Rheumatoid Arthritis Susceptibility Research Articles

Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease. Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility. However, accumulating evidence demonstrates that genetics also shape the gut microbiota. It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis (CIA), while the others are resistant to CIA. Here, we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice. C57BL/6J mice and healthy human individuals have enriched B. fragilis than DBA/1J mice and RA patients. Transplantation of B. fragilis prevents CIA in DBA/1J mice. We identify that B. fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate. Fibroblast-like synoviocytes (FLSs) in RA are activated to undergo tumor-like transformation. Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1, resulting in reduced FOXK1 stability, blocked interferon signaling and deactivation of RA-FLSs. We treat CIA mice with propionate and show that propionate attenuates CIA. Moreover, a combination of propionate with anti-TNF etanercept synergistically relieves CIA. These results suggest that B. fragilis or propionate could be an alternative or complementary approach to the current therapies.

Evaluation of genetic polymorphisms in TNF‑α‑308G/A rs1800629 associated with susceptibility and severity of rheumatoid arthritis: A systematic review and meta‑analysis.

To investigate the association of gene polymorphisms of TNF-α-308G/A rs1800629 with the susceptibility and severity of rheumatoid arthritis (RA), literature from PubMed, EMBASE, Web of Science and CNKI databases was searched. Two authors screened the literature independently, extracted data and evaluated the risk of bias of the included studies. According to the inclusion and exclusion criteria, five genetic models were established: The allelic model (A vs. G), dominant model (GA + AA vs. GG), recessive model (AA vs. GG + GA), co-dominant model (AA vs. GG) and super-dominant model (GG + AA vs. GA). Stata 17.0 software was used for the meta-analysis. A total of 34 eligible studies with 12,611 subjects were included, including 6,030 cases in the RA group and 6,581 controls. Meta-analysis calculations revealed that the genetic polymorphisms of TNF-α-308G/A rs1800629 were not significantly associated with susceptibility to RA, with an odds ratio and 95% confidence interval (CI) for each genetic model [A vs. G: 0.937 (0.762-1.152); GA + AA vs. GG: 0.918 (0.733-1.148); AA vs. GG + GA: 1.131 (0.709-1.802); AA vs. GG: 1.097 (0.664-1.813); and GG + AA vs. GA: 1.108 (0.894-1.373)]. For the association between TNF-α-308G/A rs1800629 gene polymorphisms and the severity of RA, the results of subgroup analysis calculations showed that TNF-α-308G/A rs1800629 gene polymorphisms were associated with the severity of RA in European populations, with the gene model and 95% CI [GA + AA vs. GG: 0.503 (0.297-0.853); and GG + AA vs. GA: 2.268 (1.434-3.590)]. When assessing the confidence in the positive results of the present study through the false-positive report probability, the positive results were observed to be reliable. No significant association was observed between genetic polymorphisms in TNF-α-308G/A rs1800629 and susceptibility to RA. However, a significant association exists with the severity of RA in European populations.

The 5' untranslated region variant rs3811050 C/T of the interleukin-38 encoding gene is associated with susceptibility to rheumatoid arthritis in Iraqi women.

Interleukin (IL)-38, the latest member of the IL-1 cytokine family, is proposed to have a pathogenic role in rheumatoid arthritis (RA). It is encoded by the IL1F10 gene, which harbors single nucleotide polymorphisms (SNPs) that may predict the risk of autoimmune diseases. Among them are 5' untranslated region (UTR) SNPs, which play a key role in post-transcriptional control, but have not been studied in Iraqi RA patients. Two novel IL1F10 5'UTR SNPs (rs3811050 C/T and rs3811051 T/G) were explored in RA and control women (n = 120 and 110, respectively). SNPs were genotyped using TaqMan assay. An ELISA kit was used to measure serum IL-38 concentrations. A reduced risk of RA was associated with rs3811050 T allele and CT genotype (corrected probability [pc] = 0.01 and < 0.001, respectively), while there was no significant association with rs3811051. Haplotype analysis demonstrated that C-T haplotype was associated with a 1.65-fold greater risk of RA, whereas a reduced risk was linked to T-G haplotype. IL-38 concentrations were higher in patients than in controls (p < 0.001). In addition, IL-38 showed acceptable performance in distinguishing between RA and control women (p < 0.001). When IL-38 concentrations were stratified according to SNP genotypes, no significant differences were found. The rs3811050 variant was more likely to affect RA susceptibility in Iraqi women, and the T allele may play a role in reducing disease risk. IL-38 concentrations were elevated in RA patients, but were not affected by the rs3811050 and rs3811051 genotypes.

