Fas Polymorphisms Influence Susceptibility to Autoimmune Hepatitis

Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba City, Japan.
The American Journal of Gastroenterology (Impact Factor: 10.76). 07/2005; 100(6):1322-9. DOI: 10.1111/j.1572-0241.2005.41053.x
Source: PubMed


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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    • "Although genetic background is one of the predisposing factors for the development of autoimmunity, the FAS -670A>G polymorphism likely has no significant effect on susceptibility to pSS. However, it has been reported the -670A>G polymorphism is in linkage disequilibrium with other variations in the FAS gene (Hiraide et al., 2005). Therefore, further studies are needed to determine whether susceptibility to pSS could be due to a specific haplotype. "
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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 07/2014; 13(3):4831-8. DOI:10.4238/2014.July.2.12 · 0.78 Impact Factor
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    • "equency of - 1377A allele in this study was 11 . 6% , which was close to the Caucasians ( 12 . 0% ) and southern Australians ( 9 . 7% ) , but lower compared with the Han Chinese population ( 34 . 0% ) , another Han Chinese population ( 34 . 3% ) , and Jap - anese ( 46 . 2% ) ( Sibley et al . , 2003 ; Mullighan et al . , 2004 ; Sun et al . , 2004 ; Hiraide et al . , 2005 ; Wang et al . , 2009 ) . In terms of FASLG - 124 A / G , the present investigation is the first screening study for association of SNP of the FAS and FASLG genes on male infertility in southeast Turkey and as far as is known , there has been no report on the association of the FASLG - 124 A / G SNP with male infertility in the lit - er"
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    ABSTRACT: To investigate the association of the genetic variants of FAS/FASLG cell death pathway genes in male infertility, we genotyped the FAS -670A/G, -1377G/A, and FASLG -124A/G single-nucleotide polymorphisms (SNPs) by real-time polymerase chain reaction in 108 infertile men with idiopathic azoospermia and in 125 proven fertile controls. The distribution of genotypes and alleles for SNPs at FAS -1377G/A and FASLG -124A/G loci were determined not to be statistically different between the case and control groups. However, the genotype frequencies of SNPs, FAS -670AA and FAS -670AG, were found to be significantly different between the case and control groups. Whereas the FAS -670AA genotype might be regarded as a higher predisposition for idiopathic azoospermia, FAS -670AG could be interpreted to mean that this genotype provides protection against idiopathic azoospermia. The study of combined genotype and haplotype frequencies has found statistically significant differences between case and control subjects for some combinations. The AA-GG binary genotype for the FAS670 and FAS1377 loci couple, in particular, may have a high degree of predisposition to idiopathic azoospermia. Our results suggest that FAS -670A/G SNP may be a genetic predisposing factor of idiopathic azoospermia among southeastern Anatolian men. Larger studies are needed to verify these findings. Furthermore, our data indicated a possible linkage between the FAS and FASLG genes and idiopathic azoospermia.
    Genetic Testing and Molecular Biomarkers 03/2014; 18(6). DOI:10.1089/gtmb.2013.0454 · 1.46 Impact Factor
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    • "In young white AIH patients, the tumor necrosis factor (TNF) polymorphism -308G > A is associated with a poorer response to corticosteroid therapy. A Fas gene promoter polymorphism was found to influence susceptibility to AIH and its progression (Hiraide et al. 2005; Agarwal et al. 2007), leading to a more aggressive disease with an early development of cirrhosis (Hiraide et al. 2005). "
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    ABSTRACT: The precise etiology of autoimmune hepatitis (AIH) remains unknown, although a number of genetic loci have been implicated in the susceptibility of type 1 AIH. The purpose of this study was to test for association of these loci with type 1 AIH in New Zealand Caucasians. 77 AIH patients and 485 healthy controls were genotyped for the SNPs rs2187668 (HLA-DRB*03:01), rs660895 (HLA-DRB*04:01), rs3749971 (HLA-A1-B8-DR3), rs231775 (CLTLA4), rs1800629 (TNF), and rs1800682 (FAS) using predesigned TaqMan SNP genotyping assays. Chi square analysis was used to test for association of allele and genotype with overall AIH, and with severe fibrosis and ALT levels at 6 months. Significant risk of AIH was conferred by the minor alleles of rs2187668 (OR = 2.45, 95% CI 1.65-3.61, p < 0.0001), rs3749971 (OR = 1.89, 95% CI 1.21-2.94, p = 0.004) and rs1800629 (OR = 2.06, 95% CI 1.41-3.01, p = 0.0001). Multivariate analysis showed that rs2187668 was independently associated with type 1 AIH susceptibility (OR = 2.40, 95% CI 1.46-3.93, p = 0.001). The C allele of FAS SNP rs1800682 was associated with increased risk of severe fibrosis at diagnosis (OR = 2.03, 95% CI 1.05-3.93, p = 0.035) and with incomplete normalization of ALT levels at 6 months post-diagnosis (OR = 3.94, 95% CI 1.62-9.54, p = 0.0015). This is the first population-based study to investigate genetic risk loci for type 1 AIH in New Zealand Caucasians. We report significant independent association of HLA-DRB1*03:01 with overall susceptibility to type 1 AIH, as well as FAS with a more aggressive disease phenotype.
    SpringerPlus 07/2013; 2(1):355. DOI:10.1186/2193-1801-2-355
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