Anni A V Antikainen1,2,3, Niina Sandholm1,2,3, David-Alexandre Trégouët4,5,6, Romain Charmet4,5, Amy Jayne McKnight7, Tarunveer S Ahluwalia8, Anna Syreeni1,2,3, Erkka Valo1,2,3, Carol Forsblom1,2,3, Daniel Gordin1,2,3,9, Valma Harjutsalo1,2,3,10, Samy Hadjadj11,12,13, Alexander P Maxwell7, Peter Rossing8,14, Per-Henrik Groop1,2,3,15. 1. Folkhälsan Institute of Genetics, Folkhälsan Research Center, FI-00290 Helsinki, Finland. 2. Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, FI-00290 Helsinki, Finland. 3. Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, FI-00290 Helsinki, Finland. 4. Sorbonne Université, UPMC Univ Paris 06, INSERM UMR_S 1166, Paris, France. 5. ICAN Institute for Cardiometabolism and Nutrition, Paris, France. 6. INSERM UMR_S 1219, Bordeaux Population Health Research Center, Bordeaux University, Bordeaux, France. 7. Centre for Public Health, Queens University of Belfast, Northern Ireland BT7 1NN, UK. 8. Steno Diabetes Center Copenhagen, DK 2820 Gentofte, Denmark. 9. Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA. 10. The Chronic Disease Prevention Unit, National Institute for Health and Welfare, FI-00271 Helsinki, Finland. 11. Department of Endocrinology and Diabetology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France. 12. INSERM CIC 1402, Poitiers, France. 13. L'institut du thorax, INSERM, CNRS, UNIV, Nantes CHU Nantes, Nantes, France. 14. University of Copenhagen, Copenhagen, Denmark. 15. Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Abstract
AIMS: Diabetes is a known risk factor for coronary artery disease (CAD). There is accumulating evidence that CAD pathogenesis differs for individuals with type 1 diabetes (T1D). However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing CAD susceptibility, especially in T1D, to examine the function of these discoveries and to study the role of the known risk loci in T1D. METHODS AND RESULTS: We performed the largest genome-wide association study to date for CAD in T1D, comprising 4869 individuals with T1D (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 [odds ratio (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 T1D 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 T1D with the known susceptibility loci. General population risk variants were modestly but significantly associated with CAD also in T1D (P = 4.21 × 10-7). CONCLUSION: While general population CAD risk loci had limited effect on the risk in T1D, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with CAD in individuals with T1D. The novel finding on β-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility, and CAD, although pending on future confirmation. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Diabetes is a known risk factor for coronary artery disease (CAD). There is accumulating evidence that CAD pathogenesis differs for individuals with type 1 diabetes (T1D). However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing CAD susceptibility, especially in T1D, to examine the function of these discoveries and to study the role of the known risk loci in T1D. METHODS AND RESULTS: We performed the largest genome-wide association study to date for CAD in T1D, comprising 4869 individuals with T1D (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 [odds ratio (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 T1D 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 T1D with the known susceptibility loci. General population risk variants were modestly but significantly associated with CAD also in T1D (P = 4.21 × 10-7). CONCLUSION: While general population CAD risk loci had limited effect on the risk in T1D, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with CAD in individuals with T1D. The novel finding on β-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility, and CAD, although pending on future confirmation. Published on behalf of the European Society of Cardiology. All rights reserved.
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