Association of gene polymorphisms and the decreased expression of long non-coding RNA LOC553103 with rheumatoid arthritis.

Long non-coding RNAs (lncRNAs) are involved in many key bioprocesses, including the occurrence and development of rheumatoid arthritis (RA). We aimed to analyze the association of genetic variants of long non-coding RNA LOC553103 and its peripheral blood mononuclear cells (PBMC) expression with RA. We enrolled 457 RA patients and 551 healthy controls and conducted a case-control study to analyze the relationship between LOC553103 gene rs272879 and the susceptibility of RA by TaqMan single nucleotide polymorphism genotyping. Among them, we sampled 92 cases and 92 controls, respectively, to detect the PBMC level of LOC553103 using quantitative real-time polymerase chain reaction technology. We explored the association between LOC553103 rs272879 and its PBMC expression levels in 71 RA patients. Mann-Whitney, Chi-square, and Spearman correlation analysis were used for statistical analysis and P-value <.05 was considered statistically significant. The genotype frequency of LOC553103 rs272879 CC was increased, and CG was decreased in RA patients compared to the control group (χ2 = 6.772, P = .034). The LOC553103 expression level in PBMC of RA patients was downregulated compared to healthy control (Z = -4.497, P < .001). Moreover, negative correlations were observed between the PBMC level of LOC553103 and erythrocyte sedimentation rate (rs = -0.262, P = .018), white blood cell count (rs = -0.382, P = .004), platelet (rs = -0.293, P = .030), and disease activity score in 28 joints (rs = -0.271, P = .016) in RA patients. This study provides the first evidence supporting an association between LOC553103 gene polymorphisms and susceptibility of RA and a relationship of PBMC level of LOC553103 with clinical manifestations and laboratory indicators of RA patients.

OA27 Molecular divergences in CD4+ T Cells between early and refractory rheumatoid arthritis

Abstract Background/Aims Up to 21% of rheumatoid arthritis (RA) patients remain refractory to available treatments. This represents a clinical challenge due to the lack of efficacious alternatives for refractory RA (rRA) patients. Although CD4+ T cells are paramount in RA pathogenesis, a comprehensive understanding of their roles in rRA versus non-refractory RA has not been characterised. The aim of this study is to dissect the molecular differences in CD4+ T cells across these patient sub-groups and identify novel mechanisms driving rRA, which may inform tailored therapeutic strategies, using single cell multiomic analysis. Methods Primary CD4+ T-cells were isolated from PBMCs obtained from 3 rRA patients (defined as per EULAR definition of difficult-to-treat RA) and 3 treatment-naïve, early RA (ERA) patients, all seropositive with active disease (DAS28-ESR &amp;gt; 3.2), collected as part of the PRECISE-RA programme. Following nuclei extraction, the 10x Genomics Multiome ATAC + Gene Expression assay was used to simultaneously determine the transcriptional and chromatin landscapes from individual cells. Results Patient characteristics are reported in Table 1. 8,215 T-cells cells were clustered into 11 distinct cell states, which showed a trend towards diminished Tregs and modulated effector memory (TEM)/Th17 phenotype expressions in rRA compared to ERA patients. In ERA, expression of INPP4B, pivotal for cell growth and survival, was upregulated within naïve CD4+ T-cell subsets. ITGA4, crucial in leukocyte migration and adhesion, was elevated within a subset of naïve CD4+ T cells in early RA. ZEB2 exhibited increased expression within CD4 TEM/Th17 phenotype cells, potentially implicating divergent cellular differentiation, and migratory pathways within early RA contexts. Next, we utilised the multiomic nature of the data to functionally annotate GWAS variants, by creating peak-gene maps and overlaying RA risk SNPs. For example, an RA susceptibility SNP mapping to an intron of ANKRD55, rs7731626, was linked to the novel RA causal gene IL6ST. Furthermore, the RA SNP rs71508903, previously assigned to the ARID5B gene, was linked to the RTKN2 promoter, elucidating potential avenues for further exploration into RA pathogenesis. Conclusion These findings, to be validated in a larger cohort, suggest distinct biological mechanisms driving rRA and may help identify novel biomarkers and therapeutic avenues. Disclosure S.L. Smith: None. S. Rossi: None. R. Shukla: None. Y. Tan: None. A. Ariff: None. I. Lazar: None. K. Patel: None. C.F. Yap: None. N. Nair: None. S. Eyre: None. M.H. Buch: None. M.H. Buch: None. P. Martin: None. G. Orozco: None.

