期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2018
卷号：115
期号：51
页码：13045-13050
DOI：10.1073/pnas.1808850115
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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, in PTK2B , LILRA3 / LILRB2 , DUSP22 , and KLHL33 , respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6 / FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB , a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B . Rs103294 risk allele in LILRA3 / LILRB2 is known to be a tagging SNP for the deletion of LILRA3 , 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 between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.
关键词：genome-wide association study ; Takayasu arteritis ; autoimmunity ; HLA ; epistasis
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