Increased Risk Of Rheumatoid Arthritis Research Articles

Inflammatory cytokines, metabolites, and rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint destruction. Although the roles of inflammatory cytokines and metabolites in RA pathogenesis have caught a lot of attention, there is a lack of systematic studies, and their causal relationships remain unclear. We conducted a two-step mendelian randomization analysis utilizing genetic data from genome-wide association studies (GWAS) of inflammatory cytokines, metabolites, and RA. The first step assessed the causal effect of 91 inflammatory cytokines and 1400 metabolites on RA risk using inverse variance weighted method, complemented by MR-Egger, weighted median, simple mode and MR-PRESSO to ensure robustness and assess pleiotropy. The second step evaluated the mediation effects of selected metabolites on the relationship between cytokines and RA. The analysis identified 9 inflammatory cytokines, including IL-1α and IL-10, which significantly increase RA risk, while TNF-β exhibited a protective effect. Additionally, 6 metabolites were associated with increased RA risk, including 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE and arachidonate (20:4n6). Conversely, 5 metabolites, such as docosatrienoate (22:3n3) and Cholesterol, were found to reduce RA risk. The mediation analysis revealed that TNF-β may exerts its protective effect through its influence on specific metabolites, and X-24949, which accounted for a -2.58% mediated effect in the TNF-β-RA causal pathway. This study explores the complex interplay between inflammatory cytokines, metabolites, and RA. The findings suggest potential biomarkers for early diagnosis and novel therapeutic targets, particularly those related to lipid metabolites and specific cytokines like TNF-β. Key message What is already known on this topic Inflammatory factors and metabolites are considered to be related to the onset and progression of RA. What this study adds We conducted a MR analysis to identify all inflammatory factors and metabolites associated with RA and calculated the mediation effect of inflammatory cytokines on RA through metabolites. This study contributes to a comprehensive understanding of the pathophysiological processes of RA. How this study might affect research, practice or policy This has laid the groundwork for developing early diagnosis methods and future treatments.

Air Pollution and Rheumatoid Arthritis Risk and Progression: Implications for the Mucosal Origins Hypothesis and Climate Change for RA Pathogenesis.

The goal of this review paper is to summarize the main research and findings regarding air pollution and its association with the risk and progression of rheumatoid arthritis (RA). The most studied components of air pollution included particulate matter of ≤ 2.5 microns in diameter (PM2.5), PM10, carbon monoxide (CO), nitrogen dioxide (NO2), nitric oxide (NOx), sulfur dioxide (SO2), and ozone (O3). In addition, specific occupations and occupational inhalants have been investigated for RA risk. Several studies showed that increased exposure to air pollutants increased the risk of developing RA, particularly seropositive RA. There was evidence of gene-inhalant interactions for seropositive RA risk. Fewer studies have been conducted on RA disease activity and bone erosions. Some studies suggest that patients with RA-associated interstitial lung disease may have worse outcomes if exposed to air pollution. We summarized associations between air pollution and increased RA risk, including RA-associated interstitial lung disease. Relatively few studies investigated air pollution and RA disease activity or other outcomes. These results suggest an important role of air pollution for seropositive RA development and suggest that climate change could be a driver in increasing RA incidence as air pollution increases.

Higher Risk of Rheumatoid Arthritis in Patients With Chronic Rhinosinusitis: Prospective Association in the U.K. Biobank and Genetic Evidence by Mendelian Randomization Analysis.

Previous studies have shown that respiratory diseases are associated with an increased risk of rheumatoid arthritis (RA). However, whether there is a correlation between chronic rhinosinusitis (CRS) and RA is not known. Due to the high incidence of CRS, it remains to be clarified whether we should pay additional attention to RA risk in the huge population of CRS. We used a 2-sample Mendelian randomization (MR) analysis to explore the causal effects of CRS on the incidence of RA. The inverse variance weighted (IVW) approach was used as the main analysis in the MR randomization study. Then, we used the data from the U.K. Biobank to examine the association between RA and CRS at the individual level in a prospective cohort. We identified patients with CRS at the time of recruitment and further followed the incidence of RA until 2021. The risk of developing RA in patients with CRS was determined by a multivariate Cox regression model. We used 3 multivariate Cox models to adjust for individual characteristics, lifestyle factors and concomitant diseases, respectively. The MR analysis by the IVW model suggested that the odds ratio of RA associated with genetically predicted CRS was 2.39 (95% CI [1.08-5.30]; p = .032). In the first multivariate model adjusting for individual characteristics, CRS was associated with a 47% increase of risk of developing RA (hazard ratio [HR] = 1.47; 95% CI [1.12-1.90]). In the second multivariate model adjusting for lifestyle factors, the HR of RA associated with CRS was 1.48 (95% CI [1.15-1.90]). In the third multivariate model, chronic sinusitis was associated with a 32% increase in RA risk (HR = 1.32; 95% CI [1.03-1.70]). CRS has a genetically causal effect on the incidence of RA, and the risk of RA is greatly higher in CRS at the individual level. This is the first study to reveal an association between CRS and RA. Due to the high incidence of CRS, it is recommended that additional attention should be paid to the increased RA risk in patients with CRS compared to that in common people.

Presence of periodontal disease and the incidence of inflammatory arthritides in the general population: data from the UK Biobank.

To investigate the association between periodontal disease and the development of inflammatory arthritides in the general population. In total, 489 125 participants from the UK Biobank without a previous history of RA, AS and PsA were enrolled. The primary outcome was the incidence of inflammatory arthritides, which was a composite of RA, AS and PsA according to the presence of periodontal disease based on self-reported oral health indicators. Multivariate Cox proportional hazard regression analyses using four different models were performed to assess the association between periodontal disease and inflammatory arthritides development. In all, 86 905 and 402 220 individuals were categorized as with and without periodontal disease, respectively. Cox hazard analysis indicated that the presence of periodontal disease was an independent predictor of the occurrence of composite outcomes of inflammatory arthritides, which was also consistent for RA and AS. Significant associations were found to be consistent in the four Cox models and were replicated even when different criteria were used to define periodontal disease. Subgroup analyses indicated that periodontal disease was associated with an increased RA risk in those aged <60 years, and this risk was persistent for both male and female patients and for patients with seropositive/seronegative RA. Self-reported periodontal disease is associated with inflammatory arthritides incidence in participants included in the UK Biobank, particularly for RA and AS. Higher clinical attention and optimal dental care in patients with signs of periodontal disease may be recommended for early disease detection and for reducing this risk.

Hypothyroidism and rheumatoid arthritis: a two-sample Mendelian randomization study.

Meta-analysis of genome-wide association studies (GWAS) data showed that the relationship between hypothyroidism and rheumatoid arthritis (RA) risk remains under debate. This study is conducted to test the causal relationship of hypothyroidism and RA. A two-sample Mendelian randomization (TSMR) analysis was employed to estimate the causality of hypothyroidism and rheumatoid arthritis in European ancestry and Asian ancestry. Integrating the effects generated by TSMR, functional annotations and noncoding variant prediction framework were applied to analyze and interpret the functional instrument variants (IVs). The results of the inverse variance weighted method showed a strong significant causal relationship between hypothyroidism and risk of RA in European ancestry [odds ratio (OR) = 1.96; 95% confidence interval (CI) 1.49, 2.58; p < 0.001]. The outcomes of MR-Egger, weighted median, weighted mode, and simple mode also showed that hypothyroidism was significantly associated with increased risk of RA in European ancestry. The MR-PRESSO method also showed significant results [Outlier-corrected Causal Estimate = 0.70; standard error (SE) = 0.06; p < 0.001]. An independent dataset and an Asian ancestry dataset were applied to estimate and obtain the coincident results. Furthermore, we integrated the effect of variants in TSMR analysis, functional annotations, and prediction methods to pinpoint the single-nucleotide polymorphism (SNP) rs4409785 as one of the causal variants, which suggested that this variant could impact the binding of CTCF-cohesin and play a vital role in immune cells. In this study, we prove that hypothyroidism is significantly causally associated with increased RA risk, which has not been shown in previous studies. Furthermore, we pinpoint the potential causal variants in RA.

