Journal
HUMAN GENOMICS
Volume 13, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s40246-019-0205-7
Keywords
African Americans; Genome-wide association study; Type 2 diabetes; Diabetic kidney disease; End-stage kidney disease
Categories
Funding
- National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services [HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, HHSN268201700005I, R01HL087641, R01HL086694]
- National Human Genome Research Institute [U01HG004402]
- National Institutes of Health [HHSC268200782096C, UL1RR025005]
- NIH Roadmap for Medical Research
- National Heart, Lung, and Blood Institute (NHLBI)
- University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]
- Northwestern University [HHSN268201300027C]
- University of Minnesota [HHSN268201300028C]
- Kaiser Foundation Research Institute [HHSN268201300029C]
- Johns Hopkins University School of Medicine [HHSN268200900041C]
- Intramural Research Program of the National Institute on Aging (NIA)
- NIA [AG0005]
- NHLBI [AG0005, N02-HL-64278]
- NHLBI Candidate-gene Association Resource [N01-HC-65226]
- NIDDK [DK07024]
- Intramural Research Program of the NIDDK
- National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300049C, HHSN268201300050C, HHSN268201300048C, HHSN268201300046C, HHSN268201300047C]
- National Institute for Minority Health and Health Disparities (NIMHD) [HHSN268201300049C, HHSN268201300050C, HHSN268201300048C, HHSN268201300046C, HHSN268201300047C]
- National Center for Advancing Translational Sciences, CTSI [UL1TR001881]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]
- NIH [K99 DK081350, R01 DK066358, R01 DK053591, R01 DK087914, U01 DK105556, R01 HL56266, R01 DK070941]
- General Clinical Research Center of the Wake Forest School of Medicine [M01 RR07122]
- [U01DK57292]
- [U01DK57329]
- [U01DK057300]
- [U01DK057298]
- [U01DK057249]
- [U01DK57295]
- [U01DK070657]
- [U01DK057303]
- [U01DK57304]
- [HHSN268201500003I]
- [N01-HC-95159]
- [N01-HC-95160]
- [N01-HC-95161]
- [N01-HC-95162]
- [N01-HC-95163]
- [N01-HC-95164]
- [N01-HC-95165]
- [N01-HC-95166]
- [N01-HC-95167]
- [N01-HC-95168]
- [N01-HC-95169]
- [UL1-TR-000040]
- [UL1-TR-001079]
- [UL1-TR-001420]
- [UL1-TR-001881]
Ask authors/readers for more resources
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<5x10(-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=9.84x10(-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=2.17x10(-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.
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