Rheumatoid Arthritis Susceptibility Research Articles

Investigation of rs531564 Polymorphism in the Primary MicroRNA-124 Gene in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis: Association with Disease Susceptibility and Clinical Characteristics.

MicroRNA-124 (miR-124) is known as an important regulator of the immune system and inflammatory response. Studies have reported that this miRNA is dysregulated in autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis(RA). A functional analysis demonstrated that rs531564 (C>G) affects the biogenesis of primary microRNA transcript-124 (pri-miR-124) and changes the expression of mature miR-124. In the present study, for the first time, we intended to evaluate the possible association between rs531564 polymorphism with SLE and RA risk. In this case-control study, 110 patients with SLE, 115 patients with RA, and 120 healthy subjects were enrolled to evaluate rs531564 genotypes with real-time polymerase chain reaction (PCR) high resolution melting method. Our findings demonstrated that frequency of GC genotype and G allele were considerably higher in the control group than RA patients, demonstrating that that GC genotype and G allele have a protective effect for healthy individuals (GC vs CC; OR: 0.29; 95%CI [0.12,0.67] and G vs C; OR: 0.42; 95%CI [0.23,0.78]). However, no significant correlation was confirmed between allele and genotype frequencies of rs531564 with SLE risk (p>0.05). However, the G allele in rs531564 polymorphism was associated with serum level of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-dsDNA antibody, C3, C4, and creatinine, and frequency of renal involvements in SLE patients (p<0.05). Moreover, in RA patients, the G was correlated with lower concentration ESR and CRP (p<0.001). Our findings propose a considerable association between rs531564 polymorphism in the pri-miR-124 gene with susceptibility and clinical characteristics of RA and SLE in the Iranian population.

TGFB1 (rs1800470 and rs1800469) variants are independently associated with disease activity and autoantibodies in rheumatoid arthritis patients.

To evaluate the association between TGFB1 + 869T > C (rs1800470) and TGFB1-509 C > T (rs1800469) variants with susceptibility for rheumatoid arthritis (RA), disease activity, presence of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) and TGF-β1 plasma levels. A total of 262 patients with RA and 168 control individuals were tested for the TGFB1 variants using a TaqMan genotyping assay. Disease activity score in 28 joints (DAS28) classified RA patients into two groups of disease activity: remission/mild (DAS28 < 3.2) and moderate/severe (DAS28 ≥ 3.2). TGFB1 + 869T > C and -509 C > T variants, independently or in haplotype combination, were not associated with RA's susceptibility. Patients with the TGFB1-509 TT genotype had a higher frequency of DAS28 ≥ 3.2 (OR 2.58, 95% CI 1.04-6.42, p = 0.041). The TGFB1 + 869 CC genotype in seropositive patients for RF or anti-CCP was associated with decreased TGF-β1 levels (p = 0.032 and p = 0.039, respectively). Patients with the TGFB1 + 869 C allele and elevated RF titles demonstrated a higher frequency of DAS28 ≥ 3.2 (p = 0.037). The TGFB1 + 869T > C variant was associated with diminished TGF-β1 plasma levels and moderate/severe activity disease only in seropositive RF patients. This is the first study showing that TGF-β1 plasma levels can be modulated by the interaction between the TGFB1 + 869T > C variant and autoantibodies. However, the TGFB1-509 C > T variant was associated with moderate/severe activity disease, independently of autoantibodies positivity. Thus, our findings suggest that TGFB1 + 869T > C and -509 C > T variants can predict activity disease in different RA patient subgroups.

Single Immunoglobulin IL-1-Related Receptor (SIGIRR) Gene rs7396562 Polymorphism and Expression Level in Rheumatoid Arthritis.

