Causal associations between rheumatoid arthritis, cataract and glaucoma in European and East Asian populations: A bidirectional two-sample mendelian randomization study
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ABSTRACT:
SUBMITTER: Teng M
PROVIDER: S-EPMC10911615 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Previous studies have been reported that the association between rheumatoid arthritis (RA) and breast cancer remains inconclusive. A two-sample Mendelian randomization (MR) analysis can reveal the potential causal association between exposure and outcome. A two-sample MR analysis using the penalized robust inverse variance weighted (PRIVW) method was performed to analyze the association between RA and breast cancer risk based on the summary statistics of six genome-wide association studies (GWAS) targeting RA in an East Asian population along with summary statistics of the BioBank Japan (BBJ), Breast Cancer Association Consortium (BCAC), and Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) targeting breast cancer. We found that the direction of the effect of RA on breast cancer varied among GWAS-summary data from BBJ, BCAC, and CIMBA. Significant horizontal pleiotropy based on a penalized robust MR-Egger regression was observed only for BBJ and CIMBA BRCA2 carriers. As the results of the two-sample MR analyses were inconsistent, the causal association between RA and breast cancer was inconclusive. The biological mechanisms explaining the relationship between RA and breast cancer were unclear in Asian as well as in Caucasians. Further studies using large-scale patient cohorts are required for the validation of these results.
| S-EPMC7694331 | 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: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:Background: Hepatocellular carcinoma (HCC) is a primary malignant liver tumor characterized by a low survival rate and high mortality. This study aimed to investigate the causal effect of immune cell phenotypes, plasma metabolites, and HCC in East Asian populations. Methods: The summary results for 731 immunocytes, 1400 plasma metabolites, and HCCs were acquired from publicly available genome-wide association studies (GWASs). This study utilized two-sample Mendelian randomization (MR) analysis to establish causal relationships, which was achieved by employing various statistical methods including inverse variance-weighted, simple mode, MR-Egger, weighted median, and weighted mode. Multiple sensitivity analyses were conducted to confirm the reliability of the MR data. Ultimately, mediation analysis was employed to ascertain the path that leads from immunocytes to plasma metabolites. Results: Among the 20 immune cells and HCC for East Asians, causal links were found, with one showing an inverse correlation. In addition, 36 metabolites were significantly associated with HCC for East Asians. Through analysis of established causative metabolites, we identified a strong correlation between the glycerophospholipid metabolic pathway and HCC for East Asians. By employing a two-step MR analysis, we identified 11 immunocytes that are causally linked to HCC for East Asians through the mediation of 14 plasma metabolites, with Linolenate [α or γ; (18:3n3 or 6)] levels showing the highest mediation proportion (19.3%). Conclusions: Our findings affirm the causal links among immunocytes, plasma metabolites, and HCC in eastern Asia populations by calculating the percentage of the impact that is influenced by plasma metabolites. This study offers innovative perspectives on the early detection, diagnosis, and therapy of HCC.
| S-EPMC11431556 | 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
Project description:Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation in synovial joints and influenced by genetic and environmental factors. The immune system, comprising various cells that either exacerbate or reduce inflammation, plays a central role in RA pathogenesis. Despite extensive research, the causal relationships between immune cell phenotypes and RA remain unclear. We employed a two-sample Mendelian randomization (MR) approach to investigate the causal associations between 731 immune cell phenotypes and RA. Genetic variants, carefully selected based on rigorous criteria, served as instrumental variables to ensure analytical validity. Data on RA were derived from the FinnGen database, whereas immune cell phenotype data were obtained from the genome-wide association studies catalog. We employed 5 MR methods, including inverse variance weighted and MR Egger, to ensure robust causal inference. We assessed for pleiotropy and heterogeneity and adjusted findings using the False Discovery Rate. After False Discovery Rate adjustment (threshold < 0.05), inverse variance weighted analysis revealed potential causal relationships between 4 immune cell types and RA: CD62L- dendritic cells %dendritic cells (P = 3.88E-05; 95% confidence interval [CI] = 1.056), CD19 on IgD+ CD38- naive cells (P = 1.75E-04; 95% CI = 0.969), CD45RA on TD CD8br (P = 5.59E-04; 95% CI = 0.919), and HLA DR on CD33- HLA DR+ (P = 8.13E-05; 95% CI = 1.422). In reverse Mendelian studies, specific immune cell phenotypes were found to be associated with RA risk and progression: the percentage of memory B cells among lymphocytes (P = 2.74E-04; 95% CI = 0.861), IgD+ CD24+ cells among lymphocytes (P = 6.93E-04; 95% CI = 0.867), CD4+ CD8dim cells among lymphocytes (P = 2.92E-04; 95% CI = 0.802), CD4+ CD8dim cells among leukocytes (P = 4.37E-04; 95% CI = 0.814), and CD24 expression on IgD+CD24+ cells (P = 1.05E-04; 95% CI = 0.857). These results identify immune cell phenotypes closely linked to RA susceptibility and progression. The findings suggest that specific immune cell phenotypes are not only influenced by RA but may also contribute to its development and progression. These results offer new insights into the immunological underpinnings of RA and highlight potential targets for therapeutic intervention. Future research should focus on validating these causal relationships in diverse populations and exploring the molecular mechanisms involved.
| S-EPMC11813058 | biostudies-literature
Project description:Background: Glaucoma is a leading cause of blindness strongly associated with psychiatric disorders, but the causal association between glaucoