FAS Rs2234767 Research Articles

Role of Polymorphisms on the Recurrent Pregnancy Loss: A Systematic Review, Meta-analysis and Bioinformatic Analysis

Recurrent miscarriage (RM) is a major reproductive health issue. RM is a multi-factorial disease, and is affected by environmental, genetic, and epigenetic factors. Genetics has a common role in recurrent miscarriage occurrence. It seems that molecular genetics has a great role in RSA incidence. So, in these years, RM has become for a major subject of genetics research. There are many genes that are involved in each phase for successful reproduction. This research aimed to evaluate the effect of all studied polymorphisms in studies on RSA that have not been included in any meta-analysis. PubMed, Scopus, and Web of Science databases were recruited to investigate the related articles. The systematic review results identified 143 studies worldwide. Thirteen genes have been included in assessing the case-control studies. Sixty-four SNPs were recruited to assess the association between genetic factors and RSA susceptibility. Ninety-two studies containing twenty-two SNPs (from 10 genes) were included in the quantitative analysis. Bioinformatic analysis indicated that rs12722482 showed “Damaging Status” by double servers, and rs315952 and rs854560 had “Possibly damaging” status in the PolyPhen-2 server. MethPrimer server indicated that there is “CpG Island” in the rs10895068, rs1130355, and rs41557518 variants, and rs10895068-G allele makes a CpG dinucleotide which can change the gene methylation and result in altering the gene expression. So, further studies on rs12722482 and rs10895068 can demonstrate valuable results. To the best of our knowledge, this systematic review has covered the all studied polymorphisms of HLA-C, HLA-G, PON1, AGTR1, TAFI, FAS, FAS-L, ESR1, PGR, CTLA-4, MMP-2, MMP-3, MMP-9, and IL1RN for the first time. Also, we did a novel meta-analysis for AGTR1 rs5186, TAFI rs1926447, rs3742264, HLA-G rs1063320, rs1233334, rs1736936, rs2249863, PON1 rs662, rs854560, FAS rs2234767, rs1800682, FAS-L rs763110, ESR1, rs9340799, rs3798759, PGR rs1042838, CTLA4 rs4553808, rs5742909, rs231775, rs3087243, and MMP-2 rs243865 and updated statistical finding for rs2234693 and rs371194629. Rs2234693, rs9340799, rs231775, and rs371194629 demonstrated a significant association with RSA risk. Some variations showed significant association, while further studies are suggested to confirm the results. Finally, Rs4553808 and rs5742909 revealed no significant deviation in the results. It is suggested that these SNPs may be excluded from subsequent case-control studies or other analyses.

Fas and microRNAs Variations as a Possible Risk for Behçet Disease.

Behçet disease (BD) belongs to a disease family that has a transparent borderline between autoinflammatory and autoimmune disorders. Fas and some miRNAs have revealed to display remarkable roles in both autoimmune and autoinflammatory processes, and they can play important roles in defective apoptosis in BD. We investigated the association of the susceptibility of BD with Fas, miRNA variations, and their both single and combined presence in a Turkish population as a case-control study. The distributions of FAS-670 A>G rs1800682, mir146a rs2910164, and mir196a rs11614913 polymorphisms are analyzed with the polymerase chain reaction-restriction fragment length polymorphism method in 115 BD patients and 220 controls in 6-month period. Statistical analysis indicates that in the case of Fas-670 A/G rs1800682, AA genotype and A allele have a protective role in BD (p = 0.0004 and p = 0.0009, respectively). The dominant model (AA + AG/GG) also displays a protective effect on BD unlike the recessive model (p = 0.03). In addition, both homozygous genotype (CC) of rs2910164 of mir-146a (p = 0.04) and the dominant model (CC + CG vs. GG) have protective effects on BD unlike the recessive model (p < 0.0001). Both mir-196a2 rs1800682 polymorphism and combined genotype analysis of rs1800682-rs2910164 and rs1800682-rs11614913 gave no statistically significant differences within the groups for genotypes and either of the alleles (p > 0.05). These findings indicate that both Fas rs1800682 and mir-146a rs2910164 variants might be important factors participating in the protection against BD in the Turkish population.

