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

Abstract

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.

Figure 1.

Ancestry distribution Graphs. Density of ancestry proportions among African and Hispanic Americans as discerned from a panel of 40 AIMs for estimating global ancestry (left column) and 38 chromosome 22 SNPs for estimating local ancestry (right column), separately in the African American cohort (top row) and the Hispanic American cohort (bottom row). In the left graphs the ancestry is shown as a percentage (on the x-axis), although in the right graphs the local MYH9 ancestry is shown as the estimated number of chromosomes (0–2) on the x-axis. The average ancestry reported in the text is the mean of the distribution described by the corresponding curve. For example, the significant difference in average local African ancestry in the Hispanic American cohort mentioned in the text (0.87 for non-diabetic ESKD cases, 0.54 for controls) is the difference between the red and black checkmarks on the x-axis in the bottom right plot. ‘Af’ designates African ancestry, ‘Eu’ designates European ancestry and ‘NA’ designates Native American ancestry. Red lines represent non-diabetic ESKD cases, and black lines represent controls.

Figure 2.

MYH9 LD plot and ESKD associated SNPs. (A) Color scheme (D′/LOD) of the 42 MYH9 SNPs that were genotyped in this study based on the African American control samples (n = 140) was generated using the program HaploView (35). Bright red squares present SNPs with linkage LOD ≥ 2 and D′ = 1. The plot overlaps the actual locations of the SNPs tested herein and the physical map of the MYH9 gene. The SNPs demonstrating the highest peaks for association and their clustering into the haplotypes S-1 (rs5750248, rs2413396, rs5750250), E-1 (rs4821480, rs2032487, rs4821481) and F-1 (rs11912763, rs16996674, rs16996677) and the solo tenth SNP (rs2239784) are marked. A block of reduced recombination, bordered at its 5′ end with a 53 bp variable number tandem repeat in intron 11, determined using the program PHASE 2.1 (36), corresponds to the black triangle outline in the LD plot. (B) Pie charts of genotypes frequencies in non-diabetic ESKD cases versus controls for two SNPs representing the novel haplotypes S-1 (rs5750250) and F-1 (rs11912763) are shown for African and Hispanic Americans. The significant OR value for each SNP of the specified tested model is also indicated.