Tumor necrosis factor alpha induced protein 3, interleukin 10, tumor necrosis factor alpha, and interleukin 17F genes polymorphisms in Algerian patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease with chronic inflammation. Its pathogenesis involves immunological, genetic, and environmental factors. We investigate the association between Tumor Necrosis Factor α Protein 3 (TNFAIP3), Interleukin 10 (IL10), Tumor Necrosis Factor α (TNF α), and Interleukin 17F (IL17F) polymorphisms with susceptibility to RA. 191 patients with RA diagnosed according to the American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) classification and 190 healthy subjects were recruited. Rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPA), and C-reactive protein (CRP) were measured. Genotyping of the polymorphisms was performed by real-time PCR. Analysis of the allelic frequencies of TNFAIP3 showed a positive association OR (95% CI) = 1.46 (1.01-2.09); p = 0.04, but failed to meet the criteria of significance after Bonferroni Correction. The genotypic and allelic distribution of the IL10, IL17F, and TNFα showed no significant difference when comparing the RA group with controls. Furthermore, the genotype codominant model shows a moderate positive association in the presence of ACPA (OR (95% CI) = 2.82 (1.22-6.24); p = 0.01. None of the polymorphisms studied was associated with RF and CRP production. Our results show that there is a tendency for the AG genotype of IL10-1082 to be associated with the production of ACPA in patients with RA. None of the variants studied were associated with RA susceptibility in Algerians.

Exploring the Correlation between Interleukin-17A Promoter Polymorphism at its -197 G/A and Rheumatoid Arthritis: Impact on Disease Severity and Activity

T helper 17 (Th17) cells have been reported to be the most powerful factor in autoimmune disorder pathogenesis, which points to the Th17 master cytokine, interleukin (IL)-17A, as the crucial mediator. We aimed to determine the impact of IL-17A polymorphism in the -197 G/A promoter region on level of IL-17 and intensity of rheumatoid arthritis (RA) disease symptoms. This case-control study was conducted at the Department of Clinical Rheumatology of Aswan university Hospital and included 35 people suffering RA and 30 volunteer controls, matched for age and sex. Rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, erythrocyte sedimentation rate (ESR), serum IL-17, and C-reactive protein (CRP) were measured in the RA patient group. Restriction fragment length polymorphism (RFLP) was conducted by polymerase chain reaction (PCR) amplicon obtained by IL-17A -197 G /A primers. Of the 35 RA patients, RF was positive in 33 (94.29%) and anti-CCP antibodies in 25 (71.43%), CRP in 31 (88.57%). Of the 35 RA patients, 5 (14.29%) patients carried the G/G genotype, 18 (51.43%) G/A and 12 (34.29%) A/A. IL-17 serum level was significantly greater in the more active RA (DAS28 &gt;5.1) group than the less active (DAS28 ≤5.1) group. Of the RA patients carrying wild type G/G genotype, 60% had more active disease (DAS 28&gt; 5.1), as compared to those with lower activity (DAS 28 ≤5.1), 40% carried the wild type G/G genotype. In conclusion, the study findings imply that IL-17A gene polymorphism is connected to RA clinical severity rather than with RA susceptibility.