Implications of Peptidyl Arginine Deiminase 4 gene transcription and polymorphisms in susceptibility to rheumatoid arthritis in an Iranian population

BackgroundPeptidyl arginine deiminase 4 (PADI4) has been implicated in Rheumatoid arthritis (RA) pathogenesis. Here we aimed to evaluate the association of PADI4 gene rs11203367 and rs1748033 single nucleotide polymorphisms (SNPs) with RA proneness.MethodsThe mRNA expression of PADI4 was determined in the whole blood samples. The genotyping of PADI4 polymorphisms was conducted using allelic discrimination TaqMan genotyping Real-time PCR.ResultsThe alleles and genotypes of rs11203367 polymorphism were not associated with susceptibility to RA risk. The T allele (OR = 1.58, 95%CI: 1.21–2.04, P = 0.0005), TT genotype (OR = 2.79, 95%CI: 1.53–5.06, P = 0.0007), TC genotype (OR = 1.52, 95%CI: 1.04–2.23, P = 0.0291), dominant (OR = 1.72, 95%CI: 1.19–2.47, P = 0.0034) and recessive (OR = 2.19, 95%CI: 1.25–3.82, P = 0.0057) models of rs1748033 SNP were associated with higher risk of RA. There was a significant upregulation of PADI4 mRNA in the RA patients compared to controls. mRNA expression of PADI4 had significantly positive correlation with anti-CCP level (r = 0.37, P = 0.041), RF level (r = 0.39, P = 0.037), and CRP level (r = 0.39, P = 0.024).ConclusionPADI4 gene rs1748033 SNP was associated with increased RA risk. This polymorphism might affect the RA pathogenesis regardless of impressing the levels of PADI-4 in serum.

Association of Fc Gamma Receptor 3B Gene Copy Number Variation with Rheumatoid Arthritis Susceptibility.

Structural variations such as copy number variants (CNVs) have been associated with multiple autoimmune diseases. In this study, we explored the association of the Fc gamma receptor 3B gene (FCGR3B) copy number variation (CNV) with rheumatoid arthritis (RA) susceptibility and related serological traits in the Pakistani population. We also performed a meta-analysis of four published FCGR3B CNV studies along with the current study. A total of 927 subjects (597 RA cases, 330 healthy controls) were recruited from three rheumatology centers in Pakistan. Anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) were measured in RA patients. FCGR3B copy number was assayed using the TaqMan® CN assay (Hs04211858_cn, Applied Biosystems, Foster City, CA, USA) and the copy number was estimated by using CopyCaller® software (version 2.1; Applied Biosystems, USA). Logistic regression was applied to calculate the odds ratio (OR) of RA risk associated with FCGR3B CNV using sex and age as covariates in R. Meta-analysis on four previously published studies and the current study was performed using the random-effect model. We observed a significant association between FCGR3B copy number &lt; 2 and RA susceptibility (OR = 1.53; 95% CI: 1.05 to 2.22; p = 0.0259) and anti-CCP seropositivity (OR 2.56; 95% CI: 1.34 to 4.89; p = 0.0045). A non-significant association of FCGR3B copy number &lt; 2 was also observed between increased rheumatoid factor (RF) seropositivity (OR = 1.74; 95% CI:0.93 to 3.26; p = 0.0816). Meta-analysis on 13,915 subjects (7005 RA cases and 6907 controls) also showed significant association of copy number &lt; 2 with the increased risk of RA (OR = 1.30; 95% CI: 1.07 to 1.56; p = 0.00671). FCGR3B copy number &lt; 2 is associated with increased RA risk and anti-CCP seropositivity.

Interleukin 23 receptor gene polymorphisms and their role in the inflammatory status of rheumatoid arthritis patients in an Iranian population.

