Genetic Determinants of Diabetic Neuropathy

Abstract

Paper 1 Genetic factors have been postulated to be involved in the etiology of diabetic peripheral neuropathy (DPN), but their identity remains mostly unknown. The aim of this study was to conduct a systematic search for genetic variants influencing DPN risk using two well-characterized cohorts. A genome-wide association study (GWAS) testing 6.8 M SNPs was conducted among participants of the ACCORD clinical trial. Included were 4,384 White cases with type 2 diabetes (T2D) and prevalent or incident DPN (defined as a Michigan Neuropathy Screening Instrument [MNSI] clinical exam score >2.0) and 784 White controls with T2D and no evidence of DPN at baseline or during follow-up. Replication of significant loci was sought among White subjects with T2D (791 DPN-positive cases and 158 DPN-negative controls) from the BARI 2D trial. Association between significant variants and gene expression in peripheral nerves was evaluated in the GTEx database. A cluster of 28 SNPs on chromosome 2q24 reached GWAS significance (P<5x10-8) in ACCORD. The minor allele of the lead SNP (rs13417783, minor allele frequency=0.14) decreased DPN odds by 36% (OR 0.64, 95% CI 0.55-0.74, P=1.9x10-9). This effect was not influenced by ACCORD treatment assignments (P for interaction=0.6) nor was mediated by an association with known DPN risk factors. This locus was successfully validated in BARI 2D (OR 0.57, 95% CI 0.42-0.80, P=9x10-4, summary P value=7.9x10-12). In GTEx, the minor, protective allele at this locus was associated with higher tibial nerve expression of an adjacent gene (SCN2A) coding for human voltage-gated sodium channel NaV1.2 (P=9x10-4). To conclude, we have identified and successfully validated a previously unknown locus with a powerful protective effect on the development of DPN in T2D. These results may provide novel insights into DPN pathogenesis and point to a potential target for novel interventions. Paper 2. 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 <7.813 ms) and highest quartile of QT index (QTI >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=1.42 [1.25 – 1.61], P=1.8 ×10-8) – an effect that was independent of the glycemic control arm assignments within the trial (P for interaction = 0.35). Genes lying within 1Mb of the lead SNP included CAMTA1 – a calmodulin binding transcription factor affecting cardiac embryonal development, KCNAB2 – a potassium voltage-gated channel associated with fatal cardiac arrhythmia, and RNF207 – a RING finger protein regulating heart action potential duration. 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.