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

Chikashi Terao, Hajime Yoshifuji, Takayoshi Matsumura, Taeko K. Naruse, Tomonori Ishii, Yoshikazu Nakaoka, Yohei Kirino, Keitaro Matsuo, Tomoki Origuchi, Masakazu Shimizu, Yasuhiro Maejima, Eisuke Amiya, Natsuko Tamura, Takahisa Kawaguchi, Meiko Takahashi, Kazuya Setoh, Koichiro Ohmura, Ryu Watanabe, Tetsuya Horita, Tatsuya AtsumiMitsuru Matsukura, Tetsuro Miyata, Yuta Kochi, Toshio Suda, Kazuo Tanemoto, Akira Meguro, Yukinori Okada, Akiyoshi Ogimoto, Motohisa Yamamoto, Hiroki Takahashi, Shingo Nakayamada, Kazuyoshi Saito, Masataka Kuwana, Nobuhisa Mizuki, Yasuharu Tabara, Atsuhisa Ueda, Issei Komuro, Akinori Kimura, Mitsuaki Isobe, Tsuneyo Mimori, Fumihiko Matsuda

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)13045-13050
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number51
DOIs
Publication statusPublished - 2018 Dec 18

Keywords

  • Autoimmunity
  • Epistasis
  • Genome-wide association study
  • HLA
  • Takayasu arteritis

ASJC Scopus subject areas

  • General

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    Terao, C., Yoshifuji, H., Matsumura, T., Naruse, T. K., 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., ... Matsuda, F. (2018). Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis. Proceedings of the National Academy of Sciences of the United States of America, 115(51), 13045-13050. https://doi.org/10.1073/pnas.1808850115