Objectives The aim of our study was to investigate the association of single-nucleotide polymorphism (SNP) and mRNA expression profile of single immunoglobulin IL-1-related receptor (SIGIRR) in rheumatoid arthritis (RA) in a Chinese population. Methods SIGIRR rs7396562 polymorphism was genotyped using TaqMan allelic discrimination assay in 517 RA patients and 601 healthy controls. Simultaneously, the SIGIRR mRNA expression levels of 79 RA patients and 76 healthy controls were examined by real-time quantitative polymerase chain reaction (RT-qPCR). Results The frequency of SIGIRR rs7396562 T allele was significantly higher in RA patients compared with healthy controls (T versus G: OR = 1.277, 95%CI = 1.079 − 1.511, P = 0.004). The TT genotype of SIGIRR rs7396562 was more frequent in RA patients than in healthy controls (OR = 1.547, 95%CI = 1.107 − 2.163, P = 0.011). Moreover, we also found a significant difference in the recessive model (TT versus TG+GG: OR = 1.439, 95%CI = 1.122 − 1.847, P = 0.004). However, no significant evidence was observed for the association of the SIGIRR rs7396562 with RA in dominant model (TT+TG versus GG: OR = 1.275, 95%CI = 0.947 − 1.717, P = 0.109). Further analysis showed no association between SIGIRR rs7396562 polymorphism and laboratory parameters of RA patients (all P > 0.05). The mRNA expression of SIGIRR was decreased in PBMCs of patients with RA when compared to healthy controls (Z = −2.459, P = 0.014). No significant differences in SIGIRR mRNA expression levels were observed in patients with RA with different genotypes (P = 0.280). Conclusions Our findings demonstrated that the dysregulation of SIGIRR might be associated with the pathogenesis of RA, and SIGIRR rs7396562 polymorphism might contribute to RA susceptibility in the Chinese population.

The Impacts of IL1R1 and IL1R2 Genetic Variants on Rheumatoid Arthritis Risk in the Chinese Han Population: A Case-Control Study.

BackgroundRheumatoid arthritis (RA), an autoimmune systemic inflammatory disease, largely resulted from genetic factor. Our purpose was to explore the association for IL1R1 and IL1R2 genetic variants with RA susceptibility in the Chinese Han population.Patients and MethodsA total of 508 RA patients and 494 controls were involved in this case–control study; single-nucleotide polymorphisms (SNPs) genotyping was identified by the Agena MassARRAY platform. The relationship between polymorphisms and RA susceptibility was calculated using the Pearson’s Chi-square test with odds ratios and 95% confidence intervals (CIs) in multiple genetic models. The Pearson’s Chi-square test and Student’s t-test were used for sample basic characteristic analysis. And linkage disequilibrium (LD) analysis and haplotype analysis were performed by logistic regression analysis.ResultsThe result from this study showed that rs2072472 (IL1R2) was an increased risk factor of RA (adjusted OR = 1.41, p = 0.011). Stratified analysis indicated SNPs rs10490571, rs956730, rs3917318 of IL1R1, and SNPs rs4851527, rs719250, rs3218896, rs3218977, rs2072472 of IL1R2 had impacts on RA risk after stratification based on gender and average age (54 years). Finally, haplotype analysis revealed that Ars3218977Ars2072472 haplotype in IL1R2 was related to a decreased RA risk (adjusted OR = 0.79; 95% CI = 0.65–0.94; p = 0.010). Yet, rs3917225(IL1R1) and rs11674595(IL1R2) were not significant in RA association analysis.ConclusionWe determined SNPs (rs3917318, rs956730, rs1049057) of IL1R1 and SNPs (rs3218977, rs719250, rs4851527, rs3218896, rs2072472) of IL1R2 were correlated with the RA susceptibility in the Chinese Han population.

Meta-analysis of association of microRNAs genetic variants with susceptibility to rheumatoid arthritis and systemic lupus erythematosus.

Background:An increasing body of studies has investigated that genetic polymorphisms in microRNA (miRNA) may be related to susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, some results remain controversial. Thus, a meta-analysis was embarked on assessing whether some miRNA polymorphisms are associated with the risk of RA and SLE.Methods:Relevant studies were acquired on PubMed, Web of Science, Cochrane Library, CNKI, and Embase electronic databases from inception to December 2019. The strength of the association of miRNA polymorphisms with the risk of RA and SLE was assessed by odds ratios (ORs) and 95% confidence intervals (CIs).Results:Eligible 20 articles (36 studies) involving 5 miRNAs were enrolled in the meta-analysis. For RA, the polled result showed that there was no significant relationship between miR-146a rs2910164 and RA, but subgroup analysis based on ethnicity demonstrated that CC genotype may be a genetic protect factor for RA in Caucasians (CC vs CG+GG, OR = 0.825, 95% CI: 0.684–0.996, Pz = .045, Ph = .166). Besides, statistical significance of miR-499 rs3746444 (T/C) with susceptibility to RA was observed as well in the overall population, and the association was only significant in Caucasians but not Asians. For SLE, the associations of miR-146a rs2431697 T allele/T-carrier with increased risk of SLE were observed.Conclusions:Our results highlight that miR-499 rs3746444 may contribute to RA susceptibility, particularly in Caucasians. In addition, CC genotype in miR-146a rs2910164 may act as a protector of RA in Caucasians. For SLE, miR-146a rs2431697 (C/T) is most likely to the increased the risk of SLE. These findings do not support the genetic association between miR-196a2 rs11614913 and RA/SLE susceptibility, as well as the association of miR-146a rs2910164, miR-146a rs57095329, miR-499 rs3746444 with SLE.

