A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population
C-C chemokine receptor 6 (CCR6) 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 CCR6 common and rare variants de...
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Frontiers Media S.A.
2021-02-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.600598/full |
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| author | Yue-miao Zhang Yue-miao Zhang Yue-miao Zhang Xing-zi Liu Xing-zi Liu Xing-zi Liu Xu-jie Zhou Xu-jie Zhou Xu-jie Zhou Li-jun Liu Li-jun Liu Li-jun Liu Su-fang Shi Su-fang Shi Su-fang Shi Ping Hou Ping Hou Ping Hou Ji-cheng Lv Ji-cheng Lv Ji-cheng Lv Hong Zhang Hong Zhang Hong Zhang |
| author_facet | Yue-miao Zhang Yue-miao Zhang Yue-miao Zhang Xing-zi Liu Xing-zi Liu Xing-zi Liu Xu-jie Zhou Xu-jie Zhou Xu-jie Zhou Li-jun Liu Li-jun Liu Li-jun Liu Su-fang Shi Su-fang Shi Su-fang Shi Ping Hou Ping Hou Ping Hou Ji-cheng Lv Ji-cheng Lv Ji-cheng Lv Hong Zhang Hong Zhang Hong Zhang |
| author_sort | Yue-miao Zhang |
| collection | DOAJ |
| description | C-C chemokine receptor 6 (CCR6) 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 CCR6 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, P = 2.00 × 10−2) and the expression quantitative trait loci (eQTL) effect (P = 1.45 × 10−3). It was independently replicated (rs3093023-A, OR = 1.18, P = 5.56 × 10−3) and the association was reinforced in the meta-analysis (rs3093023-A, OR = 1.17, P = 6.14 × 10−7). Although rs3093023 was in a strong linkage disequilibrium with the reported CCR6 functional variant dinucleotide polymorphism, CCR6DNP, the alleles of rs3093023 (G>A) rather than of CCR6DNP 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 CCR6 mRNA (r = −0.60, P = 3.94 × 10−9). At the mRNA level, the eQTL effect of CCR6 was validated (P = 4.39 × 10−2), and CCR6 was positively associated with the expression of CCR4 and IL-17A rather than that of CXCR3 and IFNG. At the protein level, a higher CCR6+ cell ratio was observed in a risk allele dose-dependent manner in lymphocytes (P = 3.57 × 10−2), CD3+ T cells (P = 4.54 × 10−2), and CD4+ T cells (P = 1.32 × 10−2), 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 CCR6, which may contribute to IgAN susceptibility by regulating Th17 cells. |
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| spelling | doaj.art-310f38cfc6c342c5b0859049adef6b102022-12-21T19:55:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011210.3389/fimmu.2021.600598600598A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese PopulationYue-miao Zhang0Yue-miao Zhang1Yue-miao Zhang2Xing-zi Liu3Xing-zi Liu4Xing-zi Liu5Xu-jie Zhou6Xu-jie Zhou7Xu-jie Zhou8Li-jun Liu9Li-jun Liu10Li-jun Liu11Su-fang Shi12Su-fang Shi13Su-fang Shi14Ping Hou15Ping Hou16Ping Hou17Ji-cheng Lv18Ji-cheng Lv19Ji-cheng Lv20Hong Zhang21Hong Zhang22Hong Zhang23Renal Division, Department of Medicine, Peking University First Hospital, Beijing, ChinaKey Laboratory of Renal Disease, Ministry of Health of China, Beijing, ChinaKey Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, ChinaRenal Division, Department of Medicine, Peking University First Hospital, Beijing, ChinaKey Laboratory of Renal Disease, Ministry of Health of China, Beijing, ChinaKey Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, ChinaRenal Division, Department of Medicine, Peking University First Hospital, Beijing, ChinaKey Laboratory of Renal Disease, Ministry of Health of China, Beijing, ChinaKey Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, ChinaRenal Division, Department of Medicine, Peking University First Hospital, Beijing, ChinaKey Laboratory of Renal Disease, Ministry of Health of China, Beijing, ChinaKey Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, ChinaRenal Division, Department of Medicine, Peking University First Hospital, Beijing, ChinaKey Laboratory of Renal Disease, Ministry of Health of China, Beijing, ChinaKey Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, ChinaRenal Division, Department of Medicine, Peking University First Hospital, Beijing, ChinaKey Laboratory of Renal Disease, Ministry of Health of China, Beijing, ChinaKey Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, ChinaRenal Division, Department of Medicine, Peking University First Hospital, Beijing, ChinaKey Laboratory of Renal Disease, Ministry of Health of China, Beijing, ChinaKey Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, ChinaRenal Division, Department of Medicine, Peking University First Hospital, Beijing, ChinaKey Laboratory of Renal Disease, Ministry of Health of China, Beijing, ChinaKey Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, ChinaC-C chemokine receptor 6 (CCR6) 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 CCR6 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, P = 2.00 × 10−2) and the expression quantitative trait loci (eQTL) effect (P = 1.45 × 10−3). It was independently replicated (rs3093023-A, OR = 1.18, P = 5.56 × 10−3) and the association was reinforced in the meta-analysis (rs3093023-A, OR = 1.17, P = 6.14 × 10−7). Although rs3093023 was in a strong linkage disequilibrium with the reported CCR6 functional variant dinucleotide polymorphism, CCR6DNP, the alleles of rs3093023 (G>A) rather than of CCR6DNP 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 CCR6 mRNA (r = −0.60, P = 3.94 × 10−9). At the mRNA level, the eQTL effect of CCR6 was validated (P = 4.39 × 10−2), and CCR6 was positively associated with the expression of CCR4 and IL-17A rather than that of CXCR3 and IFNG. At the protein level, a higher CCR6+ cell ratio was observed in a risk allele dose-dependent manner in lymphocytes (P = 3.57 × 10−2), CD3+ T cells (P = 4.54 × 10−2), and CD4+ T cells (P = 1.32 × 10−2), 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 CCR6, which may contribute to IgAN susceptibility by regulating Th17 cells.https://www.frontiersin.org/articles/10.3389/fimmu.2021.600598/fullIgA nephropathyCCR6Th17 cellsgenetic associationfunctional annotation |
| spellingShingle | Yue-miao Zhang Yue-miao Zhang Yue-miao Zhang Xing-zi Liu Xing-zi Liu Xing-zi Liu Xu-jie Zhou Xu-jie Zhou Xu-jie Zhou Li-jun Liu Li-jun Liu Li-jun Liu Su-fang Shi Su-fang Shi Su-fang Shi Ping Hou Ping Hou Ping Hou Ji-cheng Lv Ji-cheng Lv Ji-cheng Lv Hong Zhang Hong Zhang Hong Zhang A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population Frontiers in Immunology IgA nephropathy CCR6 Th17 cells genetic association functional annotation |
| title | A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population |
| title_full | A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population |
| title_fullStr | A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population |
| title_full_unstemmed | A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population |
| title_short | A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population |
| title_sort | functional variant rs3093023 in ccr6 is associated with iga nephropathy by regulating th17 cells in a north han chinese population |
| topic | IgA nephropathy CCR6 Th17 cells genetic association functional annotation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.600598/full |
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