Several investigations have disclosed the involvement of the interleukin (IL)-23/IL-17 pathway in rheumatoid arthritis (RA) pathogenesis. Here we investigated the association of single nucleotide polymorphisms (SNPs) in the IL23 receptor (IL23R) gene with RA risk. In addition, the role of these SNPs with the inflammatory state of the patients were determined. In this case-control study, 200 RA cases and 200 healthy subjects were recruited. Using allelic discrimination real-time polymerase chain reaction, both IL23R rs10489629 and rs1004819 SNPs were genotyped. The messenger RNA (mRNA) expression levels of IL-23R, IL-23, and IL-17A were determined in peripheral blood mononuclear cells (PBMCs). The serum levels of IL-23 and IL-17A were also determined. The A allele (odds ratio [OR]=1.52, 95% CI: 1.15-2.01; P= .0030), AA genotype (OR=2.41, 95% CI: 1.33-4.35; P= .0035), and AG genotype (OR=2.55, 95% CI: 1.56-4.16, P= .0002) of rs1004819 SNP was significantly associated with increased RA risk. The mRNA expression of IL-17A (fold change=2.55, P= .00027), IL-23 (fold change=1.62, P= .0081), and IL-23R (fold change=1.59, P= .0077) was significantly upregulated in the PBMCs from RA patients compared to that of healthy controls. Serum levels of IL-17A (P= .00019) and IL-23 (P= .00055) was significantly higher in the RA patients compared to the controls. No significant association was detected between patient data and SNPs. The IL-23/IL-27 pathway plays a role in RA pathogenesis, but IL23R gene rs1004819 SNP might not be regulating this pathway in RA disease.

Causal association between rheumatoid arthritis and celiac disease: A bidirectional two-sample mendelian randomization study.

Objectives: Rheumatoid Arthritis (RA) has been associated with Celiac Disease (CD) in previous observational epidemiological studies. However, evidence for this association is limited and inconsistent, and it remains uncertain whether the association is causal or due to confounding or reverse causality. This study aimed to assess the bidirectional causal relationship between RA and CD. Methods: In this two-sample Mendelian randomization (MR) study, instrumental variables (IVs) for RA were derived from a genome-wide association studies (GWAS) meta-analysis including 58,284 subjects. Summary statistics for CD originated from a GWAS meta-analysis with 15,283 subjects. The inverse-variance weighted (IVW) method was used as the primary analysis. Four complementary methods were applied, including the weighted-median, weighted mode, MR pleiotropy residual sum and outlier (MR-PRESSO) test and MR-Egger regression, to strengthen the effect estimates. Results: Positive causal effects of genetically increased RA risk on CD were derived [IVW odds ratio (OR): 1.46, 95% confidence interval (CI): 1.19-1.79, p = 3.21E-04]. The results of reverse MR analysis demonstrated no significant causal effect of CD on RA (IVW OR: 1.05, 95% CI: 0.91-1.21, p = 0.499). According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates. Conclusion: This study reveals a causality of RA on CD but not CD on RA among patients of European descent. This outcome suggests that the features and indicators of CD should regularly be assessed for RA patients.

Meta-analysis for Association of Interleukin 4 VNTR Polymorphism with Rheumatoid Arthritis Risk and Severity.

Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by severe joint pain. There are conflicting results for the association of Interleukin 4 (IL4) variable number tandem repeats (VNTR; rs8179190) polymorphism with RA. Therefore, we performed a meta-analysis of the available studies to investigate the association of IL4 VNTR polymorphism with RA risk and severity in the overall populations and Asian, Egyptian, European, and Turkish ethnicities by sub-group analyses. Eight studies involving 1993 RA patients and 1732 controls were included in this meta-analysis. We found increased RA risk for the susceptible "R2R2" genotype and "R2" allele under heterozygous, recessive, and allelic models in the Asian populations (p < 0.00001, p < 0.0001, p = 0.001). We observed a significant association between "R2R2" genotype and "R2" allele for RA protection in the Turkish population under heterozygous, recessive, and allelic models (p = 0.01, p = 0.004, p = 0.002). Disease severity-based analysis revealed significant association for "R2R2" genotype and "R2" allele with RA severity under homozygous, heterozygous, recessive, dominant, and allelic models(p = 0.0004, p = 0.03, p = 0.02, p = 0.003, p = 0.01), specifically in Asian populations (p = 0.009, p = 0.02, p = 0.003, p = 0.03, p = 0.01) and under heterozygous, dominant, and allelic genetic models in Egyptian (p = 0.0001, p < 0.0001, p < 0.0001) and European (p = 0.002, p = 0.0007, p = 0.0006) populations. In silico analysis suggested that the susceptible "R2" allele changes the RNA secondary structure to a stable form by changing minimum free energy(ΔG) from -115.20 to -136.40kcal/mol, which might lead to increased stability of IL-4 in RA patients. Overall, the meta-analysis suggests for the involvement of susceptible "R2" allele with RA risk in the Asian populations, RA severity in the overall populations (specifically in Asian, Egyptian, & European populations), and RA protection in the Turkish population.

