4869 individuals with type 1 diabetes (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 (OR = 1.32, p=1.50 × 10-8), and rs6055069 on DEFB127 promoter (OR = 4.17, p=2.35 × 10-9), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (p=0.04) when adjusted for diabetic kidney disease in three additional type 1 diabetes cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (p<1 × 10-6), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated 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 artery disease also in type 1 diabetes (p=4.21 × 10-7).

CONCLUSIONS: While general population coronary artery disease risk loci had limited effect on the risk in type 1 diabetes, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with coronary artery disease in individuals with type 1 diabetes. The novel finding on β-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility and coronary artery disease, although pending on future confirmation.

TRANSLATIONAL PERSPECTIVE: Genetic association studies enable the discovery of novel genes and genetic pathways associated with the disease. Thus, this study provides an insight into coronary artery disease mechanisms specific to type 1 diabetes. The DEFB127 discovery may lead to a therapeutic target and improve patient care, if replicated in the future. Furthermore, genetic studies on coronary artery disease in type 1 diabetes are required for accurate personalized treatment plans achieved through genetic data for those with type 1 diabetes.