Confirmation of the genetic association of CTLA4 and PTPN22 with ANCA-associated vasculitis.
Confirmation of the genetic association of CTLA4 and PTPN22 with ANCA-associated vasculitis.
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DOI：
10.1186/1471-2350-10-121
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发表时间：
2009-12-01
影响因子：
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通讯作者：
Smith KG
中科院分区：
文献类型：
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作者：
Carr EJ;Niederer HA;Williams J;Harper L;Watts RA;Lyons PA;Smith KG
抗中性粒细胞胞浆抗体(ANCA)相关性小血管炎(AAV)的发病机制尚不清楚。在不同的自身免疫性疾病中，一些具有免疫调节作用的基因，如PTPN22，经常与多种疾病相关，而特定的人类白细胞抗原关联，如人类白细胞抗原-B27，往往是疾病限制性的。我们研究了10个候选基因座，根据它们的免疫调节作用和先前与1型糖尿病(T1D)的关联。这些病毒包括PTPN22、CTLA4和CD226，它们以前与AAV有关。应用TaqMan基因分型技术，对641例AAV患者的10个基因座的11个SNP进行分型：rs2476601位于PTPN22，rs1990760位于IFIH1，rs3087243位于CTLA4，rs2069763位于IL2，rs10877012位于CYP27B1，rs2292239位于ERBB3，rs3184504位于SH2B3，rs12708716位于CLEC16A，rs1893217和rs478582位于PTPN2，rs763361位于CD226。在可能的情况下，我们对之前的分析进行了荟萃分析。CTLA4 rs3087243和PTPN22 rs2476601均与AAV相关，P=6.4×10-3和P=1.4×10-4。CTLA4 rs3087243的次要等位基因(A)为保护性等位基因(优势比为0.84)，而PTPN22的次要等位基因(A)为易感基因(优势比为1.40)。这些结果证实了先前描述的与AAV的关联。Meta分析后，PTPN22 rs2476601的关联性进一步加强(联合P=4.2×10-7，优势比为1.48)。其他9个SNP，包括CD226中的rs763361，与AAV无关。我们对AAV中与T1D相关的SNPs的研究证实CTLA4和PTPN22是AAV的易感基因。这些基因编码免疫反应的两个关键调节因子，并与许多自身免疫性疾病有关，包括T1D、自身免疫性甲状腺疾病、乳糜泻、类风湿性关节炎，以及现在的AAV。
The genetic contribution to the aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is not well defined. Across different autoimmune diseases some genes with immunomodulatory roles, such as PTPN22, are frequently associated with multiple diseases, whereas specific HLA associations, such as HLA-B27, tend to be disease restricted. We studied ten candidate loci on the basis of their immunoregulatory role and prior associations with type 1 diabetes (T1D). These included PTPN22, CTLA4 and CD226, which have previously been associated with AAV. We genotyped the following 11 SNPs, from 10 loci, in 641 AAV patients using TaqMan genotyping: rs2476601 in PTPN22, rs1990760 in IFIH1, rs3087243 in CTLA4, rs2069763 in IL2, rs10877012 in CYP27B1, rs2292239 in ERBB3, rs3184504 in SH2B3, rs12708716 in CLEC16A, rs1893217 and rs478582 in PTPN2 and rs763361 in CD226. Where possible, we performed a meta-analysis with previous analyses. Both CTLA4 rs3087243 and PTPN22 rs2476601 showed association with AAV, P = 6.4 × 10-3 and P = 1.4 × 10-4 respectively. The minor allele (A) of CTLA4 rs3087243 is protective (odds ratio = 0.84), whereas the minor allele (A) of PTPN22 rs2476601 confers susceptibility (odds ratio = 1.40). These results confirmed previously described associations with AAV. After meta-analysis, the PTPN22 rs2476601 association was further strengthened (combined P = 4.2 × 10-7, odds ratio of 1.48 for the A allele). The other 9 SNPs, including rs763361 in CD226, showed no association with AAV. Our study of T1D associated SNPs in AAV has confirmed CTLA4 and PTPN22 as susceptibility loci in AAV. These genes encode two key regulators of the immune response and are associated with many autoimmune diseases, including T1D, autoimmune thyroid disease, celiac disease, rheumatoid arthritis, and now AAV.