Overlapping and Distinct FAS/FASLG Gene Polymorphisms in Alopecia Areata in an Iranian Population

ABSTRACTAlopecia areata (AA) is considered to have a multifactorial etiology and polymorphisms in certain genes have been shown to be associated with AA. Although several reports have investigated the effect of FAS/FAS ligand (FASLG) gene variations with predisposing to AA, genetic association of disease, however, varies among different ethnicities and no data have so far been reported in Iranian population. The present study aimed to uncover a possible association between variations in FAS/FASLG genes and AA. Genomic DNA was extracted from all samples and the SNPs of FAS (rs1800682) and FASLG (rs5030772) genes were genotyped in AA patients and controls. In addition, gene expression of FAS/FASLG was assessed by RT-PCR. Regarding FASLG, the frequency of the G-allele was significantly higher in the patients compared to the controls, indicating that the G-allele at this locus could be a risk for developing AA. In contrast, no association was found for rs1800682 (FAS) with AA. Similarly, compared to controls, FASLG gene expression was upregulated. While no association between clinical−demographic characteristics of the AA patients and their genotypes in FAS/FASL variations was observed, multivariate regression analysis indicated a correlation between the incidence of AA disease and its familial history as well as AG/GG genotypes of FASLG (rs5030772). In conclusion, our data indicate an association between FASLG rs5030772 variation and AA. However, previously reported the association of FAS rs1800682 polymorphism with AA was not observed here. These findings highlight overlapping and distinct genetic polymorphisms in an Iranian cohort which might influence the susceptibility to AA.

Single-Nucleotide Polymorphisms of FAS and FASL Genes and Risk of Idiopathic Aplastic Anemia

ABSTRACTFAS/FASL signaling system plays a vital role in the regulation of apoptosis, envisaged as a death process required for immune surveillance to prevent autoimmunity and tumorigenesis along with several other biological activities. Several single-nucleotide polymorphisms (SNPs) of FAS/FASL system can result in aberrant apoptosis, which can cause different cancers and autoimmune diseases. Aplastic anemia (AA) is an autoimmune dysfunction characterized by peripheral blood pancytopenia associated with hypoplasia of bone marrow. The aim of this study was to screen Pakistani AA patients and controls for two Fas SNPs rs2234767 and rs1800682 and two FASLG SNPs rs763110 and rs5030772. Genotyping of 392 DNA samples was done by Tetra-ARMS polymerase chain reaction. Genotypic frequencies of Fas rs1800682 and FASLG rs5030772 showed significance difference in their distribution in both controls and patients, while Fas rs2234767 and FASLG rs763110 SNPs had no such difference. Carriers of rs1800682 AG+GG had a very odd ratio of 4.63, with 95% confidence interval (CI) of 3.01–7.11, while individuals with FASLG rs5030772 AG+GG were more common in controls than patients with OR 0.53 and 95% CI of 0.34–0.83. Cumulative effects of these SNPs were analyzed, and they showed almost similar trends; however, Fas rs2234767 and FASLG rs763110 genotypes in combination with Fas rs1800682 and FASLG rs5030772 demonstrated significant association. This study provided information that endorsed the involvement of FAS/FASL system SNPs in the pathogenesis of AA; further studies should be designed to understand the exact role of SNPs that can help in early diagnosis and treatment.

Effect modification by apoptosis-related gene polymorphisms on the associations of phthalate exposure with spermatozoa apoptosis and semen quality

BackgroundHuman studies indicate that phthalate exposure is associated with adverse male reproductive health, and this association may be modified by genetic polymorphisms. ObjectivesWe investigated whether apoptosis-related gene polymorphisms modified the associations of phthalate exposure with spermatozoa apoptosis and semen quality. MethodsIn this Chinese population who sought for semen examination in an infertility clinic, we measured 8 phthalate metabolites in two urine samples to assess the individual's exposure levels. Apoptosis-related gene (Fas, FasL, and caspase3) polymorphisms were performed by real-time PCR. Spermatozoa apoptosis and semen quality parameters were evaluated by Annexin V/PI assay and computer-aided semen analysis, respectively. ResultsWe found that Fas rs2234767, FasL rs763110, and caspase3 rs12108497 gene polymorphisms significantly modified the associations between urinary phthalate metabolites and spermatozoa apoptosis. For example, urinary monobutyl phthalate (MBP) associated with an increased percentage of Annexin V+/PI− spermatozoa of 25.11% (95% CI: 4.08%, 50.53%) were only observed among men with CT/TT genotype of FasL rs763110. In addition, we found that caspase3 rs12108497 gene polymorphisms significantly modified the associations of urinary mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) with decreased sperm concentration and sperm count (both p-values for interactions = 0.02). ConclusionOur results provided the first evidence that apoptosis-related gene polymorphisms might contribute to the effects of phthalate exposure on male reproductive health.

Distinct role of the Fas rs1800682 and FasL rs763110 polymorphisms in determining the risk of breast cancer among Han Chinese females.

