Risk Of Rheumatoid Arthritis Research Articles

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.

Alteration of Gut Microbiota in Individuals at High-Risk for Rheumatoid Arthritis Associated With Disturbed Metabolome and the Initiation of Arthritis Through the Triggering of Mucosal Immunity Imbalance.

In this study, we aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis. Fecal samples were collected from 38 healthy individuals and 53 high-risk RA individuals with anti-citrullinated protein antibody (ACPA) positivity (Pre-RA), 12 of 53 Pre-RA individuals developed RA within 5 years of follow-up. The differences in intestinal microbial composition between the healthy controls and Pre-RA individuals or among Pre-RA subgroups were identified by 16S ribosomal RNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic-pretreated mice that received GM from the healthy control or Pre-RA groups were then evaluated for intestinal permeability, inflammatory cytokines, and immune cell populations. Collagen-induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from Pre-RA individuals on arthritis severity in mice. Stool microbial diversity was lower in Pre-RA individuals than in healthy controls. The bacterial community structure and function significantly differed between healthy controls and Pre-RA individuals. Although there were differences to some extent in the bacterial abundance among the Pre-RA subgroups, no robust functional differences were observed. The metabolites in the serum of the Pre-RA group were dramatically different from those in the healthy controls group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the Pre-RA group increased intestinal permeability in FMT mice and zonula occludens-1 expression in the small intestine and Caco-2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving Pre-RA feces compared to healthy controls. The changes in intestinal permeability and Th17-cell activation prior to arthritis induction enhanced CIA severity in PreRA-FMT mice compared with HC-FMT mice. Gut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to the development of arthritis.

Increased risk of rheumatoid arthritis in patients with asthma: a genetic association study using two-sample Mendelian randomization analysis.

Observational studies have explored the association between asthma and some types of arthritis, including rheumatoid arthritis and osteoarthritis, but the results are largely contradictory. We aimed to investigate the causal effects of asthma on arthritis including osteoarthritis, rheumatoid arthritis, gout and ankylosing spondylitis. Two-sample Mendelian randomization (MR) analysis was used to investigate the causal effects of asthma on each arthritis. The genetic instruments for asthma were obtained from a large genome-wide association study of asthma. Inverse-variance weighted (IVW) method was used as the main analysis of MR. Bonferroni-adjusted P value threshold was used to account for multiple comparisons. MR-IVW analysis suggested that adult-onset asthma (AOA) was associated with increased risk of rheumatoid arthritis. The odds ratio for rheumatoid arthritis associated with AOA and childhood-onset asthma (COA) were 1.018 (95% CI, 1.011 to 1.025; P < 0.001) and 1.006 (95% CI, 1.001 to 1.012; P=0.046), respectively. For osteoarthritis, gout, or ankylosing spondylitis, all the MR analyses showed no significant causal effects of AOA or COA on them. We also performed a reverse MR analysis to explore the causal effects of rheumatoid on all asthma, allergic asthma or non-allergic asthma, and found no significant causal effects on them. Genetically predicted AOA predisposes patients to an increased risk of rheumatoid arthritis, but has no causal effects on osteoarthritis, gout, and ankylosing spondylitis. The result of COA on rheumatoid arthritis is suggestive of potential causal relationship but needs to be confirmed in further studies.

Microscopic colitis and risk of incident rheumatoid arthritis: A nationwide population-based matched cohort study.