HLA-DPB1 rs9277535 polymorphism is associated with rheumatoid arthritis risk in a Chinese Han population

We used a custom-by-design 48-Plex single nucleotide polymorphism scan™ kit to investigate the relationship between susceptibility to rheumatoid arthritis (RA) and HLA-DPB1 rs9277535 polymorphism in 805 RA patients and 1095 healthy controls from the Chinese Han population. Blood plasma levels of HLA-DPB1 were also examined using enzyme-linked immunosorbent assays in 170 RA patients and 170 matched control individuals. Quantitative reverse transcription PCR (qRT-PCR) was used to evaluate relative HLA-DPB1 mRNA levels in these blood samples as well. The results indicated that some HLA-DPB1 rs9277535 polymorphisms decreased RA susceptibility. Stratified analysis indicated that risk of RA decreased specifically in women and those who were at least 55 years old. In addition, the AG and GG+AG genotypes were associated with CRP status, ACPA status, and ESR in RA patients when the AA genotype was used as the reference group. Furthermore, average HLA-DPB1 plasma levels were increased in RA patients, and HLA-DPB1 plasma levels and mRNA expression were lower in those with the GG genotype than in those with the AA genotype. These results indicate that HLA-DPB1 rs9277535 polymorphism is associated with a decreased risk of RA in the Chinese population.

Association of CTLA-4 (+49 A/G) polymorphism with susceptibility to autoimmune diseases: A meta-analysis with trial sequential analysis

ObjectivesIn recent years, more and more studies have been focusing on the association between Cytotoxic T lymphocyte antigen-4 (CTLA-4) (+49 A/G) gene polymorphism and autoimmune diseases. However, the results of previous studies are still controversial. The meta-analysis is aiming at determining the association in CTLA-4 (+49 A/G) gene rs231775 polymorphism and ankylosing spondylitis (AS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE). MethodsWe searched PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM) up to November 2020, use random or fixed-effect models to perform meta-analysis to compare alleles and other genetic models, including homozygous, heterozygous, recessive and dominant models. The odds ratio (OR) with a 95% confidence interval (95% CI) was used to assess the correlation between CTLA-4 (+49 A/G) gene polymorphism and the genetic affectability of AS, RA, and SLE. Meanwhile, we used sequential trial analysis (TSA) to analyze the reliability of the results. Finally, we searched the relevant data of genome-wide association studies (GWAS) to further verify the accuracy of the experimental results. Results47 studies with 11,893 cases and 12,032 healthy controls were included. The rs231775 G allele was relevant to high risk of autoimmune disease over all people (P < 0.05). The G allele of rs231775 was significantly related to RA susceptibility (P < 0.05), but not with AS or SLE. Subgroup analysis by ethnicity indicated that rs231775 G allele was closely related to RA in Caucasian populations and Mongolian populations (P < 0.05). A strong connection within rs231775 G allele and AS affectability was uncovered in Caucasian populations (P < 0.05). The analysis of the TSA shows that the meta-analysis can draw the conclusion. ConclusionCTLA-4 (+49 A/G) gene rs231775 G allele increases the risk of autoimmune diseases in Caucasian populations. And it also increases the risk of RA in Caucasian and Mongolian populations. More sample size and more elaborately designed studies are needed to elucidate the relationship in CTLA-4 (+49 A/G) gene rs231775 G allele and autoimmune diseases, especially AS, SLE.

