Relation of the Fas and FasL gene polymorphisms with susceptibility to and severity of rheumatoid arthritis

Abstract

To investigate associations of the Fas and FasL genes polymorphisms with rheumatoid arthritis (RA). One hundred patients with RA and age-, sex- and ethnically matched 101 controls were included. Four polymorphisms of Fas (-670 A>G rs1800682, -1377 G>A rs2234767) and FasL (IVS2nt-124 A>G rs5030772, -844 T>C rs763110) genes were typed from genomic DNA. Genotype distributions and allelic frequencies were compared between patients and control subjects. After the history and clinical examination of patients with RA, in terms of pain, fatigue and general health status were evaluated by visual analogue scale. Thereafter, erythrocyte sedimentation rate, C-reactive protein, blood count and rheumatoid factor levels were measured. The Disease Activity Score-28, Health Assessment Questionnaire and modified Sharp score were used to evaluate the disease activity, functional disability and radiological damage, and their relationships with the Fas and FasL gene polymorphisms were investigated. In patients with RA, CT and TT genotypes of FasL-844, polymorphism were twofold and 4.8-fold higher, and AA genotype of FasL IVS2nt-124 polymorphism was 3.4-fold higher than the control group (respectively, p = 0.05, p = 0.002, p = 0.039). T allele of FasL-844 polymorphism was more frequent in patients than controls (respectively, 52.5 vs. 41.4 %, p = 0.027). Any association was not detected between Fas (-670 A>G, -1377 G>A) and FasL (-844 T>C, IVS2nt-124 A>G) gene polymorphisms with the disease activity scores, functional disability and radiological damage. However, the Fas-670 A>G polymorphism was associated with drug therapy (p = 0.049). The distribution of GG genotype was higher compared to GA or AA genotypes in patients using triple disease-modifying antirheumatic drug therapy (71.4, 14.3 and 14.3 %, respectively). These findings suggest that the -844 T>C and IVS2nt-124 A>G polymorphisms in the FasL gene related with apoptosis may increase genetic susceptibility to RA in a Turkish population. In addition, the Fas-670 A>G gene polymorphism may be associated with disease progression. There is a need for further studies to clarify the genetic role of apoptosis in RA.

Dual Role of Fas/FasL-Mediated Signal in Peripheral Immune Tolerance

“…Moreover, a defect in B-cell selection occurs in patients with ALPS, which is caused by impaired class-switch recombination and somatic hypermutation of the genes encoding immunoglobulins (100). Polymorphisms in the genes encoding Fas and FasL are associated with the susceptibility and severity of autoimmune lesions in patients with RA (101, 102) as well as in patients with primary SS (103). …”

Association between Fas/FasL gene polymorphism and musculoskeletal degenerative diseases: a meta-analysis

“…We also noted that the overall ORs significantly changed when we deleted Zhu et al (published in 2011) [ 24 ] in homozygote model (GG vs. AA, OR = 0.843, 95% CI: 0.647–1.098, P = 0.204) and Zhu et al (published in 2016) [ 31 ] in homozygote model (GG vs. AA, OR = 0.755, 95% CI: 0.550–1.037, P = 0.082) for Fas (rs2234767) site. We found that the pooled ORs significantly differed when we deleted Sun et al 19] in dominant model (GG + GA vs. AA, OR = 0.760, 95%CI: 0.560–1.031, P = 0.078) and Seyfi et al [ 30 ] in dominant model (GG + GA vs. AA, OR = 0.679, 95% CI: 0.459–1.005, P = 0.053) for FasL (rs763110) site as well. However, there was no change in the significance of results in any models for FasL (rs5030772) site.…”

“…What’s more, the genotype distributions of controls in all of models were in accordance with HWE, except Sezgin et al [ 22 ] in Fas (rs2234767) and Seyfi et al [ 30 ] in FasL (rs5030772). However, the association was not significant change when ruled out these two studies by excluding one at a time.…”

“…We corrected the mistakes and analyzed again. Compared with Zhu et al (published in 2016) [ 31 ], the small differences of result in Fas (rs2234767) for RA might be due to a new study [ 30 ] that we added in analysis. Furthermore, these Fas/FasL polymorphisms influencing the risk of MSDD can be explained partly by that these mutations can remarkably alter the percent of resident cells in tissues, such as disc cells in IVD and T-lymphocyte in synovial tissue, gradually causing occurrence of these MSDD [ 17 , 19 ].…”

Responsiveness to i.v. immunoglobulin therapy in patients with toxic epidermal necrolysis: A novel pharmaco‐immunogenetic concept

“…A functional study revealed that FasL rs763110−844 C allele could increase its basal expression, suggesting that this polymorphism may affect the FasL‐mediated apoptotic signaling. The FasL rs5030772 (−124 A>G, IVS2nt) polymorphism in intron 2 was associated with breast cancer, 107 RA 108 or clinical parameters in HIV‐positive patients; 109 its functional relevance has, however, not been studied. To understand the dual mechanism of Fas/FasL‐mediated apoptosis in vivo , studies on mutations in genes encoding Fas and FasL are being performed in humans and mice (homozygous for the FasL gld mutation) 110 …”