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Proc Natl Acad Sci U S A. 2018 Nov 29. pii: 201808850. doi: 10.1073/pnas.1808850115. [Epub ahead of print]

Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis.

Author information

1
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan; a0001101@kuhp.kyoto-u.ac.jp.
2
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
3
Clinical Research Center, Shizuoka General Hospital, Shizuoka 420-0881, Japan.
4
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan.
5
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
6
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
7
Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
8
Department of Hematology and Rheumatology, Tohoku University School of Medicine, Sendai 980-8574, Japan.
9
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
10
Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita 565-0873, Japan.
11
Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
12
Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
13
Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan.
14
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
15
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
16
Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan.
17
Department of Surgical Oncology and Vascular Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
18
Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
19
Department of Cardiovascular Surgery, Kawasaki Medical School, Kurashiki 701-0192, Japan.
20
Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokoham 236-0004, Japan.
21
Laboratory of Statistical Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
22
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
23
Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan.
24
Department of Rheumatology, Sapporo Medical University School of Medicine, Sapporo Medical University, Sapporo 060-8556, Japan.
25
First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu 807-8556, Japan.
26
Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo 113-8603, Japan.
27
Sakakibara Heart Institute, Tokyo 183-0003, Japan.

Abstract

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.

KEYWORDS:

HLA; Takayasu arteritis; autoimmunity; epistasis; genome-wide association study

PMID:
30498034
DOI:
10.1073/pnas.1808850115

Conflict of interest statement

Conflict of interest statement: Editor Tasuku Honjo and several authors are affiliated with Kyoto University but do not have any active collaborations.

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