Article abstract
Nature Genetics 40, 1175 - 1184 (2008)
Published online: 14 September 2008 | doi:10.1038/ng.226
MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis
Jeffrey B Kopp1,17, Michael W Smith2,16,17, George W Nelson2,17, Randall C Johnson2, Barry I Freedman3, Donald W Bowden3, Taras Oleksyk2, Louise M McKenzie2, Hiroshi Kajiyama1, Tejinder S Ahuja4, Jeffrey S Berns5, William Briggs6, Monique E Cho1, Richard A Dart7, Paul L Kimmel8, Stephen M Korbet9, Donna M Michel10, Michele H Mokrzycki11, Jeffrey R Schelling12, Eric Simon13, Howard Trachtman14, David Vlahov15 & Cheryl A Winkler2
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.
- Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
- Laboratory of Genomic Diversity, SAIC-Frederick, National Cancer Institute, Frederick, Maryland 21702, USA.
- Section of Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
- University of Texas Medical Branch, Galveston, Texas 77555, USA.
- Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
- William Beaumont Hospital, Royal Oak, Michigan 48073, USA.
- Department of Hypertension and Nephrology, Marshfield Clinic, Marshfield, Wisconsin 54449, USA.
- Department of Medicine, Division of Renal Diseases and Hypertension, George Washington University Medical Center, Washington, DC 20037, USA.
- Department of Medicine, Rush University Medical Center, Chicago, Illinois 60612, USA.
- Hypertension and Kidney Specialists, Lancaster, Pennsylvania 17601, USA.
- Division of Nephrology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44109, USA.
- Nephrology Section, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
- Department of Pediatrics, Division of Nephrology, Schneider Children's Hospital System, New Hyde Park, New York 11040, USA.
- New York Academy of Medicine, New York, New York 10029, USA.
- Present address: Genetics and Genomics, Advanced Technology Program, SAIC-Frederick, National Cancer Institute, Frederick, Maryland 21701, USA.
- These authors contributed equally to this work.
Correspondence to: Cheryl A Winkler2 e-mail: winkler@ncifcrf.gov
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