Abstract

The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1–associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR = 5.0, 95% CI = 3.5–7.1; P = 4 × 10−23, n = 852). This association extended to hypertensive ESKD (OR = 2.2, 95% CI = 1.5–3.4; n = 433), but not type 2 diabetic ESKD (n = 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.

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Acknowledgements

We thank the subjects and controls who participated in the NIH Genetic Study and the Wake Forest ESRD Study, and the physicians who assisted by identifying cases for these studies. M. Branton, D. Smith, L. Bartlett and L. Howard provided clinical support. E. Binns, Y. Zhou and M. Jamba provided laboratory assistance. The following members of the NIH FSGS Genetics Study Group also contributed samples: F. Hutchinson (University of South Carolina); R. Mannon (Duke University); P. Nachman (University of North Carolina, Chapel Hill); T.K. Rao (State University of New York, Downstate) and M. Smith (Cincinnati Children's Hospital). Research blood donor samples were provided by S. Leitman (NIH). We thank S.J. O'Brien and B. Gold for discussions, N. Patterson for assistance with the ANCESTRYMAP program, and S. Leitman for assistance in identifying healthy volunteers.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. The publisher or recipient acknowledges right of the US government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.

This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400, the Intramural Research Programs of the National Institute for Diabetes, Digestive, and Kidney Diseases (ZO-1 DK043308), and by a grant from the NIH (RO1 DK 070941 (B.I.F.)).

Author information

Author notes

    • Michael W Smith

    Present address: Genetics and Genomics, Advanced Technology Program, SAIC-Frederick, National Cancer Institute, Frederick, Maryland 21701, USA.

    • Jeffrey B Kopp
    • , Michael W Smith
    •  & George W Nelson

    These authors contributed equally to this work.

Affiliations

  1. Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Jeffrey B Kopp
    • , Hiroshi Kajiyama
    •  & Monique E Cho
  2. Laboratory of Genomic Diversity, SAIC-Frederick, National Cancer Institute, Frederick, Maryland 21702, USA.

    • Michael W Smith
    • , George W Nelson
    • , Randall C Johnson
    • , Taras Oleksyk
    • , Louise M McKenzie
    •  & Cheryl A Winkler
  3. Section of Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.

    • Barry I Freedman
    •  & Donald W Bowden
  4. University of Texas Medical Branch, Galveston, Texas 77555, USA.

    • Tejinder S Ahuja
  5. Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

    • Jeffrey S Berns
  6. William Beaumont Hospital, Royal Oak, Michigan 48073, USA.

    • William Briggs
  7. Department of Hypertension and Nephrology, Marshfield Clinic, Marshfield, Wisconsin 54449, USA.

    • Richard A Dart
  8. Department of Medicine, Division of Renal Diseases and Hypertension, George Washington University Medical Center, Washington, DC 20037, USA.

    • Paul L Kimmel
  9. Department of Medicine, Rush University Medical Center, Chicago, Illinois 60612, USA.

    • Stephen M Korbet
  10. Hypertension and Kidney Specialists, Lancaster, Pennsylvania 17601, USA.

    • Donna M Michel
  11. Division of Nephrology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

    • Michele H Mokrzycki
  12. Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44109, USA.

    • Jeffrey R Schelling
  13. Nephrology Section, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.

    • Eric Simon
  14. Department of Pediatrics, Division of Nephrology, Schneider Children's Hospital System, New Hyde Park, New York 11040, USA.

    • Howard Trachtman
  15. New York Academy of Medicine, New York, New York 10029, USA.

    • David Vlahov

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Competing interests

The following authors have filed a patent application for MYH9 risk variants and haplotypes: Randy Johnson, Cheryl Winkler, Michael Smith, Jeffrey Kopp and George Nelson.

Corresponding author

Correspondence to Cheryl A Winkler.

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DOI

https://doi.org/10.1038/ng.226

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