321-OR: A Genetic Locus on Chromosome 1p36 Associated with Cardiovascular Autonomic Neuropathy in Type 2 Diabetes

Cardiovascular autonomic neuropathy (CAN) is an independent predictor of cardiovascular disease (CVD) morbidity and all-cause and CVD mortality in diabetes. In light of its significant heritability, we aimed to identify genetic predictors of CAN through an unbiased genome-wide association study (GWAS) among whites in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) cohort, comprising individuals with type 2 diabetes (T2D) and high CVD risk. CAN was defined based on indices of heart rate variability derived from 10-s resting electrocardiograms, namely, as the lowest quartile of standard deviation of normally conducted R-R intervals (SDNN 104.32%). Applying logistic regression models, we conducted a GWAS testing 6.8 million common single nucleotide polymorphisms (SNPs), with cases (N=807) having CAN at baseline and/or during follow-up and controls (N=3,144) being without CAN at end of follow-up. The top signal, rs779142, on chromosome 1p36, was associated with 35% increased odds of CAN (OR=1.35 [1.20-1.51], P=1.9 ×10-7). Among incident cases (N=499), this SNP reached GWAS significance (OR=1.48 [1.29-1.69], P=1.7 ×10-8). In a time-to-event analysis, rs779142 was associated with increased risk of progression to CAN (HR=1.45 [1.28-1.64], P=6.9 ×10-9) - an effect that was independent of the glycemic control arm assignments within the trial (P for interaction = 0.40). Genes lying within 1Mb of the lead SNP included KCNAB2 - a potassium voltage-gated channel associated with fatal cardiac arrhythmia, and PER3 - period circadian clock 3, which is involved in the regulation of the cardiac sympathovagal balance. To conclude, we have identified a locus on 1p36 having a genome-wide significant effect on the development of incident CAN in T2D. Pending further studies, these findings may provide better mechanistic insights into CAN pathophysiology as well as potential new therapeutic targets against this complication. Disclosure Y. Tang: None. H. Shah: None. X. Sun: None. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. M.J. Wagner: None. A. Motsinger-Reif: None. J.B. Buse: Consultant; Self; Neurimmune AG. Research Support; Self; AstraZeneca, National Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk A/S, Sanofi, vTv Therapeutics. Stock/Shareholder; Self; Mellitus Health, PhaseBio Pharmaceuticals, Inc., Stability Health. Other Relationship; Self; ADOCIA, AstraZeneca, Dance Biopharm Holdings Inc., Eli Lilly and Company, MannKind Corporation, NovaTarg, Novo Nordisk A/S, Senseonics, vTv Therapeutics, Zafgen, Inc. J. Mychaleckyj: None. R. Pop-Busui: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association. A. Doria: Research Support; Self; Sanofi-Aventis. Funding National Institutes of Health