Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients

Aiba, Yoshihiro; Nakamura, Minoru; Joshita, Satoru; Inamine, Tatsuo; Komori, Atsumasa; Yoshizawa, Kaname; Umemura, Takeji; Horie, Hisanaga; Migita, Kiyoshi; Yatsuhashi, Hiroshi; Nakamuta, Makoto; Fukushima, Nobuyoshi; Saoshiro, Takeo; Hayashi, Shigeki; Kouno, Hiroshi; Ota, Hajime; Muro, Toyokichi; Watanabe, Yukio; Nakamura, Yoko; Komeda, Toshiki; Shimada, Muneaki; Masaki, Naohiko; Komatsu, Tatsuji; Yagura, Michiyasu; Sugi, Kazuhiro; Koga, Michiaki; Tsukamoto, Kazuhiro; Tanaka, Eiji; Ishibashi, Hiromi

doi:10.1007/s00535-011-0417-7

Cited by 31 publications

(24 citation statements)

References 35 publications

(61 reference statements)

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“…Allelic variations in TNFa and solute carrier family 4 anion exchanger, member 2 (SLC4A2) but not CTLA4 have a significant impact on the progression of PBC [9]. However, the latter was not confirmed in a Japanese study, which reported association of CTLA4 SNPs with progression of the disease [50]. Our study is in agreement with other previous European [46] and Japanese studies [48].…”

Section: Discussionsupporting

confidence: 93%

Polymorphisms of genes related to endothelial cells are associated with primary biliary cirrhosis patients of Cretan origin

et al. 2012

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Section: Discussionsupporting

confidence: 93%

Polymorphisms of genes related to endothelial cells are associated with primary biliary cirrhosis patients of Cretan origin

et al. 2012

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“…In follow-up studies of GWAS datasets, associations of STAT4 variation with ANA status and CTLA4 variants with anti-centromere and gp210 have been identified in Japanese PBC patients [104] and TNFSF15 polymorphisms have been linked to functional changes in the gene product. Differences in mRNA and protein expression were also seen in both PBC and healthy subjects carrying this variant, although a link to outcome or phenotype remains unclear [105].…”

Section: Relating Immunogenetic Observations To Clinical Phenotypesmentioning

confidence: 99%

The immunogenetics of primary biliary cirrhosis: A comprehensive review

Webb

Siminovitch

Hirschfield

2015

Journal of Autoimmunity

104

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Primary biliary cirrhosis (PBC), a classic autoimmune liver disease, is characterised by a progressive T cell predominant lymphocytic cholangitis, and a serologic pattern of reactivity in the form of specific anti-mitochondrial antibodies (AMA). CD4+ T cells are particularly implicated by PBC's cytokine signature, the presence of CD4+ T cells specific to mitochondrial auto-antigens, the expression of MHC II on injured biliary epithelial cells, and PBC's coincidence with other similar T cell mediated autoimmune conditions. CD4+ T cells are also central to current animal models of PBC, and their transfer typically also transfers disease. The importance of genetic risk to developing PBC is evidenced by a much higher concordance rate in monozygotic than dizygotic twins, increased AMA rates in asymptomatic relatives, and disproportionate rates of disease in siblings of PBC patients, PBC family members and certain genetically defined populations. Recently, high-throughput genetic studies have greatly expanded our understanding of the gene variants underpinning risk for PBC development, so linking genetics and immunology. Here we summarize genetic association data that has emerged from large scale genome-wide association studies and discuss the evidence for the potential functional significance of the individual genes and pathways identified; we particularly highlight associations in the IL-12-STAT4-Th1 pathway. HLA associations and epigenetic effects are specifically considered and individual variants are linked to clinical phenotypes where data exist. We also consider why there is a gap between calculated genetic risk and clinical data: so-called missing heritability, and how immunogenetic observations are being translated to novel therapies. Ultimately whilst genetic risk factors will only account for a proportion of disease risk, ongoing efforts to refine associations and understand biologic links to disease pathways are hoped to drive more rational therapy for patients.

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“…Polymorphisms in the AE2 gene that reduce transporter expression have been linked to primary biliary cirrhosis due to decreased expression of this transporter (Aiba et al, 2011;Juran, Atkinson, Larson, Schlicht, & Lazaridis, 2009;Medina, 2011). AE2-deficient mice also develop primary biliary cirrhosis (Salas et al, 2008).…”

Section: Slc4 Family Of Anion Transportersmentioning

confidence: 99%

Structure, Function, and Trafficking of SLC4 and SLC26 Anion Transporters

Cordat

Reithmeier

2014

Current Topics in Membranes

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Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients

Abstract: CTLA4 and SLC4A2 genetic polymorphisms are differentially associated with PBC development and progression, as well as anti-gp210 or anti-centromere antibody production, in Japanese PBC patients.

Cited by 31 publications

References 35 publications

Polymorphisms of genes related to endothelial cells are associated with primary biliary cirrhosis patients of Cretan origin

Polymorphisms of genes related to endothelial cells are associated with primary biliary cirrhosis patients of Cretan origin

The immunogenetics of primary biliary cirrhosis: A comprehensive review

Structure, Function, and Trafficking of SLC4 and SLC26 Anion Transporters

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