Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome
Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome
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DOI：
10.1681/asn.2018101054
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发表时间：
2019-08-01
影响因子：
13.6
通讯作者：
Bockenhauer, Detlef
中科院分区：
文献类型：
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作者：
Dufek, Stephanie;Cheshire, Chris;Bockenhauer, Detlef
背景激素敏感型肾病综合征(SSNS)是儿童时期最常见的肾病综合征，被认为是一种与经典的人类白细胞抗原(HLA)相关的自身免疫性疾病。然而，这种疾病的确切病因尚不清楚。在其他自身免疫性疾病中，通过全基因组关联研究识别经典的人类白细胞抗原区域外的基因座为疾病发病机制提供了重要的见解。方法对422例欧洲血统的SSNS患者和5642例种族匹配的对照进行了GWA研究。结果GWAS发现3个基因座具有全基因组意义，可解释SSNS约14%的遗传风险。它证实了先前报道的与人类白细胞抗原-DR/DQ区域的关联(先导单核苷酸多态[SNP]rs9273542，P=1.59x10(-43)；优势比[OR]，3.39；95%可信区间[95%CI]，2.86至4.03)，并在染色体4q13.3和6q22.1上发现了另外两个位于人类白细胞抗原区域之外的基因座。后者含有钙稳态调节剂家族成员6基因CALHM6(以前称为FAM26F)。CALHM6参与了免疫应答的调节；前导SNP(rs2637678，P=1.27x10(-17)；OR，0.51；95%CI，0.44~0.60)表现出较强的表达数量性状效应，其危险等位基因与CALHM6的低淋巴细胞表达有关。结论CALHM6参与了感染免疫应答的调节，这可能为感染引发SSNS的典型原因提供了解释。我们的结果表明，遗传导致的免疫失调风险可能是SSNS发病机制中的一个关键组成部分。
Background Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance.Methods In an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls.Results The GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59x10(-43); odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27x10(-17); OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6.Conclusions Because CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.