Vitamin D and VDR Gene Polymorphisms’ Association with Rheumatoid Arthritis in Lithuanian Population

Background and Objectives: Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune, multi-factorial disease, in which environmental and genetic factors play a major role. RA is possibly linked to vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms, and research demonstrates that FokI variant susceptibility is associated with increased disease risk among Caucasians. The aim of this study was to evaluate vitamin D deficiency prevalence and its correlation to RA clinical parameters, and to determine the possible association of VDR gene polymorphisms and RA susceptibility in the Lithuanian population. Materials and Methods: Overall, 206 RA patients and 180 age- and sex-matched healthy controls were enrolled at Vilnius University Hospital Santaros Klinikos after informed consent was obtained. The disease activity score 28 C-reactive protein (DAS28 CRP), rheumatoid arthritis impact of disease (RAID) score, and health assessment questionnaire (HAQ) were recorded in RA patients, and 25(OH)D serum levels were evaluated by chemiluminescent microparticle immunoassay for all subjects. Four VDR gene polymorphisms, BsmI, FokI, ApaI, and TaqI, were assessed using real-time PCR instruments and genotyping assays in both groups. Results: The study registered a high prevalence of 25(OH)D deficiency (<50 nmol/L) in RA patients (61.55% (n = 127)). The mean serum concentration in RA patients (44.96 ± 21.92 (nmol/L)) was significantly lower than in the healthy controls (54.90 ± 22.82 (nmol/L)), p < 0.0001. A significant inverse correlation between vitamin D level, DAS28 CRP, and HAQ scores was confirmed in RA patients, with p < 0.05. Still, there was no significant association between the overall risk of RA disease for any allele or genotype of the four VDR loci tested. Conclusions: The study confirmed that vitamin D deficiency is prevalent among RA patients and the 25(OH)D level is significantly lower compared with healthy controls. Lower vitamin D concentration was related with increased disease activity and disability scores. However, genetic analysis of four VDR polymorphisms did not confer the susceptibility to RA in Lithuanian population.

TGF-β1 +869T/C (rs1982073) gene polymorphism and susceptibility to rheumatoid arthritis: Updated systematic review and meta-analysis

Rheumatoid arthritis (RA) is a complex autoimmune disease that affects about 1% of the world's population. The conclusions about the relationship between TGF gene polymorphism and the risk of RA are still inconsistent. Therefore, we performed a meta-analysis to re-evaluate the relationship between TGF-β1 T869C gene polymorphism and the risk of rheumatoid arthritis.Method: We performed a systematic electronic search in PubMed, Embase, Elsevier, Web of Science, Cochrane Library, Medline and China National Knowledge Infrastructure database (up to August 2020). In the subgroup analysis, we divide the research into three groups: Asian, European and Mediterranean, The combined OR and 95%CI of the five models (allele model, homozygous model, heterozygous model, dominant model, recessive model) were calculated, respectively.Results: 15 case-control studies (14 articles) were involved in this meta-analysis, including 2103 cases and 2143 healthy controls. In the overall analysis, it showed that there may be an significant association between TGF-β1+869T/C polymorphism and RA sensitivity (allele model, T vs. C: OR=1.444, 95% CI=1.171-1.782, P=0.001; homozygous model, TT vs. CC: OR=1.910, 95% CI=1.322-2.761, P=0.001; heterozygous model, CT vs. CC: OR=1.558, 95% CI=1.179-2.059,P=0.002; dominant model, TT+CT vs. CC: OR= 1.742, 95% CI=1.303-2.329, P=0.001; recessive model, TT vs. CT+CC: OR=1.400, 95% CI= 1.058-1.852, P=0.018).However, the results of ethnic subgroup analysis indicated that rs1982073 was not associated with RA risk in Europeans(allele model, T vs. C: OR=0.993, 95% CI=0.849-1.162, P=0.931, I2 <0.1%, P>0.1).Conclusion: In summary, our meta-analysis showed that the rs1982073 T allele does not increase RA susceptibility in Europeans.

Association of P2X7 receptor genetic polymorphisms and expression with rheumatoid arthritis susceptibility in a sample of the Iranian population: a case-control study.

Rheumatoid arthritis (RA) is a complex inflammatory autoimmune disease with joint eruption, systemic manifestation, and numerous predisposing genetic factors. The P2X7 receptor is an essential ligand-gated channel that contributes to many physiological processes, especially inflammation. However, genetic variations can alter the P2X7 receptor function. Therefore, the present study aimed to explore the impact of P2X7 genetic polymorphisms and expression on susceptibility to RA in a sample of the Iranian population. We enrolled 160 (145 female, 15 male) RA patients and 160 (142 female, 18 male) healthy individuals in this study. Genotyping was performed using tetra amplification refractory mutation system-polymerase chain reaction (TARMS-PCR) for rs1718119, rs2230912, rs2393799, rs28360457, rs35933842, and allele-specific PCR for rs1653624 and rs3751143. Furthermore, 44 new cases of RA and 48 healthy controls were recruited to investigate whether P2X7 mRNA expression is associated with RA susceptibility. The results revealed that the rs2393799 significantly increased the risk of RA in all genetic models (p<0.05), while rs3751143 in codominant (CC vs. AA, OR=0.49, 95% CI=0.26-0.92), dominant (AC+CC, OR=0.59, 95% CI=0.37-0.94), C allele (OR=0.63, 95% CI=0.46-0.88), and rs2230912 in codominant (AG vs. AA, OR=0.56, 95% CI=0.34-0.94), dominant (AG+GG vs. AA, OR=0.59, 95% CI=0.35-0.99), and overdominant (AG vs. AA+GG, OR=0.57, 95% CI=0.33-0.98) significantly decreased the RA risk (p<0.05). Furthermore, the rs1718119 and rs1653624 were not associated with susceptibility of RA (p>0.05), and rs28360457 and rs35933842 were not polymorphic in our study. The mRNA expression level of P2X7 in both groups revealed that the P2X7 gene was significantly upregulated in RA (3.18±0.43) compared to healthy subjects (1.47±0.15, p<0.001). Our results suggest that rs2393799, rs3751143, and rs2230912 variants of the P2X7 gene are associated with RA's susceptibility in a sample of the Iranian population. Also, P2X7 mRNA expression was higher in our new RA patients. The P2X7 receptor has been considered as a potential pharmacologic target in RA. Key Points • P2X7 variants (rs2393799, rs2230912, rs3751143) were associated with RA susceptibility in a sample of the Iranian population. • rs2393799 increases the risk of RA, while rs2230912 and rs3751143 decrease the risk of RA. • P2X7 expression was significantly upregulated in new RA patients compared to controls.

Allele-Specific Quantification of HLA-DRB1 Transcripts Reveals Imbalanced Allelic Expression That Modifies the Amino Acid Effects in HLA-DRβ1.

HLA association fine-mapping studies have shown the effects of missense variants in HLA-DRB1 on rheumatoid arthritis (RA) susceptibility, prognosis, and autoantibody production. However, the phenotypic effects of expression changes in HLA-DRB1 remain poorly understood. Therefore, we investigated the allele-specific expression of HLA-DRB1 and its effect on an HLA-DRβ1 structure-associated trait in RA. We quantified the allele-specific expression of each HLA-DRB1 3-field classic allele in 48 Korean RA patients with anti-citrullinated protein antibodies (ACPAs) and 319 healthy European subjects by using both RNA sequencing and HLA-DRB1 genotype data to calculate the relative expression strength of multiple HLA-DRB1 alleles (n = 14 in Koreans and n = 25 in Europeans) in each population. The known association between ACPA level and alanine at position 74 of HLA-DRβ1 in ACPA-positive RA was revisited to understand the phenotypic effect of allele-specific expression of HLA-DRB1 by modeling multivariate logistic regression with the genomic dosage or relative expression dosage of Ala-74 in 2 independent sets of 1,723 Korean RA patients with ACPA. The relative expression strength was highly allele-specific, causing imbalanced allelic expression in HLA-DRB1 heterozygotes. The association between HLA-DRβ1 Ala-74 and ACPA level in RA was better explained by relative expression dosage of Ala-74 than by the genomic dosage (change in Akaike's information criterion = -6.98). Moreover, the expression variance of Ala-74 in Ala-74 heterozygotes with no genomic variance of Ala-74 was significantly associated with ACPA level (P = 2.26 × 10-3 ). Our findings illustrate the advantage of integrating quantitative and qualitative changes in HLA-DRB1 into a single model for understanding HLA-DRB1 associations.

The Association Between CTLA-4, CD80/86, and CD28 Gene Polymorphisms and Rheumatoid Arthritis: An Original Study and Meta-Analysis.

