African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans

• Published in: Human molecular genetics Vol. 19; no. 9; pp. 1816 - 1827
• Main Authors: Behar, Doron M., Rosset, Saharon, Tzur, Shay, Selig, Sara, Yudkovsky, Guennady, Bercovici, Sivan, Kopp, Jeffrey B., Winkler, Cheryl A., Nelson, George W., Wasser, Walter G., Skorecki, Karl
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.2010
• Subjects: African Americans - genetics; Association Studies; Biological and medical sciences; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Gene Frequency; Genetic Predisposition to Disease - genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genotype; Haplotypes - genetics; Hispanic Americans - genetics; Humans; Inheritance Patterns - genetics; Kidney Failure, Chronic - ethnology; Kidney Failure, Chronic - genetics; Linkage Disequilibrium; Logistic Models; Medical sciences; Molecular and cellular biology; Molecular Motor Proteins - genetics; Myosin Heavy Chains - genetics; New York City; Polymorphism, Single Nucleotide - genetics; New York City; Endocrinopathy; Kidney disease; Allele; Urinary system disease; American; Gene; Diabetes mellitus; Genetics; Terminal stage; African
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddq040

Recent studies identified MYH9 as a major susceptibility gene for common forms of non-diabetic end-stage kidney disease (ESKD). A set of African ancestry DNA sequence variants comprising the E-1 haplotype, was significantly associated with ESKD. In order to determine whether African ancestry variants are also associated with disease susceptibility in admixed populations with differing genomic backgrounds, we genotyped a total of 1425 African and Hispanic American subjects comprising dialysis patients with diabetic and non-diabetic ESKD and controls, using 42 single nucleotide polymorphisms (SNPs) within the MYH9 gene and 40 genome-wide and 38 chromosome 22 ancestry informative markers. Following ancestry correction, logistic regression demonstrated that three of the E-1 SNPs are also associated with non-diabetic ESKD in the new sample sets of both African and Hispanic Americans, with a stronger association in Hispanic Americans. We also identified MYH9 SNPs that are even more powerfully associated with the disease phenotype than the E-1 SNPs. These newly associated SNPs, could be divided into those comprising a haplotype termed S-1 whose association was significant under a recessive or additive inheritance mode (rs5750248, OR 4.21, P < 0.01, Hispanic Americans, recessive), and those comprising a haplotype termed F-1 whose association was significant under a dominant or additive inheritance mode (rs11912763, OR 4.59, P < 0.01, Hispanic Americans, dominant). These findings strengthen the contention that a sequence variant of MYH9, common in populations with varying degrees of African ancestry admixture, and in strong linkage disequilibrium with the associated SNPs and haplotypes reported herein, strongly predisposes to non-diabetic ESKD.