Microscopic colitis (MC) has been linked to several autoimmune conditions. Results from previous studies on the association with rheumatoid arthritis (RA) have been inconsistent. To assess the risk of future RA in MC. We conducted a nationwide matched cohort study in Sweden of 8179 patients with biopsy-verified MC (diagnosed in 2007-2017), 36,400 matched reference individuals and 8202 siblings without MC, with follow-up until 2021. Information on MC was obtained from all of Sweden's regional pathology registers (n = 28) through the ESPRESSO cohort. Data on incident RA were collected from the National Patient Register. Using Cox regression, we calculated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). During a median follow-up of 9.1 years (interquartile range = 6.7-11.7), 73 MC patients and 183 reference individuals from the general population were diagnosed with RA (99 vs. 55 events per 100,000 person-years), equivalent to one extra case of RA in 226 patients with MC followed for 10 years. These rates corresponded to an aHR of 1.83 (95% CI = 1.39-2.41). The aHR was highest during the first year of follow-up (2.31 [95% CI = 1.08-4.97]) and remained significantly elevated up to 5 years after MC diagnosis (aHR 2.16; 95% CI = 1.42-3.30). Compared to siblings, without MC, the aHR was 2.04 (95% CI = 1.18-3.56). Patients with MC are at a nearly two-fold risk of developing RA compared to the general population. Knowledge of this increased risk may expedite evaluation for RA in patients with MC presenting with joint symptoms and/or arthralgia, thus preventing delay until RA diagnosis.

The role of NLRP3 and CARD8 polymorphisms in the risk of rheumatoid arthritis: A meta-analysis of genetic association studies.

To investigate the potential associations between rheumatoid arthritis (RA) and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) rs35829419, rs10754558, s4612666, and caspase recruitment domain family member 8 (CARD8) rs2043211 polymorphisms. Relevant papers were searched for in MEDLINE, Embase, and Web of Science. Allele contrast, recessive, dominant, and homozygote contrast models were used to investigate the relationship between the NLRP3 rs35829419, rs10754558, and s4612666, and CARD8 rs2043211 polymorphisms and RA. This review was registered with PROSPERO (CRD42023451231). The meta-analysis included 11 comparative studies comprising 3789 patients with RA and 3956 controls. No significant association was found between NLRP3 rs35829419 C allele and RA in Europeans, Arabs, or Latinos. The NLRP3 rs10754558 G allele was not associated with RA in the Asian or Arab populations. However, a single study in Latin America discovered a link between RA and the NLRP3 rs10754558 G allele. The NLRP3 rs4612666 T allele was not associated with RA, according to the meta-analysis. When ethnicity was stratified, there was no association between the NLRP3 rs4612666 T allele and RA, except for a single study that found an association among Arabs. The CARD8 rs2043211 T allele did not seem to be associated with RA. According to an ethnic stratification study, the CARD8 rs2043211 T allele did not appear to be associated with RA in Europeans, Arabs, or Latinos. The meta-analysis indicated that the NLRP3 rs35829419, rs10754558, and s4612666 polymorphisms, as well as the CARD8 rs2043211 polymorphism, were not linked to RA susceptibility.

Study the association of miRNA-146a gene polymorphism and some immunological markers with the risk of Rheumatoid Arthritis incidence in a sample of Iraqi patients.

Rheumatoid arthritis is a multifactorial autoimmune disease affecting 1–2% of the population worldwide. It is more common in women than men, predominately aged 40-60. This study aims to identify the association of the polymorphism in the MIR146A gene with RA susceptibility in a sample of Iraqi patients and to examine whether these polymorphisms can influence the severity and activity of the disease. The case-control study was conducted in the period between December 2021 and February 2022. A total of 120 blood samples were collected, including 60 patients with rheumatic arthritic disease who most regularly visit the chronic arthritis diseases department of Baghdad Teaching Hospital-Medical City in Iraq and 60 healthy controls. Polymorphisms were genotyped by using HRM realtime PCR for genotyping assay. Significant differences in the frequency of miRNA-146a rs2910164 alleles and genotypes were observed between RA patients and controls. The CC genotype of the MIR146A Gene in the (rs2910164 SNP) shows a risk for rheumatoid arthritis (50% versus 23.33% in healthy individuals), the (χ2 =5.81; O.R.= 1 and the P-value = 0.0159) respectively especially in females than males the CC genotype seems the only risk factor among the other genotypes (CG and GG) with (P-value ≤ 0.05) in (31.46%), while the other genotypes (CG and GG) show no risk for rheumatoid arthritis in the studied samples of Iraqi population. Keywords: MIR146a gene, polymorphism, rs2910164, HRM, RA, Iraq.

