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. RotterJohn R. Sedor, Denyse Thornley-Brown, Adrienne Tin, James G. Wilson, Barry I. Freedman, Donald W. Bowden, Maggie C.Y. Ng

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number21
JournalHuman genomics
Volume13
Issue number1
DOIs
StatePublished - May 15 2019

Keywords

  • African Americans
  • Diabetic kidney disease
  • End-stage kidney disease
  • Genome-wide association study
  • Type 2 diabetes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Drug Discovery

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    Guan, M., Keaton, J. M., Dimitrov, L., Hicks, P. J., Xu, J., Palmer, N. D., Ma, L., Das, S. K., Chen, Y. D. I., Coresh, J., Fornage, M., Franceschini, N., Kramer, H., Langefeld, C. D., Mychaleckyj, J. C., Parekh, R. S., Post, W. S., Rasmussen-Torvik, L. J., Rich, S. S., ... Ng, M. C. Y. (2019). Genome-wide association study identifies novel loci for type 2 diabetes-Attributed end-stage kidney disease in African Americans. Human genomics, 13(1), [21]. https://doi.org/10.1186/s40246-019-0205-7