Background: Rheumatoid arthritis (RA) is related to several pivotal susceptibility genes, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and costimulatory molecule (CD80/CD86) genes. Although the connection between polymorphisms of CTLA-4 and CD86 genes in different populations of RA have been studied extensively, the results are controversial.Objective: To clarify the correlation in the Chinese Han population between CTLA-4, CD80/86, and CD28 gene polymorphisms, and RA susceptibility.Methods: A case-control study (574 RA patients and 804 controls) was conducted to determine the correlation between CTLA-4 rs231775 and rs16840252 gene polymorphisms, CD86 rs17281995 gene polymorphisms, and the risk of RA for the Chinese Han population. Furthermore, an additional meta-analysis, including three single nucleotide polymorphisms (SNPs) (CTLA-4 rs231775, CTLA-4 rs3087243, and CTLA-4 rs5742909) from 32 citations, including 43 studies, 24,703 cases and 23,825 controls was performed to elucidate the relationship between known SNPs in the CTLA-4 genes and RA for more robust conclusions.Results: The results showed that CTLA-4 rs231775 gene polymorphism decreased the RA risk (GA vs. AA, OR = 0.77, P = 0.025), whereas CTLA-4 rs16840252 and CD86 rs17281995 gene polymorphisms were not related to RA susceptibility. Stratification analyses by RF, ACPA, CRP, ESR, DAS28, and functional class identified significant associations for CTLA-4 rs231775 and rs16840252 gene polymorphisms in the RF-positive and RF-negative groups. A meta-analysis of the literature on CTLA-4 gene polymorphisms and RA risk revealed that the risk of RA was decreased by CTLA-4 rs231775 gene polymorphisms.Conclusions: The CTLA-4 rs231775 gene polymorphism decreased the risk of RA, whereas CTLA-4 rs16840252 and CD86 rs17281995 gene polymorphisms were not related to RA risk. A meta-analysis indicated that CTLA-4 rs231775 and rs3087243 gene polymorphisms decreased the risk of RA. To support these analytical results, additional clinical cases should be investigated in further studies.

Effect of mannose-binding lectin gene polymorphisms on the risk of rheumatoid arthritis: Evidence from a meta-analysis.

BackgroundThe effect of mannose‐binding lectin (MBL) gene polymorphisms on susceptibility of rheumatoid arthritis (RA) were evaluated in ethnically different populations, whereas the results were always inconsistent.Materials and methodsFourteen articles involving 36 datasets were recruited to evaluate the association between MBL gene polymorphisms and rheumatoid arthritis in a meta‐analysis. The random or fixed effect models were used to evaluate the pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs).ResultsStratified analysis by ethnicities was conducted and the result revealed that rs1800450 (T vs C, OR = 1.32, 95% CI: 1.04‐1.67, P < .05) and MBL‐A/O (T vs C, OR = 1.20, 95% CI: 1.08‐1.34, P < .001) were strongly associated with RA in Brazilian populations. In addition, the significant relationship between rs11003125 (T vs C, OR = 1.16, 95% CI: 1.06‐1.26, P < .05) with RA were also observed in East Asian populations. Meanwhile, the inverse associations between rs5030737 with RA in East Asians and rs1800450 with RA in Indians were acquired. However, no association between any MBL polymorphism with RA susceptibility was confirmed in Caucasians.ConclusionsThe structural polymorphisms in exon 1 of MBL gene may significantly contribute to susceptibility and development of RA in Brazilian and Indian populations, whereas the functional polymorphisms in the promoter region were more likely to associate with RA in East Asians.

The association of transforming growth factor beta 1 gene polymorphisms with arthritis: a systematic review and meta-analysis.

The objective of this study was to explore the association between transformation growth factor beta 1 (TGF-β1) gene polymorphisms and different types of arthritis. PubMed, Medline, Web of Science, Cochrane Library, Biosis and four Chinese databases: China Biology Medicine, China National Knowledge Infrastructure, Wanfang and CQVIP, were searched. Studies that analyzed the association of the TGF-β1 polymorphisms with different types of arthritis were included. OR, 95% confidence interval and P value were calculated in three models including allele, dominant and recessive models, using D + L method. The Newcastle-Ottawa Scale was used to assess the quality of the included studies. TGF-β1 869T > C polymorphism was significantly associated with rheumatoid arthritis (RA) in allele and recessive models, but not in dominant model (allele model T vs. C: OR = 1.30, 95% CI = 1.13-1.49, P < 0.001; recessive model CC vs. TT + TC: OR = 0.57, 95% CI = 0.43-0.76, P < 0.001; dominant model TT vs. TC + CC: OR = 1.20, 95% CI = 0.99-1.45, P = 0.063). Additionally, allele and recessive models showed that TGF-β1 -509C > T was significantly correlated with RA susceptibility, while dominant model revealed nonsignificant correlation (allele model: C vs. T: OR = 1.51; 95% CI = 1.00-2.28; P = 0.049; recessive model: TT vs. CC + TC: OR = 0.52, 95% CI = 0.37-0.72, P = 0.000; dominant model: CC vs. TT + TC: OR = 1.48; 95% CI = 0.79-2.76; P = 0.223). However, no significant association was found between TGF-β1 polymorphisms and ankylosing spondylitis (AS) or osteoarthritis (OA) risk. This study demonstrated that 869T > C, -509 C > T polymorphisms of TGF-β1 gene were associated with increased susceptibility of RA, while polymorphisms of TGF-β1 gene were not associated with OA and AS. These findings suggest that studying TGF-β1 genotype may be useful in the prevention and management of RA. However, more studies are needed to evaluate the association of TGF-β1 gene polymorphisms with the susceptibility of OA and AS.