Autoimmune and immune-mediated inflammatory diseases after exposure to acid-suppressive medication: A systematic review and meta-analysis.

Pharmacovigilance risk signals have proposed a relationship between the use of acid-suppressive medications and the development of certain autoimmune and immune-mediated inflammatory diseases. A systematic review and a meta-analysis was performed. We reviewed MEDLINE (Ovid) and Scopus for comparative observational studies between these diseases and previous exposure to proton-pump inhibitors (PPI), H2-receptor antagonists (H2RA), and antacids. The protocol was registered on the PROSPERO database (CRD42020192715). From 3,191 citations, 25 articles were eligible and covered 16 diseases. Microscopic colitis (MC) was studied the most (7 studies). In a random-effects meta-analysis, there was low certainty evidence (GRADE approach) of a non-significant relationship between exposure to any PPIs and MC (meta-OR 3.28, 95% CI 0.98-11.0, I2 98.2%, six studies, 4,436 PPI-exposed MC patients). Moderate certainty evidence pointed towards large odds of collagenous colitis after exposure to lansoprazole (meta-OR 14.5, 95% CI 9.37-22.3, I2 10.2%, three studies, 1,725 lansoprazole-exposed patients). After PPI exposure, the risk of rheumatoid arthritis was slightly increased based on low certainty evidence from two cohort studies totaling 475 diagnoses (meta-RR 1.62, 95% CI 1.12-2.34, I2 34.5%). In patients with MC, it would be reasonable to carefully review the indication of PPI, especially in CC patients using lansoprazole.

Influence of Helicobacter pylori infection on risk of rheumatoid arthritis: a nationwide population-based study

The relationship between Helicobacter pylori infection and rheumatoid arthritis has been investigated, but the results remain controversial. This study aims to determine the association between the two diseases via a 17-year retrospective cohort study. Using the National Health Insurance Research Database, a nationwide population based in Taiwan, we identified 97,533 individuals with H. pylori infection and matched controls between 2000 and 2017 using propensity score matching at a 1:1 ratio. The adjusted hazard ratio of rheumatoid arthritis was determined by multiple Cox regression. The incidence rate of rheumatoid arthritis was 1.28 per 10,000 person-months in the H. pylori cohort, with a higher risk compared to the control group. In the < 30 years old subgroup, the risk was highest, especially in women < 30 years old with H. pylori infection. Patients with < 1 year follow-up showed 1.58 times higher susceptibility to rheumatoid arthritis. Individuals with follow-ups of 1–5 years and over 5 years demonstrated 1.43 and 1.44 times higher risks of rheumatoid arthritis, respectively. Our study showed H. pylori infection was associated with the development of rheumatoid arthritis. Clinicians should note higher risk, especially < 30 years old. More research needed to understand underlying mechanism.

Modifiable risk factors linked to the development of rheumatoid arthritis: evidence, immunological mechanisms and prevention.

Rheumatoid Arthritis (RA) is a common autoimmune disease that targets the synovial joints leading to arthritis. Although the etiology of RA remains largely unknown, it is clear that numerous modifiable risk factors confer increased risk to developing RA. Of these risk factors, cigarette smoking, nutrition, obesity, occupational exposures and periodontal disease all incrementally increase RA risk. However, the precise immunological mechanisms by which these risk factors lead to RA are not well understood. Basic and translational studies have provided key insights into the relationship between inflammation, antibody production and the influence in other key cellular events such as T cell polarization in RA risk. Improving our general understanding of the mechanisms which lead to RA will help identify targets for prevention trials, which are underway in at-risk populations. Herein, we review the modifiable risk factors that are linked to RA development and describe immune mechanisms that may be involved. We highlight the few studies that have sought to understand if modification of these risk factors reduces RA risk. Finally, we speculate that modification of risk factors may be an appealing avenue for prevention for some at-risk individuals, specifically those who prefer lifestyle interventions due to safety and economic reasons.

