Laboratory of Genomic Diversity, SAIC-Frederick, Inc, NCI-Frederick, Frederick, MD, USA.
Hum Mol Genet. 2010 May 1;19(9):1805-15. doi: 10.1093/hmg/ddq039. Epub 2010 Feb 2.
Admixture mapping recently identified MYH9 as a susceptibility gene for idiopathic focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy (HIVAN) and end-stage kidney disease attributed to hypertension (H-ESKD) in African Americans (AA). MYH9 encodes the heavy chain of non-muscle myosin IIA, a cellular motor involved in motility. A haplotype and its tagging SNPs spanning introns 12-23 were most strongly associated with kidney disease (OR 2-7; P < 10(-8), recessive). To narrow the region of association and identify potential causal variation, we performed a dense-mapping study using 79 MYH9 SNPs in AA populations with FSGS, HIVAN and H-ESKD (typed for a subset of 46 SNPs), for a total of 2496 cases and controls. The strongest associations were for correlated SNPs rs5750250, rs2413396 and rs5750248 in introns 13, 14 and 15, a region of 5.6 kb. Rs5750250 showed OR 5.0, 8.0 and 2.8; P = 2 x 10(-17), 2 x 10(-10) and 3 x 10(-22), respectively, for FSGS, HIVAN and H-ESKD; OR 5.7; P = 9 x 10(-27) for combined FSGS and HIVAN, recessive. An independent association was observed for rs11912763 in intron 33. Neither the highly associated SNPs nor the results of resequencing MYH9 in 40 HIVAN or FSGS cases and controls revealed non-synonymous changes that could account for the disease associations. Rs2413396 and one of the highly associated SNPs in intron 23, rs4821480, are predicted splicing motif modifiers. Rs5750250 combined with rs11912763 had receiver operator characteristic (ROC) C statistics of 0.80, 0.73 and 0.65 for HIVAN, FSGS and H-ESKD, respectively, allowing prediction of genetic risk by typing two SNPs.
混合映射最近确定 MYH9 是非洲裔美国人（AA）特发性局灶节段性肾小球硬化症（FSGS）、HIV 相关性肾病（HIVAN）和高血压相关终末期肾病（H-ESKD）的易感基因。MYH9 编码非肌肉肌球蛋白 IIA 的重链，是一种参与运动的细胞马达。一个单倍型及其跨越内含子 12-23 的标记 SNP 与肾脏疾病的相关性最强（OR 2-7；P < 10(-8)，隐性）。为了缩小关联区域并确定潜在的因果变异，我们使用 FSGS、HIVAN 和 H-ESKD 的 AA 人群中的 79 个 MYH9 SNP 进行了密集映射研究（对 46 个 SNP 的一部分进行了分型），共 2496 例病例和对照。最强的关联是在内含子 13、14 和 15 中相关 SNP rs5750250、rs2413396 和 rs5750248 的相关性，该区域为 5.6 kb。rs5750250 对 FSGS、HIVAN 和 H-ESKD 的 OR 分别为 5.0、8.0 和 2.8；P = 2 x 10(-17)、2 x 10(-10) 和 3 x 10(-22)；rs11912763 在内含子 33 中观察到独立的关联。对于 FSGS 和 HIVAN 的合并，隐性的 OR 为 5.7；P = 9 x 10(-27)。在 40 例 HIVAN 或 FSGS 病例和对照中对 MYH9 进行重新测序后，既没有发现高度相关的 SNP，也没有发现可以解释疾病相关性的非同义变化。rs2413396 和内含子 23 中一个高度相关的 SNP rs4821480 是预测剪接基序修饰剂。rs5750250 与 rs11912763 相结合，对 HIVAN、FSGS 和 H-ESKD 的接收者操作特征（ROC）C 统计值分别为 0.80、0.73 和 0.65，通过两种 SNP 分型可以预测遗传风险。
