Zhang Yue-Miao, Liu Xing-Zi, Zhou Xu-Jie, Liu Li-Jun, Shi Su-Fang, Hou Ping, Lv Ji-Cheng, Zhang Hong
Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.
Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
Front Immunol. 2021 Feb 25;12:600598. doi: 10.3389/fimmu.2021.600598. eCollection 2021.
C-C chemokine receptor 6 () is a susceptibility gene of various immune-related diseases, which was suggested to be shared with immunoglobulin A nephropathy (IgAN). In this study, we aimed to identify the functional variants. First, we analyzed the associations of common and rare variants detected by multi-platform chips with IgAN susceptibility using imputation and identified 68 significantly associated common variants located in the regulatory region. Among them, rs3093023 showed both statistical significance (rs3093023-A, odds ratio [OR] = 1.15, = 2.00 × 10) and the expression quantitative trait loci (eQTL) effect ( = 1.45 × 10). It was independently replicated (rs3093023-A, OR = 1.18, = 5.56 × 10) and the association was reinforced in the meta-analysis (rs3093023-A, OR = 1.17, = 6.14 × 10). Although rs3093023 was in a strong linkage disequilibrium with the reported functional variant dinucleotide polymorphism, , the alleles of rs3093023 (G>A) rather than of were shown differential nuclear protein binding effect by electrophoretic mobility shift assay. The RegulomeDB and JASPAR databases predicted Pou2f1 as the potential transcription factor, which was negatively associated with mRNA ( = -0.60, = 3.94 × 10). At the mRNA level, the eQTL effect of was validated ( = 4.39 × 10), and was positively associated with the expression of and rather than that of and . At the protein level, a higher CCR6 cell ratio was observed in a risk allele dose-dependent manner in lymphocytes ( = 3.57 × 10), CD3 T cells ( = 4.54 × 10), and CD4 T cells ( = 1.32 × 10), but not in CD8 T cells. Clinical-pathological analysis showed that rs3093023 risk allele was significantly associated with diastolic blood pressure, serum creatinine, and high ratio of tubular atrophy/interstitial fibrosis. Overall, the rs3093023 was prioritized as the function variant in , which may contribute to IgAN susceptibility by regulating Th17 cells.
C-C趋化因子受体6（）是多种免疫相关疾病的易感基因，提示其与免疫球蛋白A肾病（IgAN）存在共同遗传易感性。在本研究中，我们旨在鉴定其功能变异。首先，我们通过归因分析了多平台芯片检测到的常见和罕见变异与IgAN易感性的关联，确定了68个位于调控区域的显著相关常见变异。其中，rs3093023显示出统计学意义（rs3093023 - A，优势比[OR]=1.15，=2.00×10）和表达数量性状位点（eQTL）效应（=1.45×10）。它被独立重复验证（rs3093023 - A，OR = 1.18，=5.56×10），且在荟萃分析中该关联得到加强（rs3093023 - A，OR = 1.17，=6.14×10）。尽管rs3093023与已报道的功能变异二核苷酸多态性处于强连锁不平衡状态，但通过电泳迁移率变动分析显示，rs3093023（G>A）而非的等位基因具有不同的核蛋白结合效应。RegulomeDB和JASPAR数据库预测Pou2f1为潜在转录因子，其与mRNA呈负相关（=-0.60，=3.94×10）。在mRNA水平，验证了的eQTL效应（=4.39×10），且与和的表达呈正相关，而与和的表达无关。在蛋白水平，在淋巴细胞（=3.57×10）、CD3 T细胞（=4.54×10）和CD4 T细胞（=1.32×10）中观察到风险等位基因剂量依赖性的较高CCR6细胞比例，但在CD8 T细胞中未观察到。临床病理分析表明，rs3093023风险等位基因与舒张压、血清肌酐以及肾小管萎缩/间质纤维化高比例显著相关。总体而言，rs3093023被确定为中的功能变异，其可能通过调节Th17细胞导致IgAN易感性。