Epigenome-wide methylation haplotype association analysis identified HLA-DRB1, HLA-DRB5 and HLA-DQB1 as risk factors for rheumatoid arthritis.

The aim of this study was to compare nonrandom associations between physically adjacent single methylation polymorphism loci among rheumatoid arthritis (RA) and normal subjects for investigating RA-risk methylation haplotypes (meplotype). With 354 ACPA-positive RA patients and 335 normal controls selected from a case-control study based on Swedish population, we conducted the first RA epigenome-wide meplotype association study using our software EWAS2.0, mainly including (i) converted the β value to methylation genotype (menotype) data, (ii) identified methylation disequilibrium (MD) block, (iii) calculated frequent of each meplotypes in MD block and performed case-control association test and (iv) screened for RA-risk meplotypes by odd ratio (OR) and p-values. Ultimately, 545 meplotypes on 334 MD blocks were identified significantly associated with RA (p-value<.05). These meplotypes were mapped to 329 candidate genes related to RA. Subsequently, combined with gene optimization, eight RA-risk meplotypes were identified on three risk genes: HLA-DRB1, HLA-DRB5 and HLA-DQB1. Our results reported the relationship between DNA methylation pattern on HLA-DQB1 and the risk of RA for the first time, demonstrating the co-demethylation of 'cg22984282' and 'cg13423887' on HLA-DQB1 gene (meplotype UU, p-value=2.90E-6, OR=1.68, 95% CI=[1.35, 2.10]) may increase the risk of RA. Our results demonstrates the potential of methylation haplotype analysis to identify RA-related genes from a new perspective and its applicability to the study of other disease.

High-Sucrose Diet Accelerates Arthritis Progression in a Collagen-Induced Rheumatoid Arthritis Model.

High dietary sugar and sweeteners are suspected to cause the development of rheumatoid arthritis (RA) symptoms through the induction of proinflammatory cytokine release. However, the mechanisms by which increased dietary sugar affects RA etiology are not yet fully understood. The study uses a mouse model of collagen-induced RA (CIA) to investigate the relationship between excessive sugar consumption and RA risk. RA-associated pathological features are assessed in the nonimmunized (NI) control group, the CIA-positive control group, and the CIA + high-sucrose diet (CIA+HS, 63% calories from sucrose) group. Compared with the CIA group, the CIA+HS group shows a greater increase in paw thickness and clinical scores, as well as, a higher degree of pannus formation and inflammation in the knee, ankle, and sole tissues. Moreover, the infiltration of immune cells is increased in the CIA+HS group. Although the expression of hepatic lipogenic genes, is not altered, that of toll-like receptor (TLR4) and IL-1β is considerably elevated in the CIA+HS group. These findings suggest that excessive sucrose consumption causes hepatic fibrosis and inflammation, contributing to the pathophysiology of RA.

Investigation of VEGF (rs 699947) polymorphism in the progression of Rheumatoid Arthritis (RA) and in-silico nanoparticle drug delivery of potential phytochemicals to cure RA.

Mutation in the VEGF gene disturbs the production of chondrocytes and angiogenesis which are essential for cartilage health. Cytokines and chemokines produced by auto-activation of B-cells degrade cartilage. Bruton's Tyrosine Kinase (BTK) plays a crucial role in the activation of these B-cells. VEGF has a central part in angiogenesis, in the recruitment of endothelial cells, and is involved in mechanisms that result in tumour formation. The objective of this research is to investigate the potential role of VEGF polymorphism in the development of Rheumatoid Arthritis (RA) and the screening of potential natural, synthetic BTK inhibitor compounds as possible in-silico chemotherapeutic agents to control auto-activation of B-cells and cartilage degrading cytokines. In this study, it had been shown that allele A frequency was significantly higher than that of allele C in RA-positive patients as compared to controls. Hence it depicts that allele A of VEGF (rs699947) can increase the risk of RA while allele C has a protective role. The phytochemicals which showed maximum binding affinity at the inhibitory site of BTK include beta boswellic acid, tanshinone, and baicalin. These phytochemicals as BTK inhibitor give insights to use them as anti-arthritic compounds by nanoparticle drug delivery mechanism.

Genetic polymorphisms of rs73620203 in the transforming growth interacting factor gene associated with rheumatoid arthritis in a Chinese population

ObjectiveTo explore the association of single nucleotide polymorphisms (SNPs) in the transforming growth interacting factor (TGIF) gene with bone metabolism markers and rheumatoid arthritis (RA) susceptibility. MethodsThree SNPs were genotyped in 155 RA patients and 168 healthy controls using high-resolution melting (HRM) analysis. The serum levels of osteocalcin, bone alkaline phosphatase (BALP), and β type I collagen-crosslinked C telopeptide (β-CTX) were detected using electrochemical luminescence in 108 patients randomly selected from the RA group. ResultsGenotype and allele frequency analysis showed that rs73620203 was associated with bone erosion in RA (P = 0.012 and P = 0.003, respectively), and individuals carrying the T allele for rs73620203 showed a decreased RA risk (OR = 0.59, 95% CI = 0.42–0.84; P = 0.003). In sex-specific analysis, the rs73620203 polymorphism was associated with susceptibility to RA in women (P = 0.022 and P = 0.006, respectively). In addition, RA patients with three genotypes at the rs73620203 locus showed significant differences in serum osteocalcin and BALP (P = 0.006 and P = 0.037, respectively). Haplotype analysis revealed that the haploid ATG and GCA frequencies were significantly lower in the RA group (P = 0.036, OR = 0.693; P = 0.002, OR = 0.189, respectively), while the haploid ACA frequency of the RA group was enhanced (P < 0.01, OR = 5.058). ConclusionOur study provides the first evidence that rs73620203 is associated with RA susceptibility and the relationship between TGIF gene SNPs and the regulation of bone metabolism in RA patients.

Association of integrin-β2 polymorphism and expression with the risk of rheumatoid arthritis and osteoarthritis in Egyptian patients

BackgroundThe genetic architecture of rheumatoid arthritis (RA) and osteoarthritis (OA) are still unclear. Although RA and OA have quite different causes, they share synovial inflammation, risk factors, and some disease-associated genes, including the integrin subunit β2 (ITGB2)/CD18 gene involved in extracellular matrix interactions and immune cell signaling. However, the functional role of ITGB2 genetic variants, its circulating expression pattern, and their clinical usefulness in RA and OA remain unexplored. Our study appraised the association of ITGB2 rs2070946 single nucleotide polymorphism with the vulnerability to RA and OA and its influence on ITGB2 mRNA expression, along with the potential of serum ITGB2 expression in RA and OA diagnosis.MethodsThis study included 70 RA patients, 70 primary OA patients, and 60 healthy volunteers. Genotyping and gene expression analysis were performed using qPCR. Bioinformatics analysis was employed to construct the protein-protein interaction (PPI) network of ITGB2.ResultsSerum ITGB2 mRNA expression was upregulated in both RA and OA compared to healthy controls. ITGB2 rs2070946 was associated with escalating risk of both diseases. RA patients harboring the rs2070946 CC or TC + CC genotypes had higher serum ITGB2 expression than the TT genotype carriers. Likewise, OA patients having the minor homozygote CC genotype had higher serum ITGB2 expression than those carrying the TT, TC or TT + TC genotypes. Serum ITGB2 expression showed profound diagnostic potential for RA and OA in receiver-operating characteristic analysis. In RA, serum ITGB2 expression positively correlated with rheumatoid factor and disease activity score 28 (DAS28). The ITGB2-PPI network enriched in cell-cell adhesion, ICAM-3 receptor activity, T-cell activation, leukocyte adhesion, complement binding, and NF-κB, tumor necrosis factor, and interleukin signaling pathways.ConclusionThese findings embrace the impact of ITGB2 rs2070946 as a novel genetic biomarker of both RA and OA, which could alter the ITGB2 expression. Serum ITGB2 expression could aid in timely diagnosis of RA and OA.

