title: Association of kidney structure-related gene variants with type 2 diabetes-attributed end-stage kidney disease in African Americans.
abstract: African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD) compared to European Americans. Genome-wide association studies have identified variants associated with diabetic and non-diabetic kidney diseases. Nephropathy loci, including SLC7A9, UMOD, and SHROOM3, have been implicated in the maintenance of normal glomerular and renal tubular structure and function. Herein, 47 genes important in podocyte, glomerular basement membrane, mesangial cell, mesangial matrix, renal tubular cell, and renal interstitium structure were examined for association with type 2 diabetes (T2D)-attributed ESKD in AAs. Single-variant association analysis was performed in the discovery stage, including 2041 T2D-ESKD cases and 1140 controls (non-diabetic, non-nephropathy). Discrimination analyses in 667 T2D cases-lacking nephropathy excluded T2D-associated SNPs. Nominal associations were tested in an additional 483 T2D-ESKD cases and 554 controls in the replication stage. Meta-analysis of 4218 discovery and replication samples revealed three significant associations with T2D-ESKD at CD2AP and MMP2 (Pcorr< 0.05 corrected for effective number of SNPs in each locus). Removal of APOL1 renal-risk genotype carriers revealed additional association at five loci, TTC21B, COL4A3, NPHP3-ACAD11, CLDN8, and ARHGAP24 (Pcorr< 0.05). Genetic variants at COL4A3, CLDN8, and ARHGAP24 were potentially pathogenic. Gene-based associations revealed suggestive significant aggregate effects of coding variants at four genes. Our findings suggest that genetic variation in kidney structure-related genes may contribute to T2D-attributed ESKD in the AA population.
authors.affiliation: Center for Genomics and Personalized Medicine Research, Medical Center Boulevard, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Meijian
authors.initials: M
authors.lastname: Guan
authors.affiliation: Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Center for Genomics and Personalized Medicine Research, Medical Center Boulevard, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Keaton
authors.affiliation: Center for Genomics and Personalized Medicine Research, Medical Center Boulevard, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Latchezar
authors.initials: L
authors.lastname: Dimitrov
authors.affiliation: Center for Genomics and Personalized Medicine Research, Medical Center Boulevard, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Poorva
authors.initials: P
authors.lastname: Mudgal
authors.affiliation: Center for Genomics and Personalized Medicine Research, Medical Center Boulevard, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Stromberg
authors.affiliation: Center for Genomics and Personalized Medicine Research, Medical Center Boulevard, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Bonomo
authors.affiliation: Center for Genomics and Personalized Medicine Research, Medical Center Boulevard, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hicks
authors.affiliation: Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Center for Genomics and Personalized Medicine Research, Medical Center Boulevard, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.affiliation: Center for Genomics and Personalized Medicine Research, Medical Center Boulevard, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. mng@wakehealth.edu.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA. mng@wakehealth.edu.
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D003598:Cytoskeletal Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D050533:Glomerular Basement Membrane / Q000378:metabolism / Q000648:ultrastructure; D006239:Haplotypes; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000235:genetics* / Q000473:pathology; D007686:Kidney Tubules, Distal / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D050527:Mesangial Cells / Q000378:metabolism / Q000648:ultrastructure; D008875:Middle Aged; D050199:Podocytes / Q000378:metabolism / Q000648:ultrastructure; D020641:Polymorphism, Single Nucleotide; D044465:White People
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2