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

Meijian Guan; Jacob M Keaton; Latchezar Dimitrov; Pamela J Hicks; Jianzhao Xu; Nicholette D Palmer; Lijun Ma; Swapan K Das; Yii-Der I Chen; Josef Coresh; Myriam Fornage; Nora Franceschini; Holly Kramer; Carl D Langefeld; Josyf C Mychaleckyj; Rulan S Parekh; Wendy S Post; Laura J Rasmussen-Torvik; Stephen S Rich; Jerome I Rotter; John R Sedor; Denyse Thornley-Brown; Adrienne Tin; James G Wilson; Barry I Freedman; Donald W Bowden; Maggie C Y Ng; FIND Consortium

doi:10.1186/s40246-019-0205-7

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

Hum Genomics. 2019 May 15;13(1):21. doi: 10.1186/s40246-019-0205-7.

Authors

Meijian Guan^{1

2}, Jacob M Keaton^{1

2}, Latchezar Dimitrov^{1

2}, Pamela J Hicks^{1

2}, Jianzhao Xu^{1

2}, Nicholette D Palmer^{1

2

3}, Lijun Ma⁴, Swapan K Das⁵, Yii-Der I Chen⁶, Josef Coresh⁷, Myriam Fornage⁸, Nora Franceschini⁹, Holly Kramer^{10

11}, Carl D Langefeld^{12

13}, Josyf C Mychaleckyj¹⁴, Rulan S Parekh¹⁵, Wendy S Post⁷, Laura J Rasmussen-Torvik¹⁶, Stephen S Rich¹⁴, Jerome I Rotter^{6

17}, John R Sedor^{18

19}, Denyse Thornley-Brown²⁰, Adrienne Tin⁷, James G Wilson²¹, Barry I Freedman⁴, Donald W Bowden^{1

2

3}, Maggie C Y Ng^{22

23

24}; FIND Consortium

Collaborators

FIND Consortium:
A Bobelu, A Horvath, A Pickens, B Kessing, B Waseta, B I Freedman, B S Kasinath, C Garcia, C Jefferson, C Luethe, C D Langefeld, C S Brown, C Winkler, D Thornley-Brown, D Warnock, D J Leehey, D W Bowden, E Hernandez, E Ipp, F Hariri, F Thameem, G Barone, G Brooks, G Jun, G M Dunston, H Abboud, I Sili, J Chester, J Fondran, J LaPage, J Molineros, J Rioux, J Rotter, J Schelling, J Sewemaenewa, J Tayek, J Gonzalez, J M Olson, J P Briggs, J R Sedor, J Wolford, K Kramp, K Taylor, K A B Goddard, L Cardon, L Getz-Fradley, L Humbert, L Jones, L Kao, L Meoni, L M Phillips, M Aguilar, M Budgett, M Klag, M Pahl, M Spainhour, M Stern, M Thompson, M F Saad, M F Seldin, M Scavini, M W Smith, N Arar, O F Kohn, P Zager, P L Kimmel, R Chakraborty, R Duggirala, R Hanson, R Igo Jr, R Juan, R Lovelace, R Parekh, R Rasooly, R Spielman, R Young, R C Elston, R G Nelson, R L Hanson, S Adler, S Ialacci, S Snyder, S Viverette, S Warren, S B Nicholas, S C Satko, S J O'Brien, S K Iyengar, S S Rich, T Hostetter, T Whitehead, V Shah, W C Knowler, X Guo, Y-D I Chen

Affiliations

¹ Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
² Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
⁴ Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁵ Department of Internal Medicine, Section on Endocrinology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁶ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁷ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁸ Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁹ Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Departments of Public Health Sciences and Medicine, Division of Nephrology and Hypertension, Loyola University Chicago, Maywood, IL, USA.
¹¹ Department of Medicine, Hines Veteran's Affairs Medical Center, Hines, IL, USA.
¹² Center for Public Health Genomics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹³ Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹⁴ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁵ Departments of Paediatrics and Medicine, Hospital for Sick Children, University Health Network and the University of Toronto, Toronto, ON, Canada.
¹⁶ Department of Preventive Medicine, Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁷ Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁸ Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA.
¹⁹ Glickman Urology and Kidney Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
²⁰ Nephrology, University of Alabama Birmingham, Birmingham, AL, USA.
²¹ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
²² Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA. maggie.ng@vumc.org.
²³ Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA. maggie.ng@vumc.org.
²⁴ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. maggie.ng@vumc.org.

Abstract

Background: End-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.

Results: Six 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.

Conclusions: Findings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.

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

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Abstract

Publication types

Grants and funding