Genetic variant in microRNA-146a gene is associated with risk of rheumatoid arthritis

Objective To investigated the association between single nucleotide polymorphisms (SNPs) in microRNA-146a (miR-146a) gene and susceptibility of rheumatoid arthritis (RA). Methods We systemically extracted the genetic data of miR-146a from previous genome-wide association studies (GWASs) of RA. Subsequently, we performed a replication study in an independent Chinese cohort for selected variant. A meta-analysis combined the previous GWASs with the replication study was also conducted. The epigenetic annotation and cytokine assay were used for exploring potential variant function. Results The extracted genetic association data from three previous GWASs showed that the allele T of functional SNP rs2431697 increased RA susceptibility. The significant association for the SNP was also found in the Chinese replication cohort (OR = 1.24, 95% CI = 1.06–1.46, p = 8.69E-03). The estimated effect size for this SNP was larger in Asian population than that in European population (Asian meta-analysis: OR = 1.15, 95% CI = 1.09–1.22, p = 4.37E-07; Tran-ethnic meta-analysis: OR = 1.07, 95% CI = 1.04–1.10, p = 1.79E-06). The cytokine assay also showed that the risk allele T of the SNP rs2431697 is inversely associated with plasma TNF-α levels in health controls (p = .016). Conclusions In summary, this study supports that genetic variant in miR-146a gene is associated with RA risk. KEY MESSAGES The association between SNPs in miR-146a gene and susceptibility of RA was unclear. We investigated the genetic association using GWASs data and a replication study. The SNP rs2431697 in miR-146a gene is associated with RA risk.

Association of the genetic polymorphisms in inhibiting and activating molecules of immune system with rheumatoid arthritis: A systematic review and meta-analysis.

Several studies have demonstrated that the genetic polymorphisms in the genes encoding immune regulatory molecules, namely cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and CD28, play a fundamental role in susceptibility to rheumatoid arthritis (RA). Several disperse population studies have resulted in conflicting outcomes regarding the genetic polymorphisms in these genes and RA risk. This systematic review and meta-analysis study was performed to reach a conclusive understanding of the role of single-nucleotide polymorphisms (SNPs) of CTLA4-rs231775, CTLA4-rs5742909, and CD28-rs1980422 in susceptibility to RA. Databases (ISI Web of Science, MEDLINE/PubMed, and Scopus) were searched to find the case–control studies surveying the association of CTLA4 gene rs231775, CTLA4 gene rs5742909, and CD28 gene rs1980422 polymorphisms and RA susceptibility in different population until August 2020. Association comparison between the polymorphisms and RA proneness was assessed using pooled odds ratio (OR) and their corresponding 95% confidence interval. This study was conducted on 16 population studies, comprising 1078 RA patients and 1118 healthy controls for CTLA4-rs231775, 2193 RA patients and 2580 healthy controls for CTLA4-rs5742909, and 807 RA patients and 732 healthy controls for CD28-rs1980422. Analysis indicated that G-allele, GG and GA genotypes, and dominant model for rs231775, recessive model for rs5742909, and C-allele, CC and CT genotypes, and recessive model for rs1980422 were significantly associated with increased RA risk. This meta-analysis showed that genetic polymorphisms of both immune inhibitory and activating genes, including CTLA4-rs231775, CTLA4-rs5742909, and CD28-rs1980422 polymorphisms, may increase susceptibility to RA.

Association of interleukin-17A rs2275913 polymorphism with rheumatoid arthritis susceptibility in Sudanese population.