The Association of Human Leukocyte Antigen Genotyping Among Sudanese Patients With Rheumatoid Arthritis: Reference to Ethnicity.

Human leukocyte antigens (HLA) account for up to one-half of the total genetic contribution to rheumatoid arthritis (RA) risk. The study investigated the association of HLA class II genotyping with RA susceptibility in Sudanese ethnic groups. The DRB1 and DQB1 alleles and haplotypes were determined in 122 RA patients (i.e., Gaalia = 54, Johayna = 24, Baggara = 17, Nile Nubian = 12, and others = 15) and 120 healthy controls ofethnic groups (i.e., Gaalia = 44, Johayna = 11, Baggara = 15, Nile Nubian = 9, and others = 21) using a polymerase chain reaction with sequence-specific primers method. Susceptibility to RA was associated with a high frequency of DRB1*04(P = 0.04), DRB1*10(P = 0.04), and DQB1*03(P= 2.2 x 10-8/Pc = 6.6 x 10-8) between study ethnic groups, while protective effects were shown with DRB1*07(P= 0.01), DQB1*02(P= 0.02), andDQB1*06(P= 2.2 x 10-6/Pc= 6.6 x 10-6), with an inconsistent frequency between study ethnic groups.The HLA haplotypes that were high in frequency among RA ethnic groups and showed susceptibility associations were DRB1*03-DQB1*03,DRB1*04-DQB1*03,DRB1*08-DQB1*03, DRB1*13-DQB1*02,and DRB1*13-DQB1*03 (P= 0.00003/Pc = 0.0003,P= 0.0001/Pc= 0.0001,P= 0.03, P= 0.004/Pc= 0.03, and P= 3.79x10-8/Pc= 3.3x10-9,respectively). On the contrary, DRB1*03-DQB1*02,DRB1*07-DQB1*02, andDRB1*13-DQB1*06 were lower in frequency in the ethnic groups with RA and may confer protection (P= 0.004/Pc= 0.032,P= 0.002/Pc= 0.02, and P= 0.01, respectively). Our findings indicate an association between HLA-DRB1 and DQB1 genotypes and the susceptibility to RA in the Sudanese population, with a moderate frequency between our ethnic groups.

Causal effects of specific gut microbiota on musculoskeletal diseases: a bidirectional two-sample Mendelian randomization study.

Recent observational studies and clinical trials demonstrated an association between gut microbiota and musculoskeletal (MSK) diseases. Nonetheless, whether the gut microbiota composition has a causal effect on the risk of MSK diseases remains unclear. Based on large-scale genome-wide association studies (GWAS), we performed a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between gut microbiota and six MSK diseases, namely osteoporosis (OP), fracture, sarcopenia, low back pain (LBP), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). Instrumental variables for 211 gut microbiota taxa were obtained from the largest available GWAS meta-analysis (n = 18,340) conducted by the MiBioGen consortium. And the summary-level data for six MSK diseases were derived from published GWAS. The inverse-variance weighted (IVW) method was conducted as a primary analysis to estimate the causal effect, and the robustness of the results was tested via sensitivity analyses using multiple methods. The Bonferroni-corrected test was used to determine the strength of the causal relationship between gut microbiota and various MSK diseases. Finally, a reverse MR analysis was applied to evaluate reverse causality. According to the IVW method, we found 57 suggestive causal relationships and 3 significant causal relationships between gut microbiota and MSK diseases. Among them, Genus Bifidobacterium (β: 0.035, 95% CI: 0.013-0.058, p = 0.0002) was associated with increased left handgrip strength, Genus Oxalobacter (OR: 1.151, 95% CI: 1.065-1.245, p = 0.0003) was correlated with an increased risk of LBP, and Family Oxalobacteraceae (OR: 0.792, 95% CI: 0.698-0.899, p = 0.0003) was linked with a decreased risk of RA. Subsequently, sensitivity analyses revealed no heterogeneity, directional pleiotropy, or outliers for the causal effect of specific gut microbiota on MSK diseases (p > 0.05). Reverse MR analysis showed fracture may result in a higher abundance of Family Bacteroidales (p = 0.030) and sarcopenia may lead to a higher abundance of Genus Sellimonas (p = 0.032). Genetic evidence suggested a causal relationship between specific bacteria taxa and six MSK diseases, which highlights the association of the "gut-bone/muscle" axis. Further exploration of the potential microbiota-related mechanisms of bone and muscle metabolism might provide novel insights into the prevention and treatment of MSK diseases.

