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      The Apolipoprotein L1 ( APOL1) Gene and Nondiabetic Nephropathy in African Americans

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          Abstract

          Mapping by admixture linkage disequilibrium (LD) detected strong association between nonmuscle myosin heavy chain 9 gene ( MYH9) variants on chromosome 22 and nondiabetic nephropathy in African Americans. MYH9-related variants were posited to be the probable, but not necessarily the definitive, causal variants as a result of impressive statistical evidence of association, renal expression, and a role in autosomal dominant MYH9 disorders characterized by progressive glomerulosclerosis (Epstein and Fechtner syndromes). Dense mapping within MYH9 revealed striking LD patterns and racial variation in risk allele frequencies, suggesting population genetic factors such as selection may be operative in this region. Genovese and colleagues examined large chromosomal regions adjacent to MYH9 using genome-wide association methods and non-HapMap single nucleotide polymorphisms identified in Yoruba from the 1000 Genomes project. Statistically stronger associations were detected between two independent sequence variants in the Apolipoprotein L1 gene ( APOL1) and nondiabetic nephropathy in African Americans, with odds ratios of 10.5 in idiopathic FSGS and 7.3 in hypertension-attributed ESRD. These kidney disease risk variants likely rose to high frequency in Africa because they confer resistance to trypanosomal infection and protect from African sleeping sickness. Risk variants in MYH9 and APOL1 are in strong LD, and the genetic risk that was previously attributed to MYH9 may reside, in part or in whole, in APOL1, although more complex models of risk cannot be excluded. This association likely explains racial disparities in nondiabetic nephropathy as a result of the high prevalence of risk alleles in individuals of African ancestry.

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          Author and article information

          Journal
          J Am Soc Nephrol
          J. Am. Soc. Nephrol
          jnephrol
          jnephrol
          ASN
          Journal of the American Society of Nephrology : JASN
          American Society of Nephrology
          1046-6673
          1533-3450
          September 2010
          : 21
          : 9
          : 1422-1426
          Affiliations
          [* ]Department of Internal Medicine/Nephrology,
          []Department of Public Health Sciences/Biostatistical Sciences, and
          [** ]Department of Biochemistry and Centers for Diabetes Research and Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina;
          []Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;
          [§ ]Department of Internal Medicine/Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts;
          []Basic Research Laboratory,
          []SAIC-National Cancer Institute, National Institutes of Health–Frederick, Frederick, Maryland; and
          [†† ]Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
          Author notes
          Correspondence: Dr. Barry I. Freedman, Section on Nephrology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1053. Phone: 336-716-6192; Fax: 336-716-4318; E-mail: bfreedma@ 123456wfubmc.edu ; or Dr. Martin R. Pollak, Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215. Phone: 617-632-9880; Fax: 617-632-9890; E-mail: mpollak@ 123456bidmc.harvard.edu

          The views in this article are those of the authors and do not necessarily represent the views of the Department of Health and Human Services; neither does mention of trade names, commercial products, or organizations imply endorsement by the US government (C.A.W. and G.W.N.).

          Article
          PMC7391383 PMC7391383 7391383 2010070730
          10.1681/ASN.2010070730
          7391383
          20688934
          a7c1487e-e3f5-4110-9358-687bbc60e512
          Copyright © 2010 by the American Society of Nephrology
          History
          Funding
          Funded by: National Institutes of Health
          Award ID: RO1 DK54931
          Award ID: K08-DK076868
          Award ID: RO1 DK066358
          Award ID: RO1 DK053591
          Award ID: RO1 HL56266
          Award ID: RO1 DK070941
          Award ID: RO1 DK084149
          Award ID: HHSN261200800001E
          Categories
          Up Front Matters
          Clinical Commentary

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