. 2019 May 15;13(1):21.

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^{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, Affiliations

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.

PMID: 31092297
PMCID: PMC6521376
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 et al. Hum Genomics. 2019.

. 2019 May 15;13(1):21.

doi: 10.1186/s40246-019-0205-7.

Authors

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.

PMID: 31092297
PMCID: PMC6521376
DOI: 10.1186/s40246-019-0205-7

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.

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Conflict of interest statement

Ethics approval and consent to participate

Analyses were approved by local institutional review boards, and all participants provided written informed consent.

Consent for publication

Not applicable.

Competing interests

Wake Forest University Health Sciences and Barry Freedman have rights to an issued US patent related to APOL1 gene testing. Dr. Freedman is a consultant for Ionis and AstraZeneca Pharmaceuticals.

The other authors declare that they have no competing interests.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

**Fig. 1**
Workflow of T2D-ESKD GWAS in AAs (baseline model)

**Fig. 2**
Locus plots of genome-wide associations in the baseline model. a Locus plots of T2D-ESKD associations at P < 5 × 10⁻⁸ in the baseline model. b Locus plots of all-cause ESKD-associated variants at P < 5 × 10^− 8 in the baseline model. Abbreviations: T2D, type 2 diabetes; ESKD, end-stage kidney disease; Baseline model: adjusted for age, sex, and PC1. *APOL1* risk genotype carriers were included; reference genome: hg19/1000 Genomes Nov 2014 AFR.

**Fig. 3**
Locus plots of genome-wide associations in the *APOL1*-negative model. a Locus plots of T2D-ESKD associations at P < 5 × 10⁻⁸ in the *APOL1*-negative model. b Locus plots of all-cause ESKD associations at P < 5 × 10⁻⁸ in the *APOL1*-negative model. Abbreviations: T2D, type 2 diabetes; ESKD, end-stage kidney disease; P, P value; *APOL1*-negative mode, adjusted for age, sex, and PC1. *APOL1* risk genotype carriers excluded; reference genome: hg19/1000 Genomes Nov 2014 AFR.

See this image and copyright information in PMC

References

1. United States Renal Data System. 2016 USRDS annual data report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2016.
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Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Ethics approval and consent to participate

Consent for publication

Competing interests

Publisher’s Note

Figures

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