HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome
HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome
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DOI：
10.1681/asn.2014030247
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发表时间：
2015-07-01
影响因子：
13.6
通讯作者：
Winn, Michelle P.
中科院分区：
文献类型：
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作者：
Gbadegesin, Rasheed A.;Adeyemo, Adebowale;Winn, Michelle P.
类固醇敏感性肾病综合征（SSNS）占儿童肾病综合征病例的80%以上。然而，SSNS的病因和发病机制仍不清楚。假设编码变异可能是SSNS风险的基础，我们进行了SSNS外显子组阵列关联研究。我们招募了一组363人（214名患有SSNS的南亚儿童和149名对照），并使用Illumina HumanExome Beadchip对他们进行基因分型。HLA-DQA 1和HLA-DQB 1中四种常见的单核苷酸多态性（SNP）（rs 1129740、rs 9273349、rs 1071630和rs 1140343）与SSNS显著相关，在检测的单个变异体数量的Bonferroni校正P值处或附近（比值比，2.11; 95%置信区间，1.56至2.86; P=1.68x10（-6）（Fisher精确检验）。其中两个SNP--HLA-DQA 1错义变异C34 Y（rs 1129740）和F41 S（rs 1071630）在一个独立的白色欧洲血统SSNS儿童队列中重复（100例和589例对照; P=1.42x10（-17））。在基于罕见变异基因集的分析中，在PLCG 2中发现最佳信号（P=7.825x10（-5））。总之，该外显子组阵列研究鉴定了HLA-DQA 1和PLCG 2错义编码变体作为SSNS的候选位点。MHC II类基因位点的发现提示免疫应答在SSNS的发病机制中起重要作用。
Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68x10(-6) (Fisher exact test). Two of these SNPsthe missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and 589 controls; P=1.42x10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825x10(-5)). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.