title: Evaluation of candidate nephropathy susceptibility genes in a genome-wide association study of African American diabetic kidney disease.
abstract: Type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) is a complex disorder resulting from the combined influence of genetic and environmental factors. This study contains a comprehensive genetic analysis of putative nephropathy loci in 965 African American (AA) cases with T2D-ESKD and 1029 AA population-based controls extending prior findings. Analysis was based on 4,341 directly genotyped and imputed single nucleotide polymorphisms (SNPs) in 22 nephropathy candidate genes. After admixture adjustment and correction for multiple comparisons, 37 SNPs across eight loci were significantly associated (1.6E-05<P(emp)<0.049). Among these, variants in MYH9 were the most significant (1.6E-05<P(emp)<0.049), followed by additional chromosome 22 loci (APOL1, SFI1, and LIMK2). Nominal signals were observed in AGTR1, RPS12, CHN2 and CNDP1. Additional adjustment for APOL1 G1/G2 risk variants attenuated association at MYH9 (P(emp) = 0.00026-0.043) while marginally improving significance of other APOL1 SNPs (rs136161, rs713753, and rs767855; P(emp) = 0.0060-0.037); association at other loci was markedly reduced except for CHN2 (chimerin; rs17157914, P(emp)= 0.029). In addition, SNPs in other candidate loci (FRMD3 and TRPC6) trended toward association with T2D-ESKD (P(emp)<0.05). These results suggest that risk contributed by putative nephropathy genes is shared across populations of African and European ancestry.
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America ; Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America ; Diabetes Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America ; Diabetes Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hicks
authors.affiliation: Diabetes Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Poorva
authors.initials: P
authors.lastname: Mudgal
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America ; Diabetes Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America ; Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America ; Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America ; Diabetes Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America ; Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D001741:Black or African American; D000368:Aged; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D007676:Kidney Failure, Chronic / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D008075:Lipoproteins, HDL / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020409:Molecular Motor Proteins / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains