Rheumatoid arthritis increases the risk of malignant neoplasm of bone and articular cartilage: a two-sample bidirectional mendelian randomization study
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SUBMITTER: Yang M
PROVIDER: S-EPMC10642064 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:ObjectivePrevious research has demonstrated that metabolites play a significant role in modulating disease phenotypes; nevertheless, the causal association between metabolites and malignant malignancies of bones and joint cartilage (MNBAC)has not been fully elucidated.MethodsThis study used two-sample Mendelian randomization (MR) to explore the causal correlation between 1,400 metabolites and MNBAC. Data from recent genome-wide association studies (GWAS) involving 8,299 individuals were summarized. The GWAS summary data for metabolites were acquired from the IEU Open GWAS database, while those for MNBAC were contributed by the Finnish Consortium. We employed eight distinct MR methodologies: simple mode, maximum likelihood estimator, MR robust adjusted profile score, MR-Egger, weighted mode, weighted median, MR-PRESSO and inverse variance weighted to scrutinize the causal association between metabolites engendered by each gene and MNBAC. Consequently, we evaluated outliers, horizontal pleiotropy, heterogeneity, the impact of single nucleotide polymorphisms (SNPs), and adherence to the normal distribution assumption in the MR analysis.ResultsOur findings suggested a plausible causative relationship between N-Formylmethionine (FMet) levels, lignoceroylcarnitine (C24) levels, and MNBAC. We observed a nearly significant causal association between FMet levels and MNBAC within the cohort of 1,400 metabolites (P = 0.024, odds ratio (OR) = 3.22; 95% CI [1.16-8.92]). Moreover, we ascertained a significant causal link between levels of C24 and MNBAC (P = 0.0009; OR = 0.420; 95%CI [0.25-0.70]). These results indicate a potential causative relationship between FMet, C24 level and MNBAC.ConclusionThe occurrence of MNBAC may be causally related to metabolites. This might unveil new possibilities for investigating early detection and treatment of MNBAC.
| S-EPMC11911353 | biostudies-literature
Project description:There is growing evidence of bidirectional associations between rheumatoid arthritis and adverse pregnancy outcomes (APOs) in observational studies, but little is known about the causal direction of these associations. Therefore, we explored the potential causal relationships between rheumatoid arthritis and APOs using a bidirectional two-sample Mendelian randomization (MR) in European and Asian populations. We conducted a bidirectional two-sample Mendelian randomization analysis using available summary statistics from released genome-wide association studies. Summary statistics for instrument-outcome associations were retrieved from two separate databases for rheumatoid arthritis and adverse pregnancy outcomes, respectively. The inverse-variance weighted method was used as the primary MR analysis, and cML-MA-BIC was used as the supplementary analysis. MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and Cochran Q statistic method were implemented as sensitivity analyses approach to ensure the robustness of the results. Our study showed that a higher risk of rheumatoid arthritis in the European population was associated with gestational hypertension (OR: 1.04, 95%CI: 1.02-1.06), pre-eclampsia (OR: 1.06, 95%CI: 1.01-1.11), fetal growth restriction (OR: 1.08, 95%CI: 1.04-1.12), preterm delivery (OR:1.04, 95%CI: 1.01-1.07). Furthermore, we found no evidence that APOs had causal effects on rheumatoid arthritis in the reverse MR analysis. No association between rheumatoid arthritis and APOs was found in East Asian population. There was no heterogeneity or horizontal pleiotropy. This MR analysis provides the positive causal association from rheumatoid arthritis to gestational hypertension, pre-eclampsia, fetal growth restriction and preterm delivery genetically. It highlights the importance of more intensive prenatal care and early intervention among pregnant women with rheumatoid arthritis to prevent potential adverse obstetric outcomes.
| S-EPMC11293129 | biostudies-literature
Project description:BackgroundEpidemiological evidence suggests an association between rheumatoid arthritis (RA) and myocardial infarction (MI). However, causality remains uncertain. Therefore, this study aimed to explore the causal association between RA and MI.MethodsUsing publicly available genome-wide association study summary datasets, bidirectional two-sample Mendelian randomization (TSMR) was performed using inverse-variance weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode methods.ResultsThe MR results for the causal effect of RA on MI (IVW, odds ratio [OR] = 1.041, 95% confidence interval [CI]: 1.007-1.076, P = 0.017; weighted median, OR = 1.027, 95% CI: 1.006-1.049, P = 0.012) supported a causal association between genetic susceptibility to RA and an increased risk of MI. MR results for the causal effect of MI on RA (IVW, OR = 1.012, 95% CI: 0.807-1.268, P = 0.921; weighted median, OR = 1.069, 95% CI: 0.855-1.338, P = 0.556) indicated that there was no causal association between genetic susceptibility to MI and an increased risk of RA.ConclusionBidirectional TSMR analysis supports a causal association between genetic susceptibility to RA and an increased risk of MI but does not support a causal association between genetic susceptibility to MI and an increased risk of RA.