Can I Prevent Developing a Rheumatic and Musculoskeletal Disease Through Lifestyle Changes? A Focus on Nutrition

Accumulating evidence suggests that nutrition can reduce the risk of rheumatic and musculoskeletal disease and especially rheumatoid arthritis (RA) development. This effect may be achieved either directly or indirectly through the consumption of anti-inflammatory nutrients or the reduction of comorbidities, respectively. A pro-inflammatory diet increases RA risk while the Mediterranean diet and oily fish consumption providing anti-inflammatory omega-3 fatty acids both reduce risk. High sugar and salt consumption is also associated with increased RA risk. Therefore, the Mediterranean diet supplemented with dietary omega-3 fatty acids is recommended for individuals genetically susceptible to RA.

Associations of blood and urinary heavy metals with rheumatoid arthritis risk among adults in NHANES, 1999–2018

Heavy metals exposure has been widely recognized as a risk factor for human health. However, limited information is available about the impacts of heavy metals on rheumatoid arthritis (RA). Herein, we estimated the associations of 3 blood and 11 urinary metals with the risk of RA among 49830 U.S. adults from the National Health and Nutrition Examination Survey (NHANES), 1999–2018. In the single-exposure model, blood cadmium (Cd) and lead (Pb), urinary Cd, Pb, antimony (Sb), tungsten (Tu), and uranium (Ur) were identified to be positively associated with RA risk. Furthermore, weighted quantile sum (WQS) regression, quantile-based g computation (qgcomp), and Bayesian kernel machine regression (BKMR) analyses consistently showed that both blood and urinary metals-mixed exposure were positively correlated with the risk of RA, and highlighted that Cd and Pb were responsible for the outcomes. Such associations were more evident in the young and middle-aged population. These findings indicated that exposure to heavy metals increased RA risk, and advanced the identification of risk factors for RA.

Association of Sinusitis and Upper Respiratory Tract Diseases With Incident Rheumatoid Arthritis: A Case-control Study.

We aimed to determine whether specific respiratory tract diseases are associated with increased rheumatoid arthritis (RA) risk. This case-control study within the Mass General Brigham Biobank matched newly diagnosed RA cases to 3 controls on age, sex, and electronic health record history. We identified RA using a validated algorithm and confirmed by medical record review. Respiratory tract disease exposure required 1 inpatient or 2 outpatient codes at least 2 years before the index date of RA clinical diagnosis or matched date. Logistic regression models calculated ORs for RA with 95% CIs, adjusting for confounders. We then stratified by serostatus ("seropositive" was positive rheumatoid factor and/or anticitrullinated protein antibodies) and smoking. We identified 741 RA cases and 2223 controls (both median age 55, 76% female). Acute sinusitis (OR 1.61, 95% CI 1.05-2.45), chronic sinusitis (OR 2.16, 95% CI 1.39-3.35), and asthma (OR 1.39, 95% CI 1.03-1.87) were associated with increased risk of RA. Acute respiratory tract disease burden during the preindex exposure period was also associated with increased RA risk (OR 1.30 per 10 codes, 95% CI 1.08-1.55). Acute pharyngitis was associated with seronegative (OR 1.68, 95% CI 1.02-2.74) but not seropositive RA; chronic rhinitis/pharyngitis was associated with seropositive (OR 2.46, 95% CI 1.01-5.99) but not seronegative RA. Respiratory tract diseases tended towards higher associations in smokers, especially > 10 pack-years (OR 1.52, 95% CI 1.02-2.27, P = 0.10 for interaction). Acute and chronic sinusitis, pharyngitis, and acute respiratory burden increased RA risk. The mucosal paradigm of RA pathogenesis may involve the upper respiratory tract.