Mendelian randomization to evaluate the causal relationship between liver enzymes and the risk of six specific bone and joint-related diseases.

Studies of liver dysfunction in relation to bone and joint-related diseases are scarce, and its causality remains unclear. Our objective was to investigate whether serum liver enzymes are causally associated with bone and joint-related diseases using Mendelian randomization (MR) designs. Genetic data on serum liver enzymes (alkaline phosphatase (ALP); alanine transaminase (ALT); gamma-glutamyl transferase (GGT)) and six common bone and joint-related diseases (rheumatoid arthritis (RA), osteoporosis, osteoarthritis (OA), ankylosing spondylitis, psoriatic arthritis, and gout) were derived from independent genome-wide association studies of European ancestry. The inverse variance-weighted (IVW) method was applied for the main causal estimate. Complementary sensitivity analyses and reverse causal analyses were utilized to confirm the robustness of the results. Using the IVW method, the positive causality between ALP and the risk of osteoporosis diagnosed by bone mineral density (BMD) at different sites was indicated (femoral neck, lumbar spine, and total body BMD, odds ratio (OR) [95% CI], 0.40 [0.23-0.69], 0.35 [0.19-0.67], and 0.33 [0.22-0.51], respectively). ALP was also linked to a higher risk of RA (OR [95% CI], 6.26 [1.69-23.51]). Evidence of potential harmful effects of higher levels of ALT on the risk of hip and knee OA was acquired (OR [95% CI], 2.48 [1.39-4.41] and 3.07 [1.49-6.30], respectively). No causal relationship was observed between GGT and these bone and joint-related diseases. The study also found that BMD were all negatively linked to ALP levels (OR [95% CI] for TBMD, FN-BMD, and LS-BMD: 0.993 [0.991-0.995], 0.993 [0.988-0.998], and 0.993 [0.989, 0.998], respectively) in the reverse causal analysis. The results were replicated via sensitivity analysis in the validation process. Our study revealed a significant association between liver function and bone and joint-related diseases.

Causal relationship between PCSK9 inhibitor and autoimmune diseases: a drug target Mendelian randomization study

BackgroundIn addition to decreasing the level of cholesterol, proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has pleiotropic effects, including immune regulation. However, the impact of PCSK9 on autoimmune diseases is controversial. Therefore, we used drug target Mendelian randomization (MR) analysis to investigate the effect of PCSK9 inhibitor on different autoimmune diseases.MethodsWe collected single nucleotide polymorphisms (SNPs) of PCSK9 from published genome-wide association studies statistics and conducted drug target MR analysis to detect the causal relationship between PCSK9 inhibitor and the risk of autoimmune diseases. 3-Hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitor, the drug target of statin, was used to compare the effect with that of PCSK9 inhibitor. With the risk of coronary heart disease as a positive control, primary outcomes included the risk of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), myasthenia gravis (MG), multiple sclerosis (MS), asthma, Crohn’s disease (CD), ulcerative colitis (UC), and type 1 diabetes (T1D).ResultsPCSK9 inhibitor significantly reduced the risk of SLE (OR [95%CI] = 0.47 [0.30 to 0.76], p = 1.74 × 10−3) but increased the risk of asthma (OR [95%CI] = 1.15 [1.03 to 1.29], p = 1.68 × 10−2) and CD (OR [95%CI] = 1.38 [1.05 to 1.83], p = 2.28 × 10−2). In contrast, HMGCR inhibitor increased the risk of RA (OR [95%CI] = 1.58 [1.19 to 2.11], p = 1.67 × 10−3), asthma (OR [95%CI] = 1.21 [1.04 to 1.40], p = 1.17 × 10−2), and CD (OR [95%CI] = 1.60 [1.08 to 2.39], p = 2.04 × 10−2).ConclusionsPCSK9 inhibitor significantly reduced the risk of SLE but increased the risk of asthma and CD. In contrast, HMGCR inhibitor may be a risk factor for RA, asthma, and CD.

