Journal Article

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

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

2008

Overview

Cheryl Winkler and colleagues use admixture mapping to identify risk variants in MYH9 associated with focal segmental glomerulosclerosis and end-stage renal disease in African Americans. The risk variants are more common in populations with West African ancestry and contribute to the excess burden of end-stage kidney diseases in these populations. A similar finding is reported in an accompanying paper by Linda Kao and colleagues. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Adult / African Americans / Agriculture / AIDS-Associated Nephropathy - genetics / Animal Genetics and Genomics / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Black or African American - genetics / Cancer / Cancer Research / Case-Control Studies / Chromosome Mapping / Chromosomes, Human, Pair 22 - genetics / Demographic aspects / DNA Primers - chemistry / Female / Fundamental and applied biological sciences. Psychology / Gene Function / Genes / Genetic aspects / Genetic diversity / Genetic Linkage / Genetic Predisposition to Disease - genetics / Genetic variance / Genetic variation / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Genome, Human / Glomerulonephritis / Glomerulosclerosis, Focal Segmental - genetics / Glomerulosclerosis, Focal Segmental - pathology / Haplotypes / Haplotypes - genetics / Health aspects / Human Genetics / Human immunodeficiency virus / Humans / Hypertension - genetics / Kidneys / Lod Score / Male / Medical research / Medical sciences / Methods / Middle Aged / Molecular Motor Proteins - genetics / Myosin Heavy Chains - genetics / Nephrology. Urinary tract diseases / Nephropathies. Renovascular diseases. Renal failure / Polymorphism, Single Nucleotide - genetics / Risk Factors / White People - genetics