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Complications

A Genetic Locus on Chromosome 2q24 Predicting Peripheral Neuropathy Risk in Type 2 Diabetes: Results From the ACCORD and BARI 2D Studies

  1. Yaling Tang1,2,
  2. Petra A. Lenzini3,
  3. Rodica Pop-Busui4,
  4. Pradipta R. Ray5,
  5. Hannah Campbell3,6,
  6. Bruce A. Perkins7,
  7. Brian Callaghan8,
  8. Michael J. Wagner9,
  9. Alison A. Motsinger-Reif10,
  10. John B. Buse11,
  11. Theodore J. Price5,
  12. Josyf C. Mychaleckyj12,
  13. Sharon Cresci3,6,
  14. Hetal Shah1,2⇑ and
  15. Alessandro Doria1,2⇑
  1. 1Research Division, Joslin Diabetes Center, Boston, MA
  2. 2Department of Medicine, Harvard Medical School, Boston, MA
  3. 3Department of Genetics, Washington University School of Medicine, St. Louis, MO
  4. 4Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
  5. 5School of Behavioral and Brain Sciences and Center for Advanced Pain Studies, The University of Texas at Dallas, Richardson, TX
  6. 6Department of Medicine, Washington University School of Medicine, St. Louis, MO
  7. 7Leadership Sinai Centre for Diabetes, Sinai Health System, and Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada
  8. 8Department of Neurology, University of Michigan, Ann Arbor, MI
  9. 9Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC
  10. 10Bioinformatics Research Center, and Department of Statistics, North Carolina State University, Raleigh, NC
  11. 11Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
  12. 12Center for Public Health Genomics, University of Virginia, Charlottesville, VA
  1. Corresponding authors: Hetal Shah, hetal.shah{at}joslin.harvard.edu, and Alessandro Doria, alessandro.doria{at}joslin.harvard.edu
  1. H.S. and A.D. contributed equally to this work and are co-senior authors.

Diabetes 2019 Aug; 68(8): 1649-1662. https://doi.org/10.2337/db19-0109
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Abstract

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.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db19-0109/-/DC1.

  • Received January 31, 2019.
  • Accepted May 13, 2019.
  • © 2019 by the American Diabetes Association.
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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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A Genetic Locus on Chromosome 2q24 Predicting Peripheral Neuropathy Risk in Type 2 Diabetes: Results From the ACCORD and BARI 2D Studies
Yaling Tang, Petra A. Lenzini, Rodica Pop-Busui, Pradipta R. Ray, Hannah Campbell, Bruce A. Perkins, Brian Callaghan, Michael J. Wagner, Alison A. Motsinger-Reif, John B. Buse, Theodore J. Price, Josyf C. Mychaleckyj, Sharon Cresci, Hetal Shah, Alessandro Doria
Diabetes Aug 2019, 68 (8) 1649-1662; DOI: 10.2337/db19-0109

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A Genetic Locus on Chromosome 2q24 Predicting Peripheral Neuropathy Risk in Type 2 Diabetes: Results From the ACCORD and BARI 2D Studies
Yaling Tang, Petra A. Lenzini, Rodica Pop-Busui, Pradipta R. Ray, Hannah Campbell, Bruce A. Perkins, Brian Callaghan, Michael J. Wagner, Alison A. Motsinger-Reif, John B. Buse, Theodore J. Price, Josyf C. Mychaleckyj, Sharon Cresci, Hetal Shah, Alessandro Doria
Diabetes Aug 2019, 68 (8) 1649-1662; DOI: 10.2337/db19-0109
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