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Abstract
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.
Highlights
Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and is a major cause of end-stage renal disease in young adults
The chemokine receptor 6 (CCR6) mRNA expression was positively associated with the expression of C-C chemokine receptor 4 (CCR4) (r = 0.63, P = 2.9 × 10−10) and IL-17A (r = 0.40, P = 2.57 × 10−4) but not with the expression of C-X-C motif chemokine receptor 3 (CXCR3) (r = 0.09, P = 0.450) and IFNG (r = 0.18, P = 0.112) (Figure 5C), suggesting that rs3093023 may regulate the CCR6 mRNA expression in Th17 cells
In silico analysis identified POU class 2 homeobox 1 (Pou2f1) as a potential transcription factor, which was negatively associated with the CCR6 expression
Summary
Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and is a major cause of end-stage renal disease in young adults. The variable prevalence among different ethnicities [1] and high familial aggregation [2] suggest that genetic components play an important role in IgAN pathogenesis. Genetic studies have demonstrated the association between CC motif chemokine receptor 6 gene (CCR6) and susceptibility to various immune-related diseases, such as rheumatoid arthritis [8, 9], psoriasis [10], and lupus nephritis [11]. CCR6–CCL20 signaling was reported to play an important role in recruiting Th17 cells to inflammatory sites [13]. Patients with lupus nephritis have increased levels of Th17 cells [16]; in glomerulonephritis, Th17 cells migrate from gut to kidneys via CCR6–CCL20 signaling [17]
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