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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.
Pubmed ID: 31127053
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Software application designed to facilitate meta-analysis of large datasets (such as several whole genome scans) in a convenient, rapid and memory efficient manner. (entry from Genetic Analysis Software)
View all literature mentionsPortal and database of DNA sequence, functional and epigenomic information, and clinical data from studies on type 2 diabetes and analytic tools to analyze these data. .Provides data and tools to promote understanding and treatment of type 2 diabetes and its complications. Used for identifying genetic biomarkers correlated to Type 2 diabetes and development of novel drugs for this disease.
View all literature mentionsStudy testing whether strict glucose control lowers the risk of heart disease and stroke in adults with type 2 diabetes. In addition the study is exploring: 1) Whether in the context of good glycemic control the use of different lowering lipid drugs will further improve these outcomes and 2) If strict control of blood pressure will also have additional beneficial effects on reducing cardiovascular disease. The design was a randomized, multicenter, double 2 X 2 factorial trial in 10,251 patients with type 2 diabetes mellitus. It was designed to test the effects on major CVD events of intensive glycemia control, of fibrate treatment to increase HDL-cholesterol and lower triglycerides (in the context of good LDL-C and glycemia control), and of intensive blood pressure control (in the context of good glycemia control), each compared to an appropriate control. All 10,251 participants were in an overarching glycemia trial. In addition, one 2 X 2 trial addressed the lipid question in 5,518 of the participants and the other 2 X 2 trial addressed the blood pressure question in 4,733 of the participants. The glycemia trial was terminated early due to higher mortality in the intensive compared with the standard glycemia treatment strategies. The results were published in June 2008 (N Eng J Med 2008;358:2545-59). Study-delivered treatment for all ACCORD participants was stopped on June 30, 2009, and the participants were assisted as needed in transferring their care to a personal physician. The lipid and blood pressure results (as well as the microvascular outcomes and eye substudy results) were published in 2010. All participants are continuing to be followed in a non-treatment observational study.
View all literature mentionsA computer program for phasing observed genotypes and imputing missing genotypes.
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