MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis

Jeffrey B. Kopp; Michael W. Smith; George W. Nelson; Randall C. Johnson; Barry I. Freedman; Donald W. Bowden; Taras Oleksyk; Louise M. McKenzie; Hiroshi Kajiyama; Tejinder S. Ahuja; Jeffrey S. Berns; William Briggs; Monique E. Cho; Richard A. Dart; Paul L. Kimmel; Stephen M. Korbet; Donna M. Michel; Michele H. Mokrzycki; Jeffrey R. Schelling; Eric Simon; Howard Trachtman; David Vlahov; Cheryl A. Winkler

doi:10.1038/ng.226

MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis

Jeffrey B. Kopp, Michael W. Smith, George W. Nelson, Randall C. Johnson, Barry I. Freedman, Donald W. Bowden, Taras Oleksyk, Louise M. McKenzie, Hiroshi Kajiyama, Tejinder S. Ahuja, Jeffrey S. Berns, William Briggs, Monique E. Cho, Richard A. Dart, Paul L. Kimmel, Stephen M. Korbet, Donna M. Michel, Michele H. Mokrzycki, Jeffrey R. Schelling, Eric SimonHoward Trachtman, David Vlahov, Cheryl A. Winkler

Medicine

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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.

Original language	English (US)
Pages (from-to)	1175-1184
Number of pages	10
Journal	Nature Genetics
Volume	40
Issue number	10
DOIs	https://doi.org/10.1038/ng.226
State	Published - Oct 2008

ASJC Scopus subject areas

Genetics

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10.1038/ng.226

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Kopp, J. B., Smith, M. W., Nelson, G. W., Johnson, R. C., Freedman, B. I., Bowden, D. W., Oleksyk, T., McKenzie, L. M., Kajiyama, H., Ahuja, T. S., Berns, J. S., Briggs, W., Cho, M. E., Dart, R. A., Kimmel, P. L., Korbet, S. M., Michel, D. M., Mokrzycki, M. H., Schelling, J. R., ... Winkler, C. A. (2008). MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nature Genetics, 40(10), 1175-1184. https://doi.org/10.1038/ng.226

Kopp, JB, Smith, MW, Nelson, GW, Johnson, RC, Freedman, BI, Bowden, DW, Oleksyk, T, McKenzie, LM, Kajiyama, H, Ahuja, TS, Berns, JS, Briggs, W, Cho, ME, Dart, RA, Kimmel, PL, Korbet, SM, Michel, DM, Mokrzycki, MH, Schelling, JR, Simon, E, Trachtman, H, Vlahov, D & Winkler, CA 2008, 'MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis', Nature Genetics, vol. 40, no. 10, pp. 1175-1184. https://doi.org/10.1038/ng.226

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title = "MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis",

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.",

author = "Kopp, {Jeffrey B.} and Smith, {Michael W.} and Nelson, {George W.} and Johnson, {Randall C.} and Freedman, {Barry I.} and Bowden, {Donald W.} and Taras Oleksyk and McKenzie, {Louise M.} and Hiroshi Kajiyama and Ahuja, {Tejinder S.} and Berns, {Jeffrey S.} and William Briggs and Cho, {Monique E.} and Dart, {Richard A.} and Kimmel, {Paul L.} and Korbet, {Stephen M.} and Michel, {Donna M.} and Mokrzycki, {Michele H.} and Schelling, {Jeffrey R.} and Eric Simon and Howard Trachtman and David Vlahov and Winkler, {Cheryl A.}",

note = "Funding Information: 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.)).",

year = "2008",

month = oct,

doi = "10.1038/ng.226",

language = "English (US)",

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AU - Kopp, Jeffrey B.

AU - Smith, Michael W.

AU - Nelson, George W.

AU - Johnson, Randall C.

AU - Freedman, Barry I.

AU - Bowden, Donald W.

AU - Oleksyk, Taras

AU - McKenzie, Louise M.

AU - Kajiyama, Hiroshi

AU - Ahuja, Tejinder S.

AU - Berns, Jeffrey S.

AU - Briggs, William

AU - Cho, Monique E.

AU - Dart, Richard A.

AU - Kimmel, Paul L.

AU - Korbet, Stephen M.

AU - Michel, Donna M.

AU - Mokrzycki, Michele H.

AU - Schelling, Jeffrey R.

AU - Simon, Eric

AU - Trachtman, Howard

AU - Vlahov, David

AU - Winkler, Cheryl A.

N1 - Funding Information: 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.)).

PY - 2008/10

Y1 - 2008/10

N2 - 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.

AB - 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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MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis

Abstract

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