The Effects of -806 T/C and -857 T/C Single Nucleotide Polymorphisms in the TNF-α Gene on Rheumatoid Arthritis Severity and Inflammatory Markers

Background: Polymorphisms in the TNF-α gene affect the development and progression of rheumatoid arthritis. Objective: To investigate the associations between (-806 T/C) and (-857 T/C) SNPs with rheumatoid arthritis severity and susceptibility in a sample of Iraqi patients. Methods: A case-control study was conducted in Baghdad, Iraq. Twenty healthy controls and 63 patients confirmed to be newly diagnosed with rheumatoid arthritis were included. Those are divided into two groups (patients and controls), and the patients were further subdivided into severe and mild-moderate groups. Samples from those participants were analyzed for clinical and inflammatory parameter measurements. Genotyping by the Sanger method was performed to study the SNPs. Results: No associations were demonstrated between rheumatoid arthritis and polymorphisms at positions -806 and -857. Additionally, there were no differences in the distribution of those SNP genotypes and alleles among the severe and mild-moderate groups. Also, the (-806 C/T) SNP was found to be correlated with DAS 28 in all patients and with hs-CRP in the mild-moderate group. Finally, the -857 C/T SNP was found to be correlated with TNF-α within the mild-moderate group. Conclusions: Polymorphisms at positions -806 and -857 were not associated with rheumatoid arthritis susceptibility, and the CT genotype of -806 C/T SNP was associated with disease activity.

In-silico Functional and Structural Annotation of Rheumatoid arthritis linked Gene and Protein

Background: Rheumatoid arthritis (RA) is an autoimmune disease marked by chronic inflammation and immune system dysregulation. The Ankyrin repeat domain 55 (ANKRD55) gene, located on chromosome 5q11.2, has been associated with RA susceptibility. Understanding the gene and protein characteristics could illuminate pathways involved in RA and aid in the development of targeted therapies. Objective: To conduct a detailed analysis of the ANKRD55 gene and protein, focusing on its structure, expression profile, functional domains, and polymorphisms, thereby establishing its role in RA and potential as a therapeutic target. Methods: Using bioinformatics tools, we analyzed ANKRD55's genomic localization (NCBI), peptide sequences (Uniprot), physicochemical properties (Protparam Server), signal peptides (SignalP v4.1), transmembrane helices (TMHMM), and glycosylation sites (NetNGlyc 1.0). Polymorphism and methylation patterns were examined using PolyPhen and MethyCancer, respectively. Splice variants were identified, and protein-protein interaction networks were assessed (STRING database). Protein domains were characterized, including the prediction of RhoGAP domains. Structural modeling was conducted to identify potential drug-binding pockets with the DoGSite Scorer server. Results: ANKRD55's expression was predominantly observed in the testis (RPKM 1.8) and to a lesser extent in lymph nodes (0.8), appendix (0.6), and brain (0.2). It encodes a 614-amino-acid protein with a molecular weight of approximately 68.4 kDa and a pI of 6.72. Six splice variants were identified, enriching the understanding of its potential isoform diversity. No significant N-glycosylation sites were predicted, and methylation analysis suggested a nuclear localization without DNA methylation sites. Structural analysis revealed drug-binding pockets with volumes ranging from 233.35 to 5389.58 A^3, with drug scores between 0.78 and 0.82. Conclusion: The study concludes that while several factors contribute to student satisfaction in public sector medical colleges, infrastructure and facilities, along with quality instructional materials and clinical exposure, are key drivers. Enhancing these areas could lead to a more positive educational experience for students.

Association of Cytokine IL-17, IL-4, IL-6, and IL-12 Gene Polymorphisms in Rheumatoid Arthritis Patients in a Tertiary Care Hospital in Bangladesh.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that involves cytokines in its pathogenesis. This study is aimed at investigating if gene polymorphisms in cytokines like IL-17, IL-4, IL-6, and IL-12 affect RA susceptibility and severity in the Bangladeshi population. This was a cross-sectional comparative study that included 40 diagnosed RA patients according to the American College of Rheumatology (ACR) criteria 2010, who were free from other rheumatological diseases, and 40 healthy subjects for comparison. The study used PCR-RFLP to determine the IL-17, IL-4, IL-6, and IL-12 cytokine gene polymorphisms. Patients had a mean age of 37.22 ± 6.70 years. Among the patients, 31 were female and 9 were male. The mean disease duration was 18.11 ± 7.39 months. The study found that rheumatoid arthritis patients with the IL-17F (7488 A/G) polymorphism with GG genotype (P = 0.006, OR = 8.56, 95% CI = 1.77 - 41.33) and IL-12B (1188 A/C) polymorphism with AC (P = 0.012, OR = 3.69, 95% CI = 1.43 - 9.53) and CC (P = 0.013, OR = 7.58, 95% CI = 1.56 - 36.88) genotypes were significantly associated with disease risk. Furthermore, patients with the IL-17F (7488) GG genotype and IL-12B (1188) AC and CC genotypes had higher rheumatoid arthritis disease severity and activity parameters. The study found no significant association between polymorphisms involving IL-4 (590 C/T) and IL-6 (174 G/C) genes and rheumatoid arthritis disease risk in the Bangladeshi population. Gene polymorphisms in cytokines IL-17F (7488 A/G) and IL-12B (1188 A/C) can predict disease susceptibility and severity in Bangladeshi rheumatoid arthritis patients.

