title: Diabetes, lower extremity amputation, loss of protective sensation, and neuronal nitric oxide synthase associated protein in the chronic renal insufficiency cohort study.
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.
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. margo@mail.med.upenn.edu
authors.forename: David J
authors.initials: DJ
authors.lastname: Margolis
authors.forename: Jayanta
authors.initials: J
authors.lastname: Gupta
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Thom
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Townsend
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kanetsky
authors.forename: Ole
authors.initials: O
authors.lastname: Hoffstad
authors.forename: Maryte
authors.initials: M
authors.lastname: Papdopoulos
authors.forename: Michael
authors.initials: M
authors.lastname: Fischer
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Schelling
authors.forename: Nandita
authors.initials: N
authors.lastname: Mitra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000671:Amputation, Surgical / Q000706:statistics & numerical data*; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000453:epidemiology* / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics; D003925:Diabetic Angiopathies / Q000453:epidemiology* / Q000235:genetics; D003929:Diabetic Neuropathies / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000453:epidemiology* / Q000235:genetics; D035002:Lower Extremity / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C488081:NOS1AP protein, human