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Association of STAT4 polymorphisms with susceptibility to type-1 autoimmune hepatitis in the Japanese population.

ABSTRACT: BACKGROUND/AIMS: Recent studies demonstrated an association of STAT4 polymorphisms with autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, indicating multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 polymorphisms on the susceptibility and phenotype of type-1 autoimmune hepatitis in a Japanese National Hospital Organization (NHO) AIH multicenter cohort study. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 460 individuals of Japanese origin including 230 patients with type-1 autoimmune hepatitis and 230 healthy controls was analyzed for two single nucleotide polymorphisms in the STAT4 gene (rs7574865, rs7582694). The STAT4 rs7574865T allele conferred risk for type-1 autoimmune hepatitis (OR?=?1.61, 95% CI?=?1.23-2.11; P?=?0.001), and patients without accompanying autoimmune diseases exhibited an association with the rs7574865T allele (OR?=?1.50, 95%CI?=?1.13-1.99; P?=?0.005). Detailed genotype-phenotype analysis of type-1 autoimmune hepatitis patients with (n?=?44) or without liver cirrhosis (n?=?186) demonstrated that rs7574865 was not associated with the development of liver cirrhosis and phenotype (biochemical data and the presence of auto-antibodies). CONCLUSIONS/SIGNIFICANCE: This is the first study to show a positive association between a STAT4 polymorphism and type-1 autoimmune hepatitis, suggesting that autoimmune hepatitis shares a gene commonly associated with risk for other autoimmune diseases.

SUBMITTER: Migita K

PROVIDER: S-EPMC3750035 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Association of STAT4 polymorphisms with susceptibility to type-1 autoimmune hepatitis in the Japanese population.

Migita Kiyoshi K Nakamura Minoru M Abiru Seigo S Jiuchi Yuka Y Nagaoka Shinya S Komori Atsumasa A Hashimoto Satoru S Bekki Shigemune S Yamasaki Kazumi K Komatsu Tatsuji T Shimada Masaaki M Kouno Hiroshi H Hijioka Taizo T Kohjima Motoyuki M Nakamuta Makoto M Kato Michio M Yoshizawa Kaname K Ohta Hajime H Nakamura Yoko Y Takezaki Eiichi E Nishimura Hideo H Sato Takeaki T Ario Keisuke K Hirashima Noboru N Oohara Yukio Y Naganuma Atsushi A Muro Toyokichi T Sakai Hironori H Mita Eiji E Sugi Kazuhiro K Yamashita Haruhiro H Makita Fujio F Yatsuhashi Hiroshi H Ishibashi Hiromi H Yasunami Michio M

PloS one 20130822 8

<h4>Background/aims</h4>Recent studies demonstrated an association of STAT4 polymorphisms with autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, indicating multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 polymorphisms on the susceptibility and phenotype of type-1 autoimmune hepatitis in a Japanese National Hospital Organization (NHO) AIH multicenter cohort study.<h4>Methodology/principal findings< ...[more]

PMID: 23990947

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Project description:INTRODUCTION: Recent studies identified STAT4 (signal transducers and activators of transcription-4) as a susceptibility gene for systemic lupus erythematosus (SLE). STAT1 is encoded adjacently to STAT4 on 2q32.2-q32.3, upregulated in peripheral blood mononuclear cells from SLE patients, and functionally relevant to SLE. This study was conducted to test whether STAT4 is associated with SLE in a Japanese population also, to identify the risk haplotype, and to examine the potential genetic contribution of STAT1. To accomplish these aims, we carried out a comprehensive association analysis of 52 tag single nucleotide polymorphisms (SNPs) encompassing the STAT1-STAT4 region. METHODS: In the first screening, 52 tag SNPs were selected based on HapMap Phase II JPT (Japanese in Tokyo, Japan) data, and case-control association analysis was carried out on 105 Japanese female patients with SLE and 102 female controls. For associated SNPs, additional cases and controls were genotyped and association was analyzed using 308 SLE patients and 306 controls. Estimation of haplotype frequencies and an association study using the permutation test were performed with Haploview version 4.0 software. Population attributable risk percentage was estimated to compare the epidemiological significance of the risk genotype among populations. RESULTS: In the first screening, rs7574865, rs11889341, and rs10168266 in STAT4 were most significantly associated (P < 0.01). Significant association was not observed for STAT1. Subsequent association studies of the three SNPs using 308 SLE patients and 306 controls confirmed a strong association of the rs7574865T allele (SLE patients: 46.3%, controls: 33.5%, P = 4.9 x 10(-6), odds ratio 1.71) as well as TTT haplotype (rs10168266/rs11889341/rs7574865) (P = 1.5 x 10(-6)). The association was stronger in subgroups of SLE with nephritis and anti-double-stranded DNA antibodies. Population attributable risk percentage was estimated to be higher in the Japanese population (40.2%) than in Americans of European descent (19.5%). CONCLUSIONS: The same STAT4 risk allele is associated with SLE in Caucasian and Japanese populations. Evidence for a role of STAT1 in genetic susceptibility to SLE was not detected. The contribution of STAT4 for the genetic background of SLE may be greater in the Japanese population than in Americans of European descent.

Dataset Information

Association of STAT4 polymorphisms with susceptibility to type-1 autoimmune hepatitis in the Japanese population.

Publications

Association of STAT4 polymorphisms with susceptibility to type-1 autoimmune hepatitis in the Japanese population.

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