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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 million single nucleotide polymorphisms was conducted among participants of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial. Included were 4,384 white case patients with type 2 diabetes (T2D) and prevalent or incident DPN (defined as a Michigan Neuropathy Screening Instrument clinical examination score >2.0) and 784 white control subjects 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 case subjects and 158 DPN-negative control subjects) from the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial. Association between significant variants and gene expression in peripheral nerves was evaluated in the Genotype-Tissue Expression (GTEx) database. A cluster of 28 SNPs on chromosome 2q24 reached GWAS significance (P < 5 × 10-8) in ACCORD. The minor allele of the lead SNP (rs13417783, minor allele frequency = 0.14) decreased DPN odds by 36% (odds ratio [OR] 0.64, 95% CI 0.55-0.74, P = 1.9 × 10-9). This effect was not influenced by ACCORD treatment assignments (P for interaction = 0.6) or 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 = 9 × 10-4; summary P = 7.9 × 10-12). 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 = 9 × 10-4). 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. [ABSTRACT FROM AUTHOR]