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Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population.

ABSTRACT: For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

SUBMITTER: Nakamura M

PROVIDER: S-EPMC3484650 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population.

Nakamura Minoru M Nishida Nao N Kawashima Minae M Aiba Yoshihiro Y Tanaka Atsushi A Yasunami Michio M Nakamura Hitomi H Komori Atsumasai A Nakamuta Makoto M Zeniya Mikio M Hashimoto Etsuko E Ohira Hiromasa H Yamamoto Kazuhide K Onji Morikazu M Kaneko Shuichi S Honda Masao M Yamagiwa Satoshi S Nakao Kazuhiko K Ichida Takafumi T Takikawa Hajime H Seike Masataka M Umemura Takeji T Ueno Yoshiyuki Y Sakisaka Shotaro S Kikuchi Kentaro K Ebinuma Hirotoshi H Yamashiki Noriyo N Tamura Sumito S Sugawara Yasuhiko Y Mori Akira A Yagi Shintaro S Shirabe Ken K Taketomi Akinobu A Arai Kuniaki K Monoe Kyoko K Ichikawa Tatsuki T Taniai Makiko M Miyake Yasuhiro Y Kumagi Teru T Abe Masanori M Yoshizawa Kaname K Joshita Satoru S Shimoda Shinji S Honda Koichi K Takahashi Hiroki H Hirano Katsuji K Takeyama Yasuaki Y Harada Kenichi K Migita Kiyoshi K Ito Masahiro M Yatsuhashi Hiroshi H Fukushima Nobuyoshi N Ota Hajime H Komatsu Tatsuji T Saoshiro Takeo T Ishida Jinya J Kouno Hirotsugu H Kouno Hirotaka H Yagura Michiyasu M Kobayashi Masakazu M Muro Toyokichi T Masaki Naohiko N Hirata Keiichi K Watanabe Yukio Y Nakamura Yoko Y Shimada Masaaki M Hirashima Noboru N Komeda Toshiki T Sugi Kazuhiro K Koga Michiaki M Ario Keisuke K Takesaki Eiichi E Maehara Yoshihiko Y Uemoto Shinji S Kokudo Norihiro N Tsubouchi Hirohito H Mizokami Masashi M Nakanuma Yasuni Y Tokunaga Katsushi K Ishibashi Hiromi H

American journal of human genetics 20120920 4

For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938 ...[more]

PMID: 23000144

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Project description:Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9-10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13-15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC.

Dataset Information

Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population.

Publications

Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population.

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