title: Analysis of coding variants identified from exome sequencing resources for association with diabetic and non-diabetic nephropathy in African Americans.
abstract: Prior studies have identified common genetic variants influencing diabetic and non-diabetic nephropathy, diseases which disproportionately affect African Americans. Recently, exome sequencing techniques have facilitated identification of coding variants on a genome-wide basis in large samples. Exonic variants in known or suspected end-stage kidney disease (ESKD) or nephropathy genes can be tested for their ability to identify association either singly or in combination with known associated common variants. Coding variants in genes with prior evidence for association with ESKD or nephropathy were identified in the NHLBI-ESP GO database and genotyped in 5,045 African Americans (3,324 cases with type 2 diabetes associated nephropathy [T2D-ESKD] or non-T2D ESKD, and 1,721 controls) and 1,465 European Americans (568 T2D-ESKD cases and 897 controls). Logistic regression analyses were performed to assess association, with admixture and APOL1 risk status incorporated as covariates. Ten of 31 SNPs were associated in African Americans; four replicated in European Americans. In African Americans, SNPs in OR2L8, OR2AK2, C6orf167 (MMS22L), LIMK2, APOL3, APOL2, and APOL1 were nominally associated (P = 1.8 × 10(-4)-0.044). Haplotype analysis of common and coding variants increased evidence of association at the OR2L13 and APOL1 loci (P = 6.2 × 10(-5) and 4.6 × 10(-5), respectively). SNPs replicating in European Americans were in OR2AK2, LIMK2, and APOL2 (P = 0.0010-0.037). Meta-analyses highlighted four SNPs associated in T2D-ESKD and all-cause ESKD. Results from this study suggest a role for coding variants in the development of diabetic, non-diabetic, and/or all-cause ESKD in African Americans and/or European Americans.
authors.affiliation: Program in Molecular Medicine and Translational Science, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Center for Diabetes Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.
authors.forename: Jessica N Cooke
authors.initials: JNC
authors.lastname: Bailey
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Center for Diabetes Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Department of Biochemistry, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Center for Diabetes Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.
authors.forename: Maggie C Y
authors.initials: MCY
authors.lastname: Ng
authors.affiliation: Program in Molecular Medicine and Translational Science, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Center for Diabetes Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Bonomo
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Center for Diabetes Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Department of Biochemistry, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hicks
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Center for Diabetes Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Hester
authors.affiliation: Department of Biostatistical Sciences - Division of Public Health Sciences, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Department of Internal Medicine - Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Center for Diabetes Research, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Department of Biochemistry, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.|Department of Internal Medicine - Section on Endocrinology; Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D000328:Adult; D001741:Black or African American; D000368:Aged; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D030541:Databases, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000208:ethnology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005260:Female; 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; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D014481:United States; D044465:White People
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL