Fas polymorphisms influence susceptibility to autoimmune hepatitis
ABSTRACT Genetic factors associated with autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), immune-mediated chronic inflammatory liver diseases of unknown etiology, remain to be elucidated. Polymorphisms of the gene encoding Fas have been linked to a variety of autoimmune diseases. We hypothesized that Fas gene polymorphisms might be genetic markers for AIH and PBC.
To determine the frequency and significance of Fas polymorphisms in patients with AIH and PBC, 74 Japanese AIH patients, 98 Japanese PBC patients, and 132 ethnically matched control subjects were investigated by the use of the Taqman assay.
We found significant differences between AIH patients and controls in allele frequencies of Fas-670 (p=0.009), Fas IVS (intervening sequence) 2nt176 (p=0.018), Fas IVS3nt46 (p=0.031), and Fas IVS5nt82 (p=0.013) polymorphisms. Haplotype analysis revealed that one of the haplotypes, GATGC, was associated with increased AIH prevalence. On the other hand, we found no statistically significant differences between PBC patients and controls in allele frequencies of the Fas polymorphisms genotyped in this study.
These results indicate a genetic link of Fas polymorphisms to the development of AIH. Further studies are needed to determine the genetic factors contributing to the development of AIH.
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ABSTRACT: Apoptosis is the predominant mechanism of liver cell death in autoimmune hepatitis, and interventions that can modulate this activity are emerging. The aim of this review was to describe the apoptotic mechanisms, possible aberrations, and opportunities for intervention in autoimmune hepatitis. Studies cited in PubMed from 1972 to 2014 for autoimmune hepatitis, apoptosis in liver disease, apoptosis mechanisms, and apoptosis treatment were examined. Apoptosis is overactive in autoimmune hepatitis, and the principal pathway of cell death is receptor mediated. Surface death receptors are activated by extrinsic factors including liver-infiltrating cytotoxic T cells and the cytokine milieu. The executioner caspases 3 and 7 cleave nuclear deoxyribonucleic acid, and the release of apoptotic bodies can stimulate inflammatory, immune, and fibrotic responses. Changes in mitochondrial membrane permeability can be initiated by caspase 8, and an intrinsic pathway of apoptosis can complement the extrinsic pathway. Defects in the apoptosis of activated effector cells can prolong their survival and sustain the immune response. Caspase inhibitors have been used in diverse experimental and human diseases to retard apoptosis. Oligonucleotides that inhibit the signaling of toll-like receptors can limit the presentation of auto-antigens, and inhibitors of apoptosis that extend the survival of effector cells can be blocked by antisense oligonucleotides. Mechanisms that enhance the clearance of apoptotic bodies and affect key signaling pathways are also feasible. Interventions that influence the survival of liver and effector cells by altering their apoptosis are candidates for study in autoimmune hepatitis.Digestive Diseases and Sciences 07/2014; 59(12). DOI:10.1007/s10620-014-3284-2 · 2.55 Impact Factor
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ABSTRACT: Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. Soluble Fas receptor (sFas) has been suggested as a Fas-mediated apoptosis blocker that could impair clonal deletion in infiltrated autoreactive cells. The FAS -670A>G promoter polymorphism has been studied in pSS. However, a relationship between FAS -670A>G promoter polymorphism and sFas levels in pSS had not been found. We examined this relationship in 77 Mexican pSS patients and 84 healthy subjects were included. Genotypes were identified by PCR-RFLP, and Fas soluble levels were quantified by ELISA. No significant differences between allele and genotype frequencies were found between these two groups. The sFas levels in the serum of pSS patients were significantly higher than in controls (9961 vs 8840 pg/mL, respectively). In addition, AA genotype carriers had significantly higher levels of sFas than GG carriers (pSS: 10,763 and 9422 pg/mL; controls: 9712 and 8305 pg/mL, respectively). An additive model analysis between genotypes (AG+GG vs AA) in both groups, demonstrated a significant association between carriers of the A allele and high sFas levels. In conclusion, carrying the double dose of A allele of FAS -670A>G polymorphism is associated with high levels of sFas in pSS, but it is not a susceptibility marker for pSS.Genetics and molecular research: GMR 01/2014; 13(3):4831-8. DOI:10.4238/2014.July.2.12 · 0.85 Impact Factor
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ABSTRACT: Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. We performed a genome-wide association study of 649 adults in the Netherlands with AIH type-1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type-1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the MHC region. We associated AIH with a variant in the MHC region, at rs2187668 (P=1.5x10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3x10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P=2.8x10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P=7.7x10(-8)) and CARD10 (rs6000782, 22q13.1; P=3.0x10(-6)). Furthermore, strong inflation of association signal was found with single-nucleotide polymorphisms (SNPs) associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with SNPs associated with other genetic traits. In a genome-wide association study, we associated AIH type-1with variants in the MHC region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.Gastroenterology 08/2014; 147(2):443-452. DOI:10.1053/j.gastro.2014.04.022 · 13.93 Impact Factor