BackgroundIn recent years, studies have demonstrated that polymorphisms in the promoters of Fas and FasL are significantly associated with breast cancer risk. However, the results of these studies were inconsistent. This case–control study was performed to explore the associations between Fas rs1800682 and FasL rs763110 polymorphisms and breast cancer.Materials and methodsA hospital-based case–control study of 560 Han Chinese females with breast cancer (583 controls) was conducted. The MassARRAY system was used to search for a possible association between the disease risk and the two single nucleotide polymorphisms, Fas rs1800682 and FasL rs763110. Statistical analyses were performed using SNPStats software to conduct Pearson’s chi-square tests in five different genetic models. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated after adjustment to age and body mass index. PHASE v2.1 software was used to reconstruct all common haplotypes.ResultsA statistically significant association was found between Fas rs1800682 and increased breast cancer risk (AG vs AA: OR =1.37, 95% CI =1.06–1.78; AA+AG vs GG: OR =1.32, 95% CI =1.04–1.66), and also it was found that the FasL rs763110 polymorphism may decrease the risk. Stratified analyses demonstrated that the rs763110 polymorphism was associated with lower breast cancer risk among postmenopausal females (heterozygote model: OR =0.69, 95% CI =0.49–0.97; dominant model: OR =0.70, 95% CI =0.51–0.96). The T allele of rs763110 was also associated with a decreased risk of lymph node metastasis (allele model: OR =0.75, 95% CI =0.57–0.97) and an increased risk of the breast cancer being human epidermal growth factor receptor 2 positive (allele model: OR =1.37, 95% CI =1.03–1.18). Moreover, haplotype analysis showed that Ars1800682Trs763110 was associated to a statistically significant degree with lower risk of breast cancer (OR =0.70, 95% CI =0.53–0.91).ConclusionThese data suggest that the presence of Fas rs1800683 is an important risk factor for breast cancer, whereas FasL rs763110 may exert a protective effect against the onset of breast cancer.

Fas/FasL, Bcl2 and Caspase-8 gene polymorphisms in Chinese patients with rheumatoid arthritis

Apoptosis signals are necessary for maintaining homeostasis and an adequate immune response. Dysregulation of apoptosis-related genes in the immune system has an important impact on autoimmune diseases such as rheumatoid arthritis (RA). Thus, we investigated the association between Fas rs2234767 G/A, FasL rs763110 C/T, Bcl2 rs12454712 T/C, Bcl2 rs17757541 C/G, and Caspase-8 rs1035142 G/T polymorphisms and RA susceptibility in a Chinese population. These five single-nucleotide polymorphisms (SNPs) were studied in a Chinese population consisting of 615 patients with RA and 839 controls. Genotyping was performed using a custom-by-design 48-Plex SNP scan TM kit. Furthermore, we undertook a meta-analysis between FasL rs763110 C/T and RA. This study indicated that Fas rs2234767 and Bcl2 rs17757541 polymorphisms were risk factors for RA. No association was observed between FasL rs763110 C/T, Bcl2 rs12454712 T/C, and Caspase-8 rs1035142 G/T polymorphisms and RA in this study. The results of this meta-analysis suggested no significant association between FasL rs763110 C/T and RA. However, stratification analysis of this meta-analysis indicated that FasL rs763110 C/T increased the risk of Caucasian RA patients. In conclusion, this study demonstrated that Fas rs2234767 G/A and Bcl2 rs17757541 T/C polymorphisms might be associated with an increased risk of RA. This meta-analysis revealed that FasL rs763110 C/T was associated with an increased risk of Caucasian RA patients.

FAS rs2234767 and rs1800682 polymorphisms jointly contributed to risk of colorectal cancer by affecting SP1/STAT1 complex recruitment to chromatin

FAS rs2234767 (−1377 G>A), rs1800682 (−670 A>G) and FASLG rs763110 (−844 C>T) promoter polymorphisms can influence transcriptional activities of the genes and thus multiple tumors susceptibility. To investigate their association with risk of colorectal cancer (CRC), the three SNPs were genotyped in 878 cases and 884 controls and the results showed that the FAS rs2234767 and rs1800682 were in a high linkage disequilibrium (LD) with each other (D’ = 0.994) and jointly contributed to an increased risk of CRC (without vs. with rs2234767 GG/rs1800682 AA genotypes, adjusted OR = 1.30, 95% CI = 1.05 − 1.61). In vivo ChIP assays evaluated the effect of rs2234767 and rs1800682 on recruitment of SP1 and STAT1, respectively, to chromatin. The results showed SP1 interacting specifically with STAT1 recruited to their respective motifs for transcriptional activation. The mutant alleles rs2234767 A and rs1800682 G jointly affected coupled SP1 and STAT1 recruitment to chromatin. The interplay between SP1 and STAT1 was critical for the functional outcome of rs2234767 and rs1800682 in view of their high LD. In conclusion, the FAS rs2234767 and rs1800682 polymorphisms were in high LD with each other, and they jointly contributed to an increased risk of CRC by altering recruitment of SP1/STAT1 complex to the FAS promoter for transcriptional activation.