Interleukin-18 Gene Polymorphisms and Rheumatoid Arthritis Susceptibility: An Umbrella Review of Meta-Analyses.

This study systematically analyzes the association between interleukin-18 (IL-18) gene polymorphisms and rheumatoid arthritis (RA) susceptibility. The electronic databases Ovid MEDLINE, Ovid Excerpta Medica Database, and Cochrane Library were searched to identify meta-analyses that included case-control studies reporting IL-18 gene polymorphisms and RA susceptibility. Data were reanalyzed using Review Manager Software 5.1, and Mantel-Haenszel random effects were applied for the five genetic models: allelic, recessive, dominant, homozygote, and heterozygote. The effect size of odds ratios (ORs) and their corresponding 95% confidence interval (CI) were calculated. A total of seven meta-analyses with poor quality were included. The IL-18 polymorphisms -607 A/C, -137 C/G, -920 T/C, and -105 C/A have been reported. With weak evidence, IL-18 -607 A/C polymorphisms were associated with a reduced risk of RA susceptibility using the allele model (OR = 0.76, 95% CI: 0.61 - 0.93, p=0.01), dominant model (OR = 0.67, 95% CI: 0.50 - 0.90, p=0.008), homozygote model (OR = 0.57, 95% CI: 0.35 - 0.91, p=0.02), and heterozygote model (OR = 0.71, 95% CI: 0.54 - 0.93, p=0.01) in the overall population. IL-18 gene polymorphisms and RA susceptibility are affected by ethnicity: With weak evidence, IL-18 -137 C/G polymorphisms were related to reduce RA susceptibility in the Asian population (allele model: OR = 0.59, 95% CI: 0.40 - 0.88, p=0.01; dominant model: OR = 0.57, 95% CI: 0.37 - 0.89, p=0.01; heterozygote model: OR = 0.60, 95% CI: 0.38 - 0.94, p=0.03). IL-18 -607 A/C gene polymorphisms are a protective factor for RA susceptibility in the overall population, and IL-18 -137 C/G gene polymorphisms are a protective factor for RA susceptibility in the Asian population. Further studies are needed to confirm these results owing to the limitations of the included studies.

Gene polymorphisms of an interleukin-23 receptor associated with susceptibility to rheumatoid arthritis in the Western Chinese Han population.

Rheumatoid arthritis (RA) is a chronic inflammatory disease which is closely related to genetic background. Single-nucleotide polymorphisms (SNPs) have been found to play an important role in the development of RA. This study intends to investigate the links between gene polymorphisms in the interleukin-23 receptor (IL23R) and interleukin 17A (IL17A) and susceptibility to RA in the Western Chinese Han population. Four SNPs (rs6693831 T>C, rs1884444 G>T, and rs7517847 T>G in IL23R gene, and rs2275913 G>A in IL17A gene) were genotyped in 246 RA patients and 362 healthy controls by high resolution melting analysis. The comparative analyses among genotype distributions, clinical indicators, and IL-17A and IL-23R levels in RA patients were also performed. The study revealed that the SNP rs6693831 and rs1884444 of IL23R had a significant association with RA susceptibility. The frequencies of rs6693831 genotype CC and allele C were significantly higher in the RA group and associated with higher RA risk compared with genotype TT and allele T (OR=7.797, 95% confidence interval [CI]=4.072-14.932 and OR=5.984, 95%CI=3.190-11.224, respectively). The TT genotype of rs1884444 appeared to decrease the RA risk compared with the GG genotype (OR=.251, 95%CI=.118-.536). The genotype CC and allele C of rs6693831 and the genotype GG and allele G of rs1884444 may be risk factors for RA. IL23R gene polymorphisms may be involved in the risk of RA susceptibility in the Western Chinese Han population.

