title: STAT4 gene polymorphisms are associated with susceptibility and ANA status in primary biliary cirrhosis.
abstract: Recent genome-wide association studies suggest that genetic factors contribute to primary biliary cirrhosis (PBC) susceptibility. Although several reports have demonstrated that the interleukin (IL) 12 signaling pathway is involved in PBC pathogenesis, its precise genetic factors have not been fully clarified. Here, we performed an association analysis between IL12A, IL12RB, and signal transducer and activator of transcription 4 (STAT4) genetic variations and susceptibility to PBC. Single nucleotide polymorphisms (SNPs) were genotyped in 395 PBC patients and 458 healthy subjects of Japanese ethnicity and evaluated for associations with PBC susceptibility, anti-nuclear antibody (ANA) status, and anti-mitochondrial antibody (AMA) status. We detected significant associations with PBC susceptibility for several STAT4 SNPs (rs10168266; P = 9.4 × 10(-3), rs11889341; P = 1.2 × 10(-3), rs7574865; P = 4.0 × 10(-4), rs8179673; P = 2.0 × 10(-4), and rs10181656; P = 4.2 × 10(-5)). Three risk alleles (rs7574865; P = 0.040, rs8179673; P = 0.032, and rs10181656; P = 0.031) were associated with ANA status, but not with AMA positivity. Our findings confirm that STAT4 is involved in PBC susceptibility and may play a role in ANA status in the Japanese population.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Satoru
authors.identifier: 0000-0002-6364-9654
authors.initials: S
authors.lastname: Joshita
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Takeji
authors.initials: T
authors.lastname: Umemura
authors.affiliation: Clinical Research Center, NHO Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 2-1001-1 Kubara, Omura 856-8562, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Pharmacy, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Katsuyama
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Takefumi
authors.identifier: 0000-0002-1481-1029
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Morita
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Michiharu
authors.identifier: 0000-0002-7860-2816
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Kaname
authors.initials: K
authors.lastname: Yoshizawa
authors.affiliation: Clinical Research Center, NHO Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 2-1001-1 Kubara, Omura 856-8562, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ishibashi
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.affiliation: Department of Legal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
authors.forename: Masao
authors.identifier: 0000-0002-6400-5658
authors.initials: M
authors.lastname: Ota
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000974:Antibodies, Antinuclear / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D053765:Interleukin-12 Subunit p35 / Q000235:genetics; D007564:Japan; D015810:Linkage Disequilibrium; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D053707:Receptors, Interleukin-12 / Q000235:genetics; D050797:STAT4 Transcription Factor / Q000235:genetics*
chemical_list: D000974:Antibodies, Antinuclear; C508858:IL12A protein, human; C508438:IL12RB1 protein, human; D053765:Interleukin-12 Subunit p35; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human