Rare Variants in the Complement Factor H-Related Protein 5 Gene Contribute to Genetic Susceptibility to IgA Nephropathy
Rare Variants in the Complement Factor H-Related Protein 5 Gene Contribute to Genetic Susceptibility to IgA Nephropathy
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DOI：
10.1681/asn.2015010012
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发表时间：
2016-09-01
影响因子：
13.6
通讯作者：
Zhang, Hong
中科院分区：
文献类型：
--
作者：
Zhai, Ya-Ling;Meng, Si-Jun;Zhang, Hong
最近的伊加肾病（IgAN）全基因组关联研究确定1 q32为IgAN易感基因座，1 q32含有多个补体调节基因，包括补体因子H（CFH）基因和补体因子H相关（CFHRs）基因。由CFHR 5突变引起的异常补体激活被证明可引起CFHR 5肾病，其与IgAN具有许多共同特征。为了探讨CFHR 5变异对IgAN易感性的遗传效应，我们招募了500例IgAN患者和576例健康对照进行遗传分析。我们对CFHR 5的所有外显子及其内含子侧翼区以及非翻译区进行了测序，并使用序列核关联检验比较了鉴定出的变体的频率。我们在CFHR 5中鉴定了32种变异，包括28种罕见变异和4种常见变异。IgAN患者CFHR 5罕见变异的分布与对照组相比有显著性差异（P=0.002）。在这些罕见的变异中，计算机程序预测了9种潜在的功能变异，然后我们在功能测定中对其进行了评估。与野生型CFHR 5相比，三种重组CFHR 5蛋白CFHR 5-M（c.508G>A/p.Val170Met），CFHR5-S（c.533A>G/p.Asn178Ser）和CFHR5-D（c.822A>T/p.Glu274Asp）的C3 b结合能力显著高于（CFHR 5-M：109.67%+/- 3.54%; P=0.02; CFHR 5-S：174.27%+/- 9.78%; P
A recent genome wide association study of IgA nephropathy (IgAN) identified 1q32, which contains multiple complement regulatory genes, including the complement factor H (CFH) gene and the complement factor H related (CFHRs) genes, as an IgAN susceptibility locus. Abnormal complement activation caused by a mutation in CFHR5 was shown to cause CFHR5 nephropathy, which shares many characteristics with IgAN. To explore the genetic effect of variants in CFHR5 on IgAN susceptibility, we recruited 500 patients with IgAN and 576 healthy controls for genetic analysis. We sequenced all exons and their intronic flanking regions as well as the untranslated regions of CFHR5 and compared the frequencies of identified variants using the sequence kernel association test. We identified 32 variants in CFHR5, including 28 rare and four common variants. The distribution of rare variants in CFHR5 in patients with IgAN differed significantly from that in controls (P=0.002). Among the rare variants, in silico programs predicted nine as potential functional variants, which we then assessed in functional assays. Compared with wild-type CFHR5, three recombinant CFHR5 proteins, CFHR5-M (c.508G>A/p.Val170Met), CFHR5-S (c.533A>G/p. Asn178Ser), and CFHR5-D (c.822A>T/p.Glu274Asp), showed significantly higher C3b binding capacity (CFHR5-M: 109.67%+/- 3.54%; P=0.02; CFHR5-S: 174.27%+/- 9.78%; P