Gene-respiratory disease interactions for rheumatoid arthritis risk

ObjectiveWe aimed to identify gene by respiratory tract disease interactions that increase RA risk. MethodsIn this case-control study using the Mass General Brigham Biobank, we matched incident RA cases, confirmed by ACR/EULAR criteria, to four controls on age, sex, and electronic health record history. Genetic exposures included a validated overall genetic risk score (GRS) for RA, a Human Leukocyte Antigen (HLA) GRS for RA, and the MUC5B promoter variant, an established risk factor for RA-associated interstitial lung disease (ILD). Preceding respiratory tract diseases came from diagnosis codes (positive predictive value 86%). We estimated attributable proportions (AP) and multiplicative odds ratios (OR) with 95% confidence intervals (CI) for RA for each genetic and respiratory exposure using conditional logistic regression models, adjusting for potential confounders. ResultsWe identified 653 incident RA cases and 2,607 matched controls (mean 54 years, 76% female). The highest tertile of the overall GRS and the HLA GRS were both associated with increased RA risk (OR 2.28, 95% CI 1.89,2.74; OR 2.02, 95% CI 1.67–2.45). ILD and the HLA GRS exhibited a synergistic relationship for RA risk (OR for both exposures 4.30, 95% CI 1.28,14.38; AP 0.51, 95% CI-0.16,1.18). Asthma and the MUC5B promoter variant also exhibited a synergistic interaction for seropositive RA (OR for both exposures 2.58, 95% CI 1.10,6.07; AP 0.62, 95% CI 0.24,1.00). ConclusionILD-HLA GRS and asthma-MUC5B promoter variant showed synergistic interactions for RA risk. Such interactions may prove useful for RA prevention and screening.

Comparison of the cardiovascular risk profile of rheumatoid arthritis versus hand osteoarthritis patients.

It is clear that there is an increased cardiovascular (CV) risk in rheumatoid arthritis (RA) as a result of systemic inflammation. Hand osteoarthritis (HOA) patients, also have an increased CV risk, but the causes are still debated. Our objective was to compare CV risk factors and risk scores between HOA and RA patients. Thirty-five HOA patients were matched by age (< 3years) and sex to 35 RA patients in a case-control study. We compared their CV risk profiles and their risk of occurrence of CV events at 10years using the risk equations SCORE1, SCORE2, and QRISK3. There was a significant increase in SCORE1, SCORE2, but not in QRISK3 in the RA group compared to the HOA group, provided that the multiplication coefficient for RA was applied. This increase was found to no longer be significant for SCORE1 when RA patients have low disease activity (DAS28 ≤ 3.2; n = 8). There was no difference between groups in the frequency of metabolic syndrome, blood pressure, abdominal circumference, body mass index, uricemia, triglyceridemia, HDL cholesterolemia, or pain intensity. Conversely, HOA patients had higher LDL cholesterol and fasting blood glucose levels, in the main analysis and in the subgroup of moderate/high RA activity patients (DAS28 > 3.2; n = 26). We found a higher CV risk in RA compared to HOA patients with moderate/high disease activity. The increased CV risk reported in OA remains to be confirmed in HOA, but these patients appear to have a pro-atherogenic lipid and glycemic profile.