Risk of rheumatoid arthritis diagnosis in statin users in a large nationwide US study

ObjectiveTo evaluate the association between statin use and the risk of developing rheumatoid arthritis (RA) in a large, US case-control study.MethodsUsing the OptumLabs Data Warehouse, RA cases were identified as patients aged ≥18 years with ≥2 RA diagnoses between January 1, 2010 and June 30, 2019 and ≥1 prescription fills for methotrexate within 1 year of the first RA diagnosis. The first RA diagnosis was the index date. Cases were matched 1:1 to controls on age, sex, region, year of index date, and length of baseline coverage. Statin users were defined by having ≥2 statin prescription fills at least 90 days pre-index. Patients identified as statin users were further classified by statin user status (current or former), statin use duration, and intensity of statin exposure. Odds ratios for RA risk with statin use were estimated using logistic regression.Results16,363 RA cases and 16,363 matched controls were identified. Among RA cases, 5509 (33.7%) patients were statin users compared to 5164 (31.6%) of the controls. Statin users had a slightly increased risk of RA compared to non-users (OR 1.12, 95% CI 1.06–1.18), and former statin users had an increased RA risk compared to current users (OR 1.21, 95% CI 1.13–1.28). However, risk was eliminated following adjustment for hyperlipidemia. The risk estimates for statin use duration and intensity did not reach significance.ConclusionThis study demonstrates no significant increase in the risk of developing RA for statin users compared to non-users after adjustment for hyperlipidemia in addition to other relevant confounders. However, more information from prospective studies would be necessary to further understand this relationship.

No association between recent antibiotic use and risk of rheumatoid arthritis: results from two prospective cohort studies

ABSTRACT Background Retrospective research partly characterizes the link between antibiotic use and rheumatoid arthritis (RA) development. This prospective cohort study may help reassess the association. Research design and methods We included 133,125 participants from the Nurses’ Health Study (NHS) and NHS II databases. Three groups were established: nonuse, short-term use (1–14 days), and middle- to long-term use (≥15 days) to explore the link. Cox regression model was chosen to evaluate the hazard ratios (HRs) for RA. Results Short-term antibiotic use was not associated with the subsequent risk of RA (adjusted HR = 0.88, 95% Confidence Interval [CI] 0.38–1.38) compared to the no antibiotic use group in the multivariable adjusted model. The age-stratified model showed no sufficient evidence of increased risk in participants with middle- to long-term antibiotic use (HR = 1.32, 95% CI 0.89–1.98). The effect further attenuated to null after controlling for confounding factors (adjusted HR = 1.06, 95% CI 0.42–1.71). Conclusions We found no evidence of an association between antibiotic use and RA risk. Our findings may reduce potential concerns about increased RA risk among antibiotic users.

Adiponectin Associates with Rheumatoid Arthritis Risk in Overweight and Obesity Independently of Other Adipokines.

We recently reported that increased serum adiponectin was associated with rheumatoid arthritis (RA) risk in subjects with obesity. We hereby aim to determine if other adipokines associate with RA risk and if the association between adiponectin and RA is independent of other adipokines. Two nested-case control studies were performed in two different cohorts: 82 participants of the Swedish Obese Subjects (SOS) study who developed RA during follow-up matched with 410 controls, and 88 matched pairs from the Medical Biobank of Northern Sweden. Baseline levels of circulating adipokines were measured using ELISA. In a multivariable analysis in the SOS cohort, higher adiponectin was associated with an increased risk of RA independently of other adipokines (OR for RA risk: 1.06, 95% CI: 1.01–1.12, p = 0.02). No association between leptin, resistin, and visfatin levels and the risk of RA was detected. In the cohort from the Medical Biobank of Northern Sweden, higher adiponectin was associated with an increased risk of RA only in participants with overweight/obesity (OR: 1.17, 95% CI: 1.01−1.36, p = 0.03), independently of other adipokines. Our results show that in individuals with overweight/obesity, higher circulating levels of adiponectin, but not leptin, resistin, or visfatin, were associated with an increased 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 NCF2, NCF4, and CYBA Gene Polymorphisms with Rheumatoid Arthritis in a Chinese Population.