Gwid: an R package and Shiny application for Genome-Wide analysis of IBD data.

Genome-wide identity by descent (gwid) is an R package developed for the analysis of identity-by-descent (IBD) data pertaining to dichotomous traits. This package offers a set of tools to assess differential IBD levels for the two states of a binary trait, yielding informative and meaningful results. Furthermore, it provides convenient functions to visualize the outcomes of these analyses, enhancing the interpretability and accessibility of the results. To assess the performance of the package, we conducted an evaluation using real genotype data derived from the SNPs to investigate rheumatoid arthritis susceptibility from the Marshfield Clinic Personalized Medicine Research Project. gwid is available as an open-source R package. Release versions can be accessed on CRAN (https://cran.r-project.org/package=gwid) for all major operating systems. The development version is maintained on GitHub (https://github.com/soroushmdg/gwid) and full documentation with examples and workflow templates is provided via the package website (http://tinyurl.com/gwid-tutorial). An interactive R Shiny dashboard is also developed (https://tinyurl.com/gwid-shiny).

Genetic Risk of Rheumatoid Arthritis: A Case Control Study.

Vitamin D effects are mediated by vitamin D receptors (VDRs), which are influenced by various genetic polymorphisms, including ApaI and BsmI. These polymorphisms have been linked to several diseases, including rheumatoid arthritis (RA). This study aimed to compare the frequency and association of VDR ApaI and BsmI gene polymorphisms, serum 25-hydroxy vitamin D (25-(OH)-D) levels, and calcium (Ca) levels between a RA group and a matched healthy control group. In one hundred RA patients and fifty healthy controls, the genotypes of the VDR ApaI and BsmI gene polymorphisms were analyzed using polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLP). Both Serum 25-(OH)-D level and calcium level were measured in the two groups. There was no significant difference between the cases and controls regarding the VDR ApaI gene polymorphism (p = 0.89). A significant difference was observed between the cases and controls in terms of the VDR BsmI gene polymorphism (p = < 0.001). The serum levels of 25-(OH)-D and calcium were significantly lower in the RA group compared to the control group (p = 0.04 and < 0.001 respectively). Significantly higher serum vitamin D levels were associated with the aa genotype (p = 0.007). Significantly increased calcium levels were associated with the AA genotype (p = 0.02). No significant difference was found among BsmI polymorphisms regarding vitamin D and Ca levels (p = 0.25 and 0.87 respectively). Vitamin D receptor gene BsmI polymorphism but not ApaI polymorphism could be a marker of RA susceptibility. Vitamin D and Ca levels are negatively affected by RA. Vitamin D receptor gene ApaI polymorphism contributes to vitamin D and Ca levels.

Single-Nucleotide Variants in PADI2 and PADI4 and Ancestry Informative Markers in Interstitial Lung Disease and Rheumatoid Arthritis among a Mexican Mestizo Population

Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized by joint inflammation. It presents extra-articular manifestations, with the lungs being one of the affected areas. Among these, damage to the pulmonary interstitium (Interstitial Lung Disease—ILD) has been linked to proteins involved in the inflammatory process and related to extracellular matrix deposition and lung fibrosis establishment. Peptidyl arginine deiminase enzymes (PAD), which carry out protein citrullination, play a role in this context. A genetic association analysis was conducted on genes encoding two PAD isoforms: PAD2 and PAD4. This analysis also included ancestry informative markers and protein level determination in samples from patients with RA, RA-associated ILD, and clinically healthy controls. Significant single nucleotide variants (SNV) and one haplotype were identified as susceptibility factors for RA-ILD development. Elevated levels of PAD4 were found in RA-ILD cases, while PADI2 showed an association with RA susceptibility. This work presents data obtained from previously published research. Population variability has been noticed in genetic association studies. We present data for 14 SNVs that show geographical and genetic variation across the Mexican population, which provides highly informative content and greater intrapopulation genetic diversity. Further investigations in the field should be considered in addition to AIMs. The data presented in this study were analyzed in association with SNV genotypes in PADI2 and PADI4 to assess susceptibility to ILD in RA, as well as with changes in PAD2 and PAD4 protein levels according to carrier genotype, in addition to the use of covariates such as ancestry markers.

