Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis.
Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis.
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高安动脉炎中 LILRA3 和 HLA-B*52 的遗传决定因素和上位性。
DOI：
10.1073/pnas.1808850115
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发表时间：
2018
期刊：
影响因子：
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et al.
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作者：
Terao C;Yoshifuji H;Matsumura T;Naruse TK;Ishii T;Nakaoka Y;Kirino Y;Matsuo K;Origuchi T;Shimizu M;Maejima Y;Amiya E;Tamura N;Kawaguchi T;Takahashi M;Setoh K;Ohmura K;Watanabe R;Horita T;Atsumi T;Matsukura M;Miyata T;et al.
大动脉炎（TAK）是一种全身性血管炎，伴有严重并发症，影响主动脉及其大分支。HLA-B*52是TAK的既定易感基因座。迄今为止，关于TAK的非HLA易感基因座的报告数量仍然有限。我们在总共633例TAK病例和5，928例对照中进行了全基因组关联研究（GWAS）和随访研究。共对510，879个SNP进行基因分型，并将5，875，450个SNP与HLA-B*52一起插补。进行了重要位点的功能注释、增强子富集和途径分析。我们在PTK 2B、LILRA 3/LILRB 2、DUSP 22和KLHL 33中发现了4个未报道的显著位点，即rs2322599、rs 103294、rs 17133698和rs 1713450。另外两个在非欧洲GWAS中未报道的显著位点被鉴定，即HSPA 6/FCGR 3A和chr21q.22。我们发现，与MICB（自然杀伤（NK）细胞受体的配体）表达相关的单一变异体可以解释与HLA-B区域的整个关联。Rs2322599与PTK 2B的表达密切相关。LILRA 3/LILRB 2中的Rs 103294危险等位基因是LILRA 3缺失的标记SNP，LILRA 3是HLA I类分子的可溶性受体。我们发现HLA-B*52和rs 103294之间存在显著的上位效应（P= 1.2 × 10−3）。增强子富集分析和途径分析表明NK细胞参与其中（P= 8.8 × 10−5，增强子富集）。总之，确定了4个未报道的TAK易感位点和LILRA 3与HLA-B*52之间的上位效应。HLA和非HLA区域表明NK细胞在TAK中的关键作用。
Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, inPTK2B,LILRA3/LILRB2,DUSP22, andKLHL33, respectively. Two additional significant loci unreported in non-European GWAS were identified, namelyHSPA6/FCGR3Aand chr21q.22. We found that a single variant associated with the expression ofMICB, a ligand for natural killer (NK) cell receptor, could explain the entire association with theHLA-Bregion. Rs2322599 is strongly associated with the expression ofPTK2B. Rs103294 risk allele inLILRA3/LILRB2is known to be a tagging SNP for the deletion ofLILRA3, a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 (P= 1.2 × 10−3). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P= 8.8 × 10−5, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect betweenLILRA3and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.