Objective Recent studies have focused on the special roles of NADPH-oxidase in multiple autoimmune diseases. Nevertheless, the association of genetic variation in NADPH-oxidase genes with rheumatoid arthritis (RA) was not extensively studied in a Chinese population. We performed this study to examine the association of NCF2, NCF4, and CYBA gene polymorphisms with RA susceptibility in a Chinese population. Methods Six single nucleotide polymorphisms (SNPs) (NCF2 rs10911363, NCF4 rs1883112, rs4821544, rs729749, CYBA rs3794624, and rs4673) were genotyped in a cohort composed of 593 RA patients and 596 normal controls. Improved multiple ligase detection reaction (iMLDR) was used for genotyping. Results We observed that NCF4 rs4821544 CT genotype and C allele frequencies in RA patients were significantly decreased when compared to controls (CT vs. TT: P = 0.043; C vs. T: P = 0.031), and rs4821544 polymorphism was significantly associated with an increased RA risk under the dominant model (TT vs. CT+CC: P = 0.031). Our results also indicated that rs729749 CT genotype frequency was significantly lower in RA patients than that in controls (CT vs. CC: P = 0.033). Moreover, the rs729749 CT genotype frequency was also significantly decreased in RA patients in males (CT vs. CC: P = 0.024). No significant association between NCF2 and CYBA gene polymorphisms and RA susceptibility was observed. There were significant associations between rs4821544 TT genotype and T allele frequencies and anti-CCP in male RA patients. Conclusions In summary, NCF4 rs4821544 and rs729749 polymorphisms might contribute to RA susceptibility, while NCF2 and CYBA gene polymorphisms were not associated with RA susceptibility.

Interleukin-1 receptor-associated kinase gene polymorphisms contribute to rheumatoid arthritis risk: A meta-analysis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting about 1% of world population. Three polymorphisms of Interleukin-1 receptor-associated kinase (IRAK1) gene, rs3027898, rs1059702 and rs1059703, are studied to associate with RA risk. However, the findings are inconclusive. Therefore, we performed a meta-analysis to derive a more precise estimation of the impact of the 3 polymorphisms on RA risk. The strength of association between 3 polymorphisms and RA risk was assessed by calculating odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). Overall, for rs3027898 polymorphism, no association was observed in pooled analysis, but the stratified analysis suggested that rs3027898 CA genotype was associated with a reduced risk of RA in an Asian population (heterozygous model: OR=0.79, 95% CI=0.66-0.96, P=.018). Rs1059702 polymorphism was related with an increased RA risk (homozygous model: OR=1.59, 95% CI=1.19-2.13, P=.002, heterozygous model: OR=1.49, 95% CI=1.17-1.88, P=.001, and allele comparison model: OR=1.35, 95% CI=1.20-1.53, P<.001). Moreover, rs1059703 was also associated with an increased RA risk (dominant model: OR=1.26, 95% CI=1.07-1.49, P=.006), especially in Caucasian populations. These results indicated that all 3 Interleukin-1 receptor-associated kinase (IRAK1) gene polymorphisms, rs3027898, rs1059702 and rs1059703 were related to RA risk.

Abdominal Obesity in Comparison with General Obesity and Risk of Developing Rheumatoid Arthritis in Women.

Being overweight or obese increases rheumatoid arthritis (RA) risk among women, particularly among those diagnosed at a younger age. Abdominal obesity may contribute to systemic inflammation more than general obesity; thus, we investigated whether abdominal obesity, compared to general obesity, predicted RA risk in 2 prospective cohorts: the Nurses' Health Study (NHS) and NHS II. We followed 50,682 women (1986-2014) in NHS and 47,597 women (1993-2015) in NHS II, without RA at baseline. Waist circumference (WC), BMI, health outcomes, and covariate data were collected through biennial questionnaires. Incident RA cases and serologic status were identified by chart review. We examined the associations of WC and BMI with RA risk using time-varying Cox proportional hazards models. We repeated analyses restricted to age ≤ 55 years. During 28 years of follow-up, we identified 844 incident RA cases (527 NHS, 317 NHS II). Women with WC > 88 cm (35 in) had increased RA risk (HR 1.22, 95% CI 1.06-1.41). A similar association was observed for seropositive RA, which was stronger among young and middle-aged women. Further adjustment for BMI attenuated the association to null. In contrast, BMI was associated with RA (HRBMI ≥ 30 vs < 25 1.33, 95% CI 1.05-1.68) and seropositive RA, even after adjusting for WC, and, as in WC analyses, this association was stronger among young and middle-aged women. Abdominal obesity was associated with increased RA risk, particularly for seropositive RA, among young and middle-aged women; however, it did not independently contribute to RA risk beyond general obesity.