Promoter polymorphisms of neuropeptide Y, interleukin-1B and increased IL-1β levels are associated with rheumatoid arthritis susceptibility in South Gujarat population

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint destruction. Interleukin-1B(IL-1β) has been implicated in RA, and neuropeptide Y (NPY) induces the release of pro-inflammatory cytokines including IL1-β, TNF-α and IL-6. Single nucleotide polymorphisms (SNPs) in NPY and IL1B gene may lead to their altered levels leading to RA pathogenesis. Therefore, we aimed to investigate association of NPY rs16147(T > C) SNP, and genotype–phenotype correlation of the IL1B rs16944(C > T) SNP in 302 RA patients and 337 controls by Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Both the genotype and allele frequencies for NPY rs16147(T > C)(p = 0.0019 &p = 0.012) and IL1B rs16944(C > T)(p = 0.0024 &p = 0.0014) SNPs differed significantly between RA patients and controls. The odds ratios of 1.23 and 1.47 for NPY rs16147(T > C) and IL1B rs16944(C > T) SNPs respectively, suggest that these SNPs may be genetic risk factor for RA in South Gujarat population. The plasma IL-1β levels(p = 0.0332) and genotype-phenotype correlation of IL1B rs16944(C > T) SNP suggested increased IL-1β levels, particularly in patients with susceptible ‘TT' genotypes(p < 0.0001). Additionally, plasma IL-1β level was significantly increased in severe RA patients (p = 0.0025) and positively correlated with Rheumatoid factor(RF) (r = 0.9240, p < 0.0001), suggesting the role of IL-1β in disease severity. Overall, the study for the first time suggests that NPY rs16147(T > C) and IL1B rs16944(C > T) SNPs may be associated with RA susceptibility in South Gujarat population. Additionally, the IL1B rs16944 susceptible ‘TT' genotype may lead to increased IL-1β levels, thereby contributing to RA pathogenesis and severity.

Association analysis of Vascular Endothelial Growth Factor-A (VEGF-A) polymorphism in rheumatoid arthritis using computational approaches

Rheumatoid arthritis (RA), is marked by joint inflammation leading to pannus formation which results in cartilage destruction promoting bone erosion. The pathological hallmark of RA includes synovial hyperplasia and synovial angiogenesis. Active tissue neovascularization is observed in RA. Vascular endothelial Growth factor A (VEGFA), an endothelial cell-specific proangiogenic molecule is triggered by hypoxic cells and its levels are upregulated in RA. The aim of this study was to investigate functional and pathogenic VEGFA variants and to identify the impact of point mutation in VEGFA’s interaction with VEGFR2 and how these polymorphisms affect the susceptibility and severity of RA. We investigated impact of these point mutations on the stability of VEGFA using various computational tools. These mutations were further identified by conservational profile as they are highly involved as structural and functional mutations. Furthermore, these selected variants were modelled and docked against targeted domain regions IGD2 and IGD3 of VEGFR2. Further molecular dynamic simulations were performed using Gromacs. Out of 168 nsSNPS, 19 were highlighted as highly pathogenic using insilico prediction tools. InterPro and ConSurf revealed domains and conserved variants respectively. After stability analysis, we concluded that almost all the mutations were responsible for decreasing the protein stability. HOPE predicted that all the selected damaging nsSNPs were present in the domain which is essential for the functioning of VEGFA protein. Constructed Ramachandran plot and ERRAT validated the quality of all the models. Based on the interactions predicted by STRING database, we performed Protein–Protein docking between VEGFA and VEGFR2. We found few conserved interactions and new polar contacts among wild-type and mutants with VEGFR2. From the simulations, we concluded that mutant R108Q was the most stabilizing mutant among all others whereas R82Q, C86Y, and R108W complexed with VEGFR2 were comparatively less stabilizing as compared to the wild type. This study provides insight into pathogenic nsSNPs that can affect VEGFA protein structure and function. These high-risk variants must be taken into consideration for genetic screening of patients suffering from RA.

