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

Citation
Guan, M., et al. “Genome-Wide Association Study Identifies Novel Loci For Type 2 Diabetes-Attributed End-Stage Kidney Disease In African Americans.”. Human Genomics, p. 21.
Center UCSD-UCLA University of Alabama at Birmingham
Multicenter
Multicenter
Author 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
Keywords African Americans, diabetic kidney disease, End-stage kidney disease, genome-wide association study, type 2 diabetes
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) 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; 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, 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.

Year of Publication
2019
Journal
Human genomics
Volume
13
Issue
1
Number of Pages
21
Date Published
12/2019
ISSN Number
1479-7364
DOI
10.1186/s40246-019-0205-7
Alternate Journal
Hum. Genomics
PMID
31092297
PMCID
PMC6521376
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