| S-EPMC9755576 | biostudies-literature
Project description:Object Though significant correlations between rheumatoid arthritis (RA) and hypothyroidism have been found in earlier observational studies, their underlying causal relationship is still unknown. Mendelian randomization (MR) was used in the current study to assess the bidirectional causation between RA and hypothyroidism. Method We gathered summary data from genome-wide association studies (GWASs) of RA and hypothyroidism in people of European descent. Then, using data from the FinnGen consortium, we replicated our findings. Three approaches were employed to assess the causal link between RA and hypothyroidism: MR-Egger, weighted median (WM), and inverse variance weighted (IVW). The pleiotropy and heterogeneity were examined using a variety of techniques, including the MR-Egger intercept, the MR-PRESSO approach, the leave-one-out method, and the Cochran’s Q test. Results The study looked at a bidirectional incidental relationship between RA and hypothyroidism. The risk of hypothyroidism increased with RA (IVW odds ratio (OR) = 1.28, 95% confidence interval (CI) = 1.18–1.39, P = 8.30E-10), as did the risk of secondary hypothyroidism (IVW OR = 1.12, 95% CI = 1.05–1.21, P = 9.64E-4). The results of reverse MR analysis revealed that hypothyroidism (IVW OR = 1.68, 95% CI = 1.51–1.88, P = 4.87E-21) and secondary hypothyroidism (IVW OR = 1.74, 95% CI = 1.50–2.01, P = 1.91E-13) were linked to an increased risk of RA. Additionally, we obtain the same results in the duplicated datasets as well, which makes our results even more reliable. This study revealed no evidence of horizontal pleiotropy. Conclusion The present study established a bidirectional causal link between RA and hypothyroidism. However, it differs slightly from the findings of prior observational studies, suggesting that future research should concentrate on the interaction mechanisms between RA and hypothyroidism.
| S-EPMC10433205 | biostudies-literature
Project description: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.
| S-EPMC9623103 | biostudies-literature
Project description:Rheumatoid arthritis (RA) is a common autoimmune disease, and some observational studies have indicated an association between Gastroesophageal Reflux Disease (GERD) and RA. However, the causal relationship between the two remains uncertain. We used Mendelian randomization (MR) to assess the causal relationship between GERD and RA. Two-sample Mendelian randomization analysis was performed using pooled data from large-scale genome-wide association studies. In addition, we performed multivariate MR analyses to exclude confounding factors between GERD and RA, including smoking quantity, drinking frequency, BMI, depression, and education attainment. The MR results for GERD on RA suggested a causal effect of the genetic susceptibility of GERD on RA (discovery dataset, IVW, odds ratio [OR] = 1.41, 95% confidence interval [CI] 1.22-1.63, p = 2.81 × 10-6; validation dataset, IVW, OR = 1.38, 95% CI 1.23-1.55, P = 1.76 × 10-8). Multivariate MR analysis also supports this result. But the results of the reverse MR analysis did not reveal compelling evidence that RA can increase the risk of developing GERD. Our bidirectional Two-Sample Mendelian randomization analysis and multivariate MR analysis provide support for the causal effect of GERD on RA. This discovery could offer new insights for the prevention and treatment of RA.
| S-EPMC11294333 | biostudies-literature
Project description:A correlation between mental illness and systemic rheumatoid arthritis (RA) has been observed in several prior investigations. However, little is known about the causative relationship between them. The present study aimed to systematically investigate the potential association between genetically determined mental illness and RA. Two-sample bidirectional Mendelian randomization (MR) analysis was performed using publicly released genome-wide association studies (GWAS). We selected independent genetic variants associated with four mental illnesses (bipolar disorder, broad depression, major depression, and anxiety) as instrumental variables. The inverse variance weighted (IVW) method was used as the primary analysis to assess the causal relationship between mental illness and RA. Results of the IVW analysis suggested that genetic predisposition to bipolar disorder was associated with a decreased risk of RA (odds ratio [OR] = 0.825, 95% CI = 0.716 to 0.95, p = 0.007). Furthermore, we did not find a significant causal effect of RA on bipolar disorder in the reverse MR analysis (p > 0.05). In addition, our study found no evidence of a bidirectional causal relationship between genetically predicted broad depression, major depression, anxiety, and RA (p > 0.05). The genetically proxied bipolar disorder population has a lower RA risk, which may indicate that there is a hidden mechanism for inhibiting the pathogenesis of RA in bipolar disorder. However, results do not support a causal connection between depression, anxiety, and RA.
