Kopp Jeffrey B, Smith Michael W, Nelson George W, Johnson Randall C, Freedman Barry I, Bowden Donald W, Oleksyk Taras, McKenzie Louise M, Kajiyama Hiroshi, Ahuja Tejinder S, Berns Jeffrey S, Briggs William, Cho Monique E, Dart Richard A, Kimmel Paul L, Korbet Stephen M, Michel Donna M, Mokrzycki Michele H, Schelling Jeffrey R, Simon Eric, Trachtman Howard, Vlahov David, Winkler Cheryl A
Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nat Genet. 2008 Oct;40(10):1175-84. doi: 10.1038/ng.226. Epub 2008 Sep 14.
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 x 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.
非洲裔人群中慢性肾脏病和终末期肾病（ESKD）负担增加的原因在很大程度上尚不清楚。为了确定易患特发性和HIV-1相关局灶节段性肾小球硬化（FSGS）的基因变异，我们对190例患有FSGS的非裔美国人和222例对照进行了混合映射连锁不平衡基因组扫描。我们在22号染色体上确定了一个区域，其全基因组优势对数（lod）评分为9.2，峰值lod为12.4，以肾足细胞中表达的功能性候选基因MYH9为中心。多个MYH9单核苷酸多态性（SNP）和单倍型与FSGS呈隐性关联，其中最强的是一个跨越外显子14至23的单倍型（比值比[OR]=5.0，95%置信区间[CI]=3.5-7.1；P=4×10-23，n=852）。这种关联延伸至高血压ESKD（OR=2.2，95%CI=1.5-3.4；n=433），但不包括2型糖尿病ESKD（n=476）。MYH9基因座的遗传变异在很大程度上解释了非裔美国人中FSGS和高血压ESKD负担的增加。
