Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population

Chikashi Terao, Hajime Yoshifuji, Akinori Kimura, Takayoshi Matsumura, Koichiro Ohmura, Meiko Takahashi, Masakazu Shimizu, Takahisa Kawaguchi, Zhiyong Chen, Taeko K. Naruse, Aiko Sato-Otsubo, Yusuke Ebana, Yasuhiro Maejima, Hideyuki Kinoshita, Kosaku Murakami, Daisuke Kawabata, Yoko Wada, Ichiei Narita, Junichi Tazaki, Yasushi KawaguchiHisashi Yamanaka, Kimiko Yurugi, Yasuo Miura, Taira Maekawa, Seishi Ogawa, Issei Komuro, Ryozo Nagai, Ryo Yamada, Yasuharu Tabara, Mitsuaki Isobe, Tsuneyo Mimori, Fumihiko Matsuda

Research output: Contribution to journalArticlepeer-review

106 Citations (Scopus)


Takayasu arteritis (TAK) is an autoimmune systemic vasculitis of unknown etiology. Although previous studies have revealed that HLA-B*52:01 has an effect on TAK susceptibility, no other genetic determinants have been established so far. Here, we performed genome scanning of 167 TAK cases and 663 healthy controls via Illumina Infinium Human Exome BeadChip arrays, followed by a replication study consisting of 212 TAK cases and 1,322 controls. As a result, we found that the IL12B region on chromosome 5 (rs6871626, overall p = 1.7 × 10-13, OR = 1.75, 95% CI 1.42-2.16) and the MLX region on chromosome 17 (rs665268, overall p = 5.2 × 10-7, OR = 1.50, 95% CI 1.28-1.76) as well as the HLA-B region (rs9263739, a proxy of HLA-B*52:01, overall p = 2.8 × 10-21, OR = 2.44, 95% CI 2.03-2.93) exhibited significant associations. A significant synergistic effect of rs6871626 and rs9263739 was found with a relative excess risk of 3.45, attributable proportion of 0.58, and synergy index of 3.24 (p ≤ 0.00028) in addition to a suggestive synergistic effect between rs665268 and rs926379 (p ≤ 0.027). We also found that rs6871626 showed a significant association with clinical manifestations of TAK, including increased risk and severity of aortic regurgitation, a representative severe complication of TAK. Detection of these susceptibility loci will provide new insights to the basic mechanisms of TAK pathogenesis. Our findings indicate that IL12B plays a fundamental role on the pathophysiology of TAK in combination with HLA-B*52:01 and that common autoimmune mechanisms underlie the pathology of TAK and other autoimmune disorders such as psoriasis and inflammatory bowel diseases in which IL12B is involved as a genetic predisposing factor.

Original languageEnglish
Pages (from-to)289-297
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - 08-08-2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population'. Together they form a unique fingerprint.

Cite this