Biochemical markers and FokI and TaqI vitamin D receptor genes polymorphism in rheumatoid arthritis

BackgroundPrevious studies have reported the role of genes in different metabolic processes in the human body, and any variation in gene polymorphisms could lead to disturbances in these processes and different diseases.ObjectiveThis study aimed to compare vitamin D receptor (VDR) FokI and TaqI genotypes in terms of parathyroid hormone (PTH) and some biomarkers of inflammation and susceptibility to rheumatoid arthritis (RA) disease.MethodsThis study included 100 patients with rheumatoid arthritis (RA). Genotyping was performed by polymerase chain reaction (PCR) and examined by specific restriction enzymes using restriction fragment length polymorphism (RFLP). Serum intact PTH, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), and anti-cyclic citrullinated peptide antibodies (ACCPs) levels were measured.ResultsAn increased PTH level (> 65 pg/ml) was found in 8% of patients. No significant differences among FokI and TaqI vitamin D receptor genes polymorphism regarding positive and negative RF or ACCPs were found. A significant difference was found among FokI (p = 0.009) and none in TaqI genotypes regarding intact parathyroid hormone level categories. No significant correlation was found between the serum intact PTH level and ESR or CRP levels (P = 0.13 and 0.28, respectively). The parathyroid hormone level was not a good predictor for RF or ACCPs (P = 0.5 and 0.06, respectively).ConclusionThe FokI gene may play a role in controlling PTH levels in patients with RA. There was no significant correlation found between the serum intact PTH level and RA severity according to ESR and CRP inflammatory biomarkers. There are no differences between VDR genes FokI and TaqI polymorphism in terms of RA susceptibility (for RF and ACCPs).

Some genetic differences in patients with rheumatoid arthritis

ObjectiveVitamin D is important for bone and cartilage metabolism. Changes in vitamin D blood level may be related to pathological disorders such as rheumatoid arthritis (RA). The main aim of this study is to investigate the association between RA and the vitamin D receptor (VDR) genes FokI and TaqI polymorphisms. One hundred RA patients and fifty healthy matched controls were assessed for VDR FokI and TaqI genotyping. Intact parathyroid hormone (PTH) and calcium (Ca) levels were measured, categorized, and compared between the cases and control groups.ResultsWe found that the FokI genotype frequencies for the RA cases and control groups were FF:Ff:ff = 46%:52%:2% and 50%:50%:0%, respectively (P = 0.76). The TaqI genotype frequencies for the RA cases and control groups were TT:Tt:tt = 45%:44%:11% and 42%:42%:16%, respectively (P = 0.69). A statistically significant high serum PTH level was associated with the ff genotype (p = 0.03), and a significantly low serum Ca level was associated with the TT genotype (p = 0.003). In comparison with controls, no influence of VDR FokI and TaqI genotypes on RA susceptibility or risk was demonstrated.

Appraising causal risk and protective factors for rheumatoid arthritis.

Mendelian randomization (MR) is considered to overcome the bias of observational studies, but there is no current meta-analysis of MR studies on rheumatoid arthritis (RA). The purpose of this study was to summarize the relationship between potential pathogenic factors and RA risk based on existing MR studies. PubMed, Web of Science, and Embase were searched for MR studies on influencing factors in relation to RA up to October 2022. Meta-analyses of MR studies assessing correlations between various potential pathogenic factors and RA were conducted. Random-effect and fixed-effect models were used to synthesize the odds ratios of various pathogenic factors and RA. The quality of the study was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization (STROBE-MR) guidelines. A total of 517 potentially relevant articles were screened, 35 studies were included in the systematic review, and 19 studies were eligible to be included in the meta-analysis. Pooled estimates of 19 included studies (causality between 15 different risk factors and RA) revealed that obesity, smoking, coffee intake, lower education attainment, and Graves' disease (GD) were related to the increased risk of RA. In contrast, the causality contribution from serum mineral levels (calcium, iron, copper, zinc, magnesium, selenium), alcohol intake, and chronic periodontitis to RA is not significant. Obesity, smoking, education attainment, and GD have real causal effects on the occurrence and development of RA. These results may provide insights into the genetic susceptibility and potential biological pathways of RA.