Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans

Human Genomics

Stephen S. Rich¹  Josyf C. Mychaleckyj¹  Myriam Fornage²  Holly Kramer³  Wendy S. Post⁴  Josef Coresh⁴  Adrienne Tin⁴  Latchezar Dimitrov⁵  Jacob M. Keaton⁵  Pamela J. Hicks⁵  Meijian Guan⁵  Jianzhao Xu⁵  Donald W. Bowden⁶  Maggie C. Y. Ng⁶  Nicholette D. Palmer⁶  Carl D. Langefeld⁷  Swapan K. Das⁸  Barry I. Freedman⁹  Lijun Ma⁹  Laura J. Rasmussen-Torvik^1,10  John R. Sedor^1,11  Rulan S. Parekh^1,12  James G. Wilson^1,13  Denyse Thornley-Brown^1,14  Nora Franceschini^1,15  Yii-Der I. Chen^1,16  Jerome I. Rotter^1,17 

[1] 0000 0000 9136 933X, grid.27755.32, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA;0000 0000 9206 2401, grid.267308.8, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA;0000 0001 1089 6558, grid.164971.c, Departments of Public Health Sciences and Medicine, Division of Nephrology and Hypertension, Loyola University Chicago, Maywood, IL, USA;Department of Medicine, Hines Veteran’s Affairs Medical Center, Hines, IL, USA;0000 0001 2171 9311, grid.21107.35, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA;0000 0001 2185 3318, grid.241167.7, Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA;0000 0001 2185 3318, grid.241167.7, Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA;0000 0001 2185 3318, grid.241167.7, Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA;0000 0001 2185 3318, grid.241167.7, Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA;0000 0001 2185 3318, grid.241167.7, Department of Biochemistry, Wake Forest School of Medicine, 27157, Winston-Salem, NC, USA;0000 0001 2185 3318, grid.241167.7, Center for Public Health Genomics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA;0000 0001 2185 3318, grid.241167.7, Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA;0000 0001 2185 3318, grid.241167.7, Department of Internal Medicine, Section on Endocrinology, Wake Forest School of Medicine, Winston-Salem, NC, USA;0000 0001 2185 3318, grid.241167.7, Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA;0000 0001 2299 3507, grid.16753.36, Department of Preventive Medicine, Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;0000 0004 0435 0569, grid.254293.b, Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA;0000 0001 0675 4725, grid.239578.2, Glickman Urology and Kidney Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA;0000 0004 0474 0428, grid.231844.8, Departments of Paediatrics and Medicine, Hospital for Sick Children, University Health Network and the University of Toronto, Toronto, ON, Canada;0000 0004 1937 0407, grid.410721.1, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA;0000000106344187, grid.265892.2, Nephrology, University of Alabama Birmingham, Birmingham, AL, USA;0000000122483208, grid.10698.36, Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA;Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA;Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA;Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA;

关键词: African Americans;    Genome-wide association study;    Type 2 diabetes;    Diabetic kidney disease;    End-stage kidney disease;   

DOI  :  10.1186/s40246-019-0205-7

来源: publisher

【 摘 要 】

BackgroundEnd-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants.ResultsSix independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P < 5 × 10−8) with T2D-ESKD. Following extension analyses in 1910 non-diabetic ESKD cases and 908 non-diabetic non-nephropathy controls, a meta-analysis of 5342 AA all-cause ESKD cases and 6977 AA non-diabetic non-nephropathy controls revealed an additional novel all-cause ESKD locus at EFNB2 (rs77113398; P = 9.84 × 10–9; OR = 1.94). Exclusion of APOL1 renal-risk genotype carriers identified two additional genome-wide significant T2D-ESKD-associated loci at GRAMD3 and MGAT4C. A second variant at GNG7 (rs373971520; P = 2.17 × 10–8, OR = 1.46) remained associated with all-cause ESKD in the APOL1-negative analysis.ConclusionsFindings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.

【 授权许可】

CC BY