A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population
| العنوان: | A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population |
|---|---|
| المؤلفون: | Yue-miao Zhang, Xing-zi Liu, Xu-jie Zhou, Li-jun Liu, Su-fang Shi, Ping Hou, Ji-cheng Lv, Hong Zhang |
| المصدر: | Frontiers in Immunology, Vol 12 (2021) Frontiers in Immunology |
| بيانات النشر: | Frontiers Media SA, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Adult, Male, Receptors, CCR6, lcsh:Immunologic diseases. Allergy, 0301 basic medicine, China, Linkage disequilibrium, Genotype, genetic association, Quantitative Trait Loci, Immunology, Gene Expression, C-C chemokine receptor type 6, Biology, Kidney Function Tests, CXCR3, Polymorphism, Single Nucleotide, Young Adult, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, Polymorphism (computer science), Humans, Immunology and Allergy, Genetic Predisposition to Disease, Th17 cells, Allele, Alleles, Original Research, Genetic association, Computational Biology, Glomerulonephritis, IGA, Molecular Sequence Annotation, IgA nephropathy, Middle Aged, functional annotation, Molecular biology, Phenotype, 030104 developmental biology, Case-Control Studies, Expression quantitative trait loci, Female, CCR6, lcsh:RC581-607, CD8 |
| الوصف: | 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 ofCCR6common 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 reportedCCR6functional variant dinucleotide polymorphism,CCR6DNP, the alleles of rs3093023 (G>A) rather than ofCCR6DNPwere 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 withCCR6mRNA (r= −0.60,P= 3.94 × 10−9). At the mRNA level, the eQTL effect ofCCR6was validated (P= 4.39 × 10−2), andCCR6was positively associated with the expression ofCCR4andIL-17Arather than that ofCXCR3andIFNG. 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 inCCR6, which may contribute to IgAN susceptibility by regulating Th17 cells. |
| تدمد: | 1664-3224 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8c25497e4fedda7fcaad3ba58eab7a6dTest https://doi.org/10.3389/fimmu.2021.600598Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8c25497e4fedda7fcaad3ba58eab7a6d |
| قاعدة البيانات: | OpenAIRE |
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In this study, we aimed to identify the functional variants. First, we analyzed the associations ofCCR6common 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 reportedCCR6functional variant dinucleotide polymorphism,CCR6DNP, the alleles of rs3093023 (G>A) rather than ofCCR6DNPwere shown differential nuclear protein binding effect by electrophoretic mobility shift assay. 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