Objectives:Rheumatoid arthritis is a chronic inflammatory autoimmune disease. This study aimed to determine the association of interleukin-17A-197G/A polymorphism with rheumatoid arthritis in Sudanese patients.Methods:A case–control study was conducted between March and December 2018. Clinical and demographic data of the study participants were collected and analyzed. Polymerase chain reaction restriction fragment length polymorphism molecular technique was done to investigate interleukin-17A-197G/A polymorphisms. All statistical tests were considered statistically significant when p < 0.05.Results:The study population included 266 participants aged between 1 and 85 years, with an average of 40 years, classified into 85 (31.2%) cases (mean age 48.5 ± 11.3 years), and 181 (68.8%) controls (mean age 35.3 ± 15.9 years). The interleukin-17A homozygote AA genotype was more frequent among the control group compared to the case group; 95 (52.5%) and 7 (8.2%), respectively. The homozygote GG and the heterozygote AG genotypes were proportionally not different among the cases and control groups; 13 (54.2%) and 11 (45.8%), and 65 (46.4%) and 75 (53.6%), respectively. According to the distribution of interleukin-17A genotypes, a statistically significant difference was observed among cases with the interleukin-17A AA and AG genotypes, p values 0.001 and 0.004, respectively. For the association interleukin-17A genotypes and family history a negatively significant association was reported (95% confidence interval, –0.219, p value = 0.001). There was also a negatively significant association of interleukin-17A genotypes and anti-cyclic citrullinated peptide (95% confidence interval, −0.141, p value = 0.002).Conclusion:This study is the first study in Sudan established the association between interleukin-17A-197G/A (rs2275913) polymorphisms and susceptibly to rheumatoid arthritis. These findings appeal for further research in Sudan to investigate the exact role of IL-17A in immunopathology and disease severity among Sudanese rheumatoid arthritis

Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci

ObjectivesNearly 110 susceptibility loci for rheumatoid arthritis (RA) with modest effect sizes have been identified by population-based genetic association studies, suggesting a large number of undiscovered variants behind a highly...

Association of interleukin-17 gene polymorphisms with the onset of Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is an autoimmune disorder where multiple cytokines including IL-17A and IL-17F produced by T helper cell 17 (Th17), contribute to its pathogenesis. By initiating inflammatory responses in joints Th17 act as pathogenic driver leading to bone and cartilage destruction in RA patients. Hence, the planned study was aimed to estimate IL-17 gene polymorphism association with RA susceptibility in Pakistani population. The present study included 100 subjects (50 RA patients and 50 healthy controls). Blood samples were taken and DNA was isolated for genotyping purpose. Chi square and Logistic regression analysis was performed to check the association of selected SNPs with RA. For rs2397084 and rs763780 polymorphism T allele acted as significant risk factor as compared to the reference C allele. TT vs. CC comparison in rs2397084 showed that T allele is a risk factor (OR 5.538; 95%Cl 1.757–17.458) in RA susceptibility. In case of rs763780 heterozygous CT (OR 10.80; 95% Cl 3.736–31.218) and homozygous mutant TT (OR 7.50; 95% Cl 2.360–23.831) genotypes proved to be a potential risk for RA patients. The significant differences in allelic and genotypic frequencies were observed for both SNPs. While for rs2275913 significantly varied frequency was observed only for dominant model of inheritance and non significant differences were seen at allelic level. Variation at all these three polymorphic sites substituted mutant amino acids leading to further functional changes in protein structure. Three polymorphic sites rs2275913, rs763780 and rs2397084 positioned on IL-17 gene were significantly strong factors in RA incidence among Pakistani population as they alter normal function of inflammatory cytokine IL-17.

Interferon III-related IL28RA variant is associated with rheumatoid arthritis and systemic lupus erythematosus and specific disease sub-phenotypes.

The interferon pathways have been commonly implicated in autoimmune disease development but the identity of the genes involved has not yet been fully clarified. Variation in genes involved in interferon pathways is expected to have a role in the etiology of these diseases. The potential association of a polymorphism in the IL28RA gene, involved in these pathways, with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and disease-related phenotypes was investigated in 603 Brazilian individuals (354 well-characterized SLE and RA patients, and 249 controls). IL28RA (rs4649203) variant was genotyped by TaqMan assay. Statistical analysis was performed including both diseases and a comprehensive list of patient clinical manifestations. The rs4649203-G (minor) allele was associated with SLE and RA occurrence and was shown to be a risk factor for serositis and anemia among SLE patients as well as a protective factor for rheumatoid vasculitis and rheumatoid nodules in RA patients, suggesting an association with a milder form of the disease. The IL28RA gene may contribute to SLE and RA susceptibility and to specific clinical manifestations of the diseases.