Diabetic peripheral neuropathy (DPN) is a significant contributor to the increased morbidity associated with type 2 diabetes (T2D). However, the risk of developing DPN varies among T2D patients, possibly due to genetic factors. We aimed to identify genetic predictors of DPN using an unbiased genome-wide association (GWAS) approach in Action to Control Cardiovascular Risk in Diabetes (ACCORD)—a large trial of intensive glycemic control in subjects with T2D and high CVD risk. Occurrence of DPN was defined as a clinical Michigan Neuropathy Screening Instrument (MNSI) score >2.0 at baseline or during follow-up. Using logistic regression, we conducted a GWAS, testing 6.8 million common single nucleotide polymorphisms (SNPs) among 4,384 DPN cases and 784 DPN-negative controls of white origin for whom genetic data were available. A locus on chromosome 2q24 reached GWAS significance (p=1.9×10-9). The minor allele of the lead SNP (rs13417783, minor allele frequency=0.14) decreased DPN odds by 36% (OR 0.64, 95% CI 0.59-0.69)—an effect not influenced by the glycemic treatment assignment (p for interaction=0.6). Adjacent to this SNP lies a cluster of genes coding for human voltage-gated sodium channels (SCN1A, SCN2A, SCN3A, SCN7A, and SCN9A) that are expressed in neurons and are mutated in monogenic forms of peripheral neuropathy and epilepsy. In an expression quantitative trait locus (eQTL) analysis, the minor (protective) allele of this SNP was associated with higher expression of SCN2A (P=0.0009) in tibial nerve. Other loci reaching notable significance (p≤1×10-6) were 8p23 in the gene CSMD1, previously implicated in epilepsy, and 11q25 in OPCML, an opioid-binding protein.
In summary, we have discovered a novel genetic locus predicting DPN risk. Pending further investigation, these findings may provide better mechanistic insights into the pathophysiology of DPN, hopefully leading to the development of novel pharmacological interventions to prevent or treat this diabetic complication.
Y. Tang: None. J. Mychaleckyj: None. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc. R. Pop-Busui: Research Support; Self; AstraZeneca. M.J. Wagner: None. A. Motsinger-Reif: None. J.B. Buse: Other Relationship; Self; ADOCIA, AstraZeneca, Dexcom, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Fractyl Laboratories, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Metavention, NovaTarg, Novo Nordisk A/S, Sanofi, VTV Therapeutics. Research Support; Self; Boehringer Ingelheim GmbH, Johnson & Johnson Services, Inc., Theracos, Inc.. Other Relationship; Self; Shenzhen Hightide Biopharmaceutical, Ltd.. Research Support; Self; National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences. Other Relationship; Self; National Institute of Diabetes and Digestive and Kidney Diseases, American Diabetes Association. Research Support; Self; Patient-Centered Outcomes Research Institute. Other Relationship; Self; National Institute of Environmental Health Sciences. H. Shah: None. A. Doria: Research Support; Self; Sanofi-Aventis.