title: Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population.
abstract: 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.
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. Electronic address: a0001101@kuhp.kyoto-u.ac.jp.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.forename: Hajime
authors.initials: H
authors.lastname: Yoshifuji
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Matsumura
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ohmura
authors.forename: Meiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shimizu
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Chen
authors.forename: Taeko K
authors.initials: TK
authors.lastname: Naruse
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ebana
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Kosaku
authors.initials: K
authors.lastname: Murakami
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kawabata
authors.forename: Yoko
authors.initials: Y
authors.lastname: Wada
authors.forename: Ichiei
authors.initials: I
authors.lastname: Narita
authors.forename: Junichi
authors.initials: J
authors.lastname: Tazaki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Kimiko
authors.initials: K
authors.lastname: Yurugi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miura
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Tabara
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D016022:Case-Control Studies; D002886:Chromosomes, Human, Pair 17; D002895:Chromosomes, Human, Pair 5; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D059950:HLA-B52 Antigen / Q000235:genetics*; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012307:Risk Factors; D013625:Takayasu Arteritis / Q000208:ethnology / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C501279:HLA-B*52:01 antigen; D059950:HLA-B52 Antigen; C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40; C403128:MLX protein, human