期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 51, 页码 13045-13050出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1808850115
关键词
genome-wide association study; Takayasu arteritis; autoimmunity; HLA; epistasis
资金
- Department of Rheumatology and Clinical Immunology, Kyoto Graduate School of Medicine
- Japan Society for the Promotion of Science KAKENHI [25860809, JP16H06251, JP16K15513]
- Kanae Foundation for the promotion of medical science
- Uehara Memorial Foundation
- John Mung Advanced Program
- Kyoto University
- Research Project of Genetic Studies for Intractable Diseases, Japan Rheumatism Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Joint Usage/Research Program of Medical Research Institute, Tokyo Medical and Dental University
- Japanese Intractable Diseases Research Foundation
- Ministry of Health, Labor, and Welfare of Japan
- Translational Research promotion program of Japanese Circulation Society
- Grants-in-Aid for Scientific Research [25860809] Funding Source: KAKEN
Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B(star)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(star)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(star)52 and rs103294 (P = 1.2 x 10(-3)). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P = 8.8 x 10(-5), enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B(star)52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.
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