APOL1 Variants Increase Risk for FSGS and HIVAN but Not IgA Nephropathy
APOL1 Variants Increase Risk for FSGS and HIVAN but Not IgA Nephropathy
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DOI：
10.1681/asn.2011040434
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发表时间：
2011-11-01
影响因子：
13.6
通讯作者：
Gharavi, Ali G.
中科院分区：
文献类型：
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作者：
Papeta, Natalia;Kiryluk, Krzysztof;Gharavi, Ali G.
染色体22 q13位点与非洲裔个体中特发性局灶节段性肾小球硬化（FSGS）、HIV-1相关肾病（HIVAN）和高血压ESRD的风险增加密切相关。虽然最初的研究涉及MYH 9，但最近的分析将最强的关联定位在邻近的APOL 1基因内。在这项复制研究中，我们在一个独立的非裔美国人队列中检查了APOL 1和MYH 9中六种最相关的变异，这些非裔美国人患有各种肾病（44例FSGS，21例HIVAN，32例伊加肾病和74例健康对照）。所有6种变异与FSGS和HIVAN相关（相加OR，1.8 - 3.0; P值3 x 10（-2）-5 x 10（-5）），但与伊加肾病无关。在条件分析和单倍型分析中，两种APOL 1单倍型几乎解释了染色体22 q13上FSGS和HIVAN的所有关联（单倍型P值= 5.6 × 10（-8））。为了评估MYH 9缺陷在肾病中的作用，我们将Myh 9-单倍不足小鼠（Myh 9（+/-））与HIV-1转基因小鼠杂交。Myh 9（+/-）小鼠是健康的，没有表现出明显的蛋白尿或肾病，无论是否存在HIV-1转基因。这些数据进一步支持APOL 1基因变异与非裔美国人对FSGS和HIVAN的易感性密切相关。
A chromosome 22q13 locus strongly associates with increased risk for idiopathic focal segmental glomerulosclerosis (FSGS), HIV-1-associated nephropathy (HIVAN), and hypertensive ESRD among individuals of African descent. Although initial studies implicated MYH9, more recent analyses localized the strongest association within the neighboring APOL1 gene. In this replication study, we examined the six top-most associated variants in APOL1 and MYH9 in an independent cohort of African Americans with various nephropathies (44 with FSGS, 21 with HIVAN, 32 with IgA nephropathy, and 74 healthy controls). All six variants associated with FSGS and HIVAN (additive ORs, 1.8 to 3.0; P values 3 x 10(-2) to 5 x 10(-5)) but not with IgA nephropathy. In conditional and haplotype analyses, two APOL1 haplotypes accounted for virtually all of the association with FSGS and HIVAN on chromosome 22q13 (haplotype P value = 5.6 x 10(-8)). To assess the role of MYH9 deficiency in nephropathy, we crossbred Myh9-haploinsufficient mice (Myh9(+/-)) with HIV-1 transgenic mice. Myh9(+/-) mice were healthy and did not demonstrate overt proteinuria or nephropathy, irrespective of the presence of the HIV-1 transgene. These data further support the strong association of genetic variants in APOL1 with susceptibility to FSGS and HIVAN among African Americans.