| S-EPMC9917759 | biostudies-literature
Project description:BackgroundAlthough there is considerable evidence of a robust correlation between rheumatoid arthritis (RA) and carpal tunnel syndrome (CTS) in previous research, the causal link between the two remains a topic of controversy.MethodsWe conducted a two-sample Mendelian randomization (MR) study to explore the causal impact of RA on CTS. We obtained aggregate data from genome-wide association studies (GWAS) of CTS (ebi database and GEO database) and RA (FinnGen database). This study employed five MR analysis methods, with a focus on the inverse variance-weighted (IVW) method. Sensitivity analyses were conducted to ensure the robustness of the results of this study. Additionally, we performed reverse MR analysis.ResultsWe selected 84 and 78 single nucleotide polymorphisms (SNPs) significantly associated with RA from two databases as instrumental variables (IVs), respectively. Our results showed that RA patients have a higher risk of getting CTS regardless of whether the ebi database (IVW, OR = 1.045, 95% CI: 1.016-1.075, P = 0.002) or the GEO database (IVW, OR = 1.001, 95% CI: 1.001-1.002, P = 0.001) is selected for CTS data. However, the MR analysis showed no causal link between CTS and the increased risk of RA (ebi: IVW, OR = 1.084, 95% CI: 0.918-1.279, P = 0.341; GEO: IVW, OR = 1.968, 95% CI: 0.011-360.791, P = 0.799).ConclusionThe analysis revealed that RA can increase the risk of CTS, but did not support the causal relationship that CTS can increase the risk of RA.
| S-EPMC11441067 | biostudies-literature
Project description:BackgroundThe frequent coexistence of Graves' disease (GD) and rheumatoid arthritis (RA) has been cited and discussed in observational studies, but it remains a question as to whether there is a causal effect between the two diseases.MethodsWe retrieved genome-wide association study (GWAS) summary data of GD and RA from BioBank Japan (BBJ). Single nucleotide polymorphisms (SNPs) associated with diseases of interest were selected as instrumental variables (IVs) at a genome-wide significance level (P < 5.0 × 10-8). The random-effects inverse variance weighted method (IVW) was used to combine the causal effect of IVs. The horizontal pleiotropy effect was analyzed by MR-Egger and weighted median method sensitivity test. A leave-one-out analysis was conducted to avoid bias caused by a single SNP. The statistical power of our MR result was calculated according to Brion's method.ResultsOur study discovered a bidirectional causal effect between GD and RA. The presence of RA may increase the risk of GD by 39% (OR 1.39, 95% CI 1.10-1.75, P = 0.007). Similarly, the existence of GD may increase the risk of RA by 30% (OR 1.30, 95% CI 0.94-1.80, P = 0.112). Our study provides 100% power to detect the causal effect of RA on GD risk, and vice versa.ConclusionsWe found a bidirectional causal effect between GD and RA in an Asian population. Our study supported the clinical need for screening GD in RA patients, and vice versa. The potential benefit of sound management of RA in GD patients (or GD in RA patients) merits excellent attention. Moreover, novel satisfactory medicine for RA may be applicable to GD and such potential is worthy of further investigation.
| S-EPMC8416061 | biostudies-literature
Project description:BackgroundHypothyroidism and hyperthyroidism are observationally associated with rheumatoid arthritis (RA), but causality is unclear. To evaluate the causal relationship between thyroid function and RA, we conducted a two-Sample bidirectional Mendelian Randomization (MR) study.MethodsSingle nucleotide polymorphisms associated with six phenotypes were selected from the FinnGen biobank database, The ThyroidOmics Consortium database, and the IEU Open GWAS database. For the forward MR analysis, we selected hypothyroidism (N=213,390), Graves' disease (GD) (N=199,034), other types of hyperthyroidism (N=190,799), free thyroxine (FT4, N=49,269), and thyroid-stimulating hormone (TSH, N=54,288) as the five related thyroid function phenotypes for exposure, with RA (N=58,284) as the outcome. Reverse MR analysis selected RA as the exposure and five phenotypes of thyroid function as the outcome. The Inverse variance weighting (IVW) method was used as the primary analysis method, supplemented by weighted median (WM) and MR-Egger methods. Cochran's Q test, MR-PRESSO, MR-Egger regression methods, and leave-one-out analysis were employed to assess sensitivity and pleiotropy.ResultsForward MR evidence indicates that genetic susceptibility to hypothyroidism is associated with an increased risk of RA (ORIvw=1.758, P=7.61×10-5). Reverse MR evidence suggests that genetic susceptibility to RA is associated with an increased risk of hypothyroidism (ORIvw=1.274, P=3.88×10-20), GD (ORIvw=1.269, P=8.15×10-05), and other types of hyperthyroidism (ORIvw=1.141, P=1.80×10-03). There is no evidence to support a forward or reverse causal relationship between genetic susceptibility to RA and FT4, TSH.ConclusionOur results provide genetic evidence supporting bidirectional causal relationships between thyroid function and RA. These findings inform preventive strategies and interventions targeting RA and thyroid dysfunction.
| S-EPMC10713877 | biostudies-literature