Association between the CTLA-4, CD226, FAS polymorphisms and rheumatoid arthritis susceptibility: A meta-analysis

ObjectiveWe explored whether cytotoxic T lymphocyte antigen-4 (CTLA-4) rs5742909, CD226 rs763361, FAS rs1800682, and FASL rs763110 polymorphisms are associated with rheumatoid arthritis (RA). MethodsWe performed a meta-analysis on the association between the four gene polymorphisms and RA. ResultsNineteen studies were included in the meta-analysis. Meta-analysis of all study subjects showed no association between RA and the CTLA-4 rs5742909 T allele (OR=1.057, 95% CI=0.782–1.429, p=0.719). However, the meta-analysis revealed an association between RA and the CD226 rs763361 T allele in all study subjects (OR=1.294, 95% CI=1.063–1.576, p=0.010), and an association was found between the CD226 rs763361 TT genotype and RA in Asians (OR=1.363, 95% CI=1.126–1.651, p=0.001). Meta-analysis showed no association between RA and the FAS rs1800682 G/A polymorphism. However, meta-analysis revealed an association between RA and the FASL rs763110 T allele in all study subjects (OR=1.366, 95% CI=1.093–1.707, p=0.006) and in Asians (OR=1.402, 95% CI=1.059–1.855, p=0.014). ConclusionsOur meta-analysis demonstrates that the CD226 rs763361 and FASL rs763110 polymorphisms are associated with RA, especially in Asians.

B-cell Lymphoma 2 rs17757541 C&gt;G Polymorphism was Associated with an Increased Risk of Gastric Cardiac Adenocarcinoma in a Chinese Population

Apoptosis has been considered as a fundamental component in cancer pathogenesis, and related genetic factors might play an important role in gastric cardiac adenocarcinoma (GCA) genesis. We conducted a hospital based case-control study to evaluate the genetic effects of functional single nucleotide polymorphisms (SNPs): BCL2 rs17757541 C>G, BCL2 rs12454712 T>C, FAS rs2234767 G>A, FASL/FASLG rs763110 C>T, ERBB2 rs1136201 A>G and VEGFR2/KDR rs11941492 C>T on the development of GCA. A total of 243 GCA cases and 476 controls were recruited for the study and genotypes were determined using a custom-by-design 48-Plex SNPscanTM Kit. The BCL2 rs17757541 C>G polymorphism was associated with increased risk of GCA. However, there was no significant associations with the other five SNPs. Stratified analyses indicated a significantly increased risk of GCA associated with the BCL2 rs17757541 C>G polymorphism among males, older patients and those with a history of smoking or drinking. These findings indicated that the functional polymorphism BCL2 rs17757541 C>G might contribute to GCA susceptibility. However, our results were limited by small sample size. Future larger studies are required to confirm our current findings.

Functional Polymorphisms of FAS and FASL Gene and Risk of Breast Cancer – Pilot Study of 134 Cases

Fas/Fas ligand (FasL) system is one of the key apoptotic signaling entities in the extrinsic apoptotic pathway. De-regulation of this pathway, i.e. by mutations may prevent the immune system from the removal of newly-formed tumor cells, and thus lead to tumor formation. The present study investigated the association between −1377 G/A (rs2234767) and −670 A/G (rs1800682) polymorphisms in Fas as well as single nucleotide polymorphisms INV2nt −124 A/G (rs5030772) and −844 C/T (rs763110) in FasL in a sample of Iranian patients with breast cancer. This case-control study was done on 134 breast cancer patients and 152 normal women. Genomic DNA was extracted from whole blood samples. The polymorphisms were determined by using tetra-ARMS-PCR method. There was no significant difference in the genotype distribution of FAS rs2234767 polymorphism between cases and controls. FAS rs1800682, FASL rs5030772, and FASL rs763110 genotypes showed significant associations with an increasing risk of breast cancer (odds ratio OR = 3.18, P = 0.019; OR = 5.08, P = 0.012; OR = 2.40, P = 0.024, respectively). In conclusion, FAS rs2234767 was not associated with breast cancer risk. Though, FAS rs1800682, FASL rs5030772, and FASL rs763110 polymorphisms were associated with the risk of breast cancer in the examined population.