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Diabetes, lower extremity amputation, loss of protective sensation, and neuronal nitric oxide synthase associated protein in the Chronic Renal Insufficiency Cohort study

Authors

  • David J. Margolis MD, PhD,

    Corresponding author
    1. Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania
    2. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania
    • Reprint requests:

      Dr. David J Margolis, 901 Blockely Hall, 423 Guardian Drive, Perelman School of Medicine, Philadelphia, PA 19104, USA.

      Tel: +1 215 898 4938;

      Fax: +1 215 573 5315;

      Email: margo@mail.med.upenn.edu

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  • Jayanta Gupta MD, PhD,

    1. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Stephen R. Thom MD, PhD,

    1. Department of Emergency Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Raymond R. Townsend MD,

    1. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Peter A. Kanetsky PhD, MPH,

    1. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Ole Hoffstad MS,

    1. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Maryte Papdopoulos BA,

    1. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Michael Fischer MD,

    1. Department of Medicine, Jesse Brown VA Medical Center and University of Hospital and Health Sciences System, Chicago, Illinois
    2. Center for Management of Complex Chronic Care, Edward Hines Jr., VA Hospital, Hines, Illinois
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  • Jeffrey R. Schelling MD,

    1. Case Western Reserve University and MetroHealth Medical Center, Cincinnati, Ohio
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  • Nandita Mitra PhD

    1. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania
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  • And all other Chronic Renal Insufficiency Cohort (CRIC) study investigators

Abstract

Lower extremity amputation (LEA) is a life-altering complication of diabetes. The goal of our study was to investigate the possibility that genetic variation in neuronal nitric oxide synthase associated protein (NOS1AP) is associated with LEA and diabetic peripheral neuropathy (DPN). Our work used data from the Chronic Renal Insufficiency Cohort (CRIC) study. CRIC is a multicenter investigation undertaken to pursue the relationship between chronic renal insufficiency and cardiovascular disease. We evaluated 3,040 CRIC study subjects; 1,490 individuals were African Americans and 1,550 were whites. LEA occurred in 162 (5.3%) subjects, 93 (6.2%) of African Americans and 69 (4.4%) of whites. In whites, NOS1AP single nucleotide polymorphism rs1963645 was most strongly associated with LEA (1.73 [1.23, 2.44]). In African Americans three NOS1AP single nucleotide polymorphisms were associated with LEA: rs6659759 (1.65 [1.21, 2.24]); rs16849113 (1.58 [1.16, 2.14]); rs880296 (1.54 [1.14, 2.10]). We tested a subset of 100 CRIC participants for DPN using Semmes–Weinstein filaments. DPN in those with diabetes was associated with rs1963645 (16.97 [2.38, 120.97]) in whites and rs16849113 and rs6659759 (3.62 [1.11, 11.83] and 3.02 [0.82, 11.12], respectively) in African Americans. In conclusion, this is one of the first studies to show that NOS1AP gene variants are associated with DPN and LEA.

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