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

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

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 journal › Article › peer-review

9 Scopus citations

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 language	English (US)
Article number	21
Journal	Human genomics
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s40246-019-0205-7
State	Published - 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

Access to Document

10.1186/s40246-019-0205-7

Cite this

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

Guan, M, Keaton, JM, Dimitrov, L, Hicks, PJ, Xu, J, Palmer, ND, Ma, L, Das, SK, Chen, YDI, Coresh, J, Fornage, M, Franceschini, N, Kramer, H, Langefeld, CD, Mychaleckyj, JC, Parekh, RS, Post, WS, Rasmussen-Torvik, LJ, Rich, SS, Rotter, JI, Sedor, JR, Thornley-Brown, D, Tin, A, Wilson, JG, Freedman, BI, Bowden, DW & Ng, MCY 2019, 'Genome-wide association study identifies novel loci for type 2 diabetes-Attributed end-stage kidney disease in African Americans', Human genomics, vol. 13, no. 1, 21. https://doi.org/10.1186/s40246-019-0205-7

@article{ae25add1a0ea4d128bef2903cc71d859,

title = "Genome-wide association study identifies novel loci for type 2 diabetes-Attributed end-stage kidney disease in African Americans",

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",

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

note = "Funding Information: Duggirala, **B.S. Kasinath, **F. Thameem, **M. Stern; Wake-Forest University: *‡B.I. Freedman, **D.W. Bowden, **C.D. Langefeld, **S.C. Satko, **S.S. Rich, #S. Warren, S. Viverette, G. Brooks, R. Young, M. Spainhour; Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD: *C. Winkler, **M.W. Smith, M. Thompson, #R. Hanson, B. Kessing; Minority Recruitment Centers: Loyola University: *D.J. Leehey, #G. Barone; University of Alabama at Birmingham: *D. Thornley-Brown, #C. Jefferson; University of Chicago: *O.F. Kohn, #C.S. Brown; NIDDK program office: J.P. Briggs, P.L. Kimmel, R. Rasooly; External Advisory Committee: D. Warnock (chair), L. Cardon, R. Chakraborty, G.M. Dunston, T. Hostetter, S.J. O{\textquoteright}Brien (ad hoc), J. Rioux, R. Spielman. We acknowledge the contributions of the Wake Forest participants and coordinators Joyce Byers, Carrie Smith, Mitzie Spainhour, Cassandra Bethea, and Sharon Warren and the contributions of FIND participants and physicians and CHOICE patients, staff, laboratory, and physicians at Dialysis Clinic Inc. and Johns Hopkins University. JHS The Jackson Heart Study is supported and conducted in collaboration with Jackson State University (HHSN268201300049C and HHSN268201300050C), Tougaloo College (HHSN268201300048C), and the University of Mississippi Medical Center (HHSN268201300046C and HHSN268201300047C) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). The authors thank the participants and data collection staff of the Jackson Heart Study. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. MESA MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 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, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Also, supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Genotyping was performed at Affymetrix (Santa Clara, CA, USA) and the Broad Institute of Harvard and MIT (Boston, MA, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. WFSM In Wake Forest School of Medicine (WFSM), genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSC268200782096C. The work at Wake Forest was supported by NIH grants K99 DK081350 (NDP), R01 DK066358 (DWB/MCYN), R01 DK053591 (DWB), R01 DK087914 (MCYN), U01 DK105556 (MCYN), R01 HL56266 (BIF), R01 DK070941 (BIF) and in part by the General Clinical Research Center of the Wake Forest School of Medicine grant M01 RR07122. Funding Information: ARIC has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. CARDIA is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C & HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). Genotyping was funded as part of the NHLBI Candidate-gene Association Resource (N01-HC-65226). FIND is supported by grants U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, U01DK070657, U01DK57304 and CHOICE study DK07024 from the NIDDK and in part by the Intramural Research Program of the NIDDK. JHS is supported and conducted in collaboration with Jackson State University (HHSN268201300049C and HHSN268201300050C), Tougaloo College (HHSN268201300048C), and the University of Mississippi Medical Center (HHSN268201300046C and HHSN268201300047C) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). Support for MESA is provided by contracts 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, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Also, supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The genotyping services of WFSM were provided by CIDR, which is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSC268200782096C. The work at Wake Forest was supported by NIH grants K99 DK081350 (NDP), R01 DK066358 (DWB/MCYN), R01 DK053591 (DWB), R01 DK087914 (MCYN), U01 DK105556 (MCYN), R01 HL56266 (BIF), R01 DK070941 (BIF) and in part by the General Clinical Research Center of the Wake Forest School of Medicine grant M01 RR07122. Funding Information: We thank all the study participants for their valuable contributions to the parent studies (ARIC, CARDIA, FIND, JHS, MESA, WFSM). We thank the contributions of investigators and staff of the parent studies for data collection, genotyping, and data analysis. ARIC The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I), R01HL087641, R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. CARDIA The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C & HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). Genotyping was funded as part of the NHLBI Candidate-gene Association Resource (N01-HC-65226). This manuscript has been reviewed by CARDIA for scientific content. FIND This study was also supported by FIND grants U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, U01DK070657, U01DK57304, and CHOICE study DK07024 from the NIDDK and in part by the Intramural Research Program of the NIDDK. A list of the members of the FIND Research Group follows (key: *Principal Investigator; **Co-investigator; #Program Coordinator; §University of California, Davis; †University of California, Irvine; ‡Study Chair). Genetic Analysis and Data Coordinating Center, Case Western Reserve University: *S.K. Iyengar,**R.C. Elston,**K.A.B. Goddard,**J.M. Olson, S. Ialacci, # J. Fondran, A. Horvath, R. Igo Jr., G. Jun, K. Kramp, J. Molineros, S.R.E. Quade; Case Western Reserve University: *J.R. Sedor, **J. Schelling, #A. Pickens, L. Humbert, L. Getz-Fradley; Harbor-University of California Los Angeles Medical Center: *S. Adler, **E. Ipp, **†M. Pahl, **§M.F. Seldin, ** S. Snyder, **J. Tayek, #E. Hernandez, #J. LaPage, C. Garcia, J. Gonzalez, M. Aguilar; Johns Hopkins University: *M. Klag, *R. Parekh, **L. Kao, **L. Meoni, T. Whitehead, #J. Chester; NIDDK, Phoenix, AZ: *W.C. Knowler, **R.L. Hanson, **R.G. Nelson, **J. Wolford, #L. Jones, R. Juan, R. Lovelace, C. Luethe, L.M. Phillips, J. Sewemaenewa, I. Sili, B. Waseta; University of California, Los Angeles: *M.F. Saad, *S.B. Nicholas, **Y.-D.I. Chen, **X. Guo, **J. Rotter, **K. Taylor, M. Budgett, #F. Hariri; University of New Mexico, Albuquerque: *P. Zager, *V. Shah, **M. Scavini, #A. Bobelu; University of Texas Health Science Center at San Antonio: *H. Abboud, **N. Arar, **R. Publisher Copyright: {\textcopyright} 2019 The Author(s).",

year = "2019",

month = may,

day = "15",

doi = "10.1186/s40246-019-0205-7",

language = "English (US)",

volume = "13",

journal = "Human Genomics",

issn = "1473-9542",

publisher = "Henry Stewart Publications",

number = "1",

}

TY - JOUR

T1 - Genome-wide association study identifies novel loci for type 2 diabetes-Attributed end-stage kidney disease in African Americans

AU - Guan, Meijian

AU - Keaton, Jacob M.

AU - Dimitrov, Latchezar

AU - Hicks, Pamela J.

AU - Xu, Jianzhao

AU - Palmer, Nicholette D.

AU - Ma, Lijun

AU - Das, Swapan K.

AU - Chen, Yii Der I.

AU - Coresh, Josef

AU - Fornage, Myriam

AU - Franceschini, Nora

AU - Kramer, Holly

AU - Langefeld, Carl D.

AU - Mychaleckyj, Josyf C.

AU - Parekh, Rulan S.

AU - Post, Wendy S.

AU - Rasmussen-Torvik, Laura J.

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Sedor, John R.

AU - Thornley-Brown, Denyse

AU - Tin, Adrienne

AU - Wilson, James G.

AU - Freedman, Barry I.

AU - Bowden, Donald W.

AU - Ng, Maggie C.Y.

N1 - Funding Information: Duggirala, **B.S. Kasinath, **F. Thameem, **M. Stern; Wake-Forest University: *‡B.I. Freedman, **D.W. Bowden, **C.D. Langefeld, **S.C. Satko, **S.S. Rich, #S. Warren, S. Viverette, G. Brooks, R. Young, M. Spainhour; Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD: *C. Winkler, **M.W. Smith, M. Thompson, #R. Hanson, B. Kessing; Minority Recruitment Centers: Loyola University: *D.J. Leehey, #G. Barone; University of Alabama at Birmingham: *D. Thornley-Brown, #C. Jefferson; University of Chicago: *O.F. Kohn, #C.S. Brown; NIDDK program office: J.P. Briggs, P.L. Kimmel, R. Rasooly; External Advisory Committee: D. Warnock (chair), L. Cardon, R. Chakraborty, G.M. Dunston, T. Hostetter, S.J. O’Brien (ad hoc), J. Rioux, R. Spielman. We acknowledge the contributions of the Wake Forest participants and coordinators Joyce Byers, Carrie Smith, Mitzie Spainhour, Cassandra Bethea, and Sharon Warren and the contributions of FIND participants and physicians and CHOICE patients, staff, laboratory, and physicians at Dialysis Clinic Inc. and Johns Hopkins University. JHS The Jackson Heart Study is supported and conducted in collaboration with Jackson State University (HHSN268201300049C and HHSN268201300050C), Tougaloo College (HHSN268201300048C), and the University of Mississippi Medical Center (HHSN268201300046C and HHSN268201300047C) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). The authors thank the participants and data collection staff of the Jackson Heart Study. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. MESA MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 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, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Also, supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Genotyping was performed at Affymetrix (Santa Clara, CA, USA) and the Broad Institute of Harvard and MIT (Boston, MA, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. WFSM In Wake Forest School of Medicine (WFSM), genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSC268200782096C. The work at Wake Forest was supported by NIH grants K99 DK081350 (NDP), R01 DK066358 (DWB/MCYN), R01 DK053591 (DWB), R01 DK087914 (MCYN), U01 DK105556 (MCYN), R01 HL56266 (BIF), R01 DK070941 (BIF) and in part by the General Clinical Research Center of the Wake Forest School of Medicine grant M01 RR07122. Funding Information: ARIC has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. CARDIA is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C & HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). Genotyping was funded as part of the NHLBI Candidate-gene Association Resource (N01-HC-65226). FIND is supported by grants U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, U01DK070657, U01DK57304 and CHOICE study DK07024 from the NIDDK and in part by the Intramural Research Program of the NIDDK. JHS is supported and conducted in collaboration with Jackson State University (HHSN268201300049C and HHSN268201300050C), Tougaloo College (HHSN268201300048C), and the University of Mississippi Medical Center (HHSN268201300046C and HHSN268201300047C) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). Support for MESA is provided by contracts 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, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Also, supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The genotyping services of WFSM were provided by CIDR, which is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSC268200782096C. The work at Wake Forest was supported by NIH grants K99 DK081350 (NDP), R01 DK066358 (DWB/MCYN), R01 DK053591 (DWB), R01 DK087914 (MCYN), U01 DK105556 (MCYN), R01 HL56266 (BIF), R01 DK070941 (BIF) and in part by the General Clinical Research Center of the Wake Forest School of Medicine grant M01 RR07122. Funding Information: We thank all the study participants for their valuable contributions to the parent studies (ARIC, CARDIA, FIND, JHS, MESA, WFSM). We thank the contributions of investigators and staff of the parent studies for data collection, genotyping, and data analysis. ARIC The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I), R01HL087641, R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. CARDIA The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C & HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). Genotyping was funded as part of the NHLBI Candidate-gene Association Resource (N01-HC-65226). This manuscript has been reviewed by CARDIA for scientific content. FIND This study was also supported by FIND grants U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, U01DK070657, U01DK57304, and CHOICE study DK07024 from the NIDDK and in part by the Intramural Research Program of the NIDDK. A list of the members of the FIND Research Group follows (key: *Principal Investigator; **Co-investigator; #Program Coordinator; §University of California, Davis; †University of California, Irvine; ‡Study Chair). Genetic Analysis and Data Coordinating Center, Case Western Reserve University: *S.K. Iyengar,**R.C. Elston,**K.A.B. Goddard,**J.M. Olson, S. Ialacci, # J. Fondran, A. Horvath, R. Igo Jr., G. Jun, K. Kramp, J. Molineros, S.R.E. Quade; Case Western Reserve University: *J.R. Sedor, **J. Schelling, #A. Pickens, L. Humbert, L. Getz-Fradley; Harbor-University of California Los Angeles Medical Center: *S. Adler, **E. Ipp, **†M. Pahl, **§M.F. Seldin, ** S. Snyder, **J. Tayek, #E. Hernandez, #J. LaPage, C. Garcia, J. Gonzalez, M. Aguilar; Johns Hopkins University: *M. Klag, *R. Parekh, **L. Kao, **L. Meoni, T. Whitehead, #J. Chester; NIDDK, Phoenix, AZ: *W.C. Knowler, **R.L. Hanson, **R.G. Nelson, **J. Wolford, #L. Jones, R. Juan, R. Lovelace, C. Luethe, L.M. Phillips, J. Sewemaenewa, I. Sili, B. Waseta; University of California, Los Angeles: *M.F. Saad, *S.B. Nicholas, **Y.-D.I. Chen, **X. Guo, **J. Rotter, **K. Taylor, M. Budgett, #F. Hariri; University of New Mexico, Albuquerque: *P. Zager, *V. Shah, **M. Scavini, #A. Bobelu; University of Texas Health Science Center at San Antonio: *H. Abboud, **N. Arar, **R. Publisher Copyright: © 2019 The Author(s).

PY - 2019/5/15

Y1 - 2019/5/15

N2 - 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.

AB - 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.

KW - African Americans

KW - Diabetic kidney disease

KW - End-stage kidney disease

KW - Genome-wide association study

KW - Type 2 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85065874354&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065874354&partnerID=8YFLogxK

U2 - 10.1186/s40246-019-0205-7

DO - 10.1186/s40246-019-0205-7

M3 - Article

C2 - 31092297

AN - SCOPUS:85065874354

SN - 1473-9542

VL - 13

JO - Human Genomics

JF - Human Genomics

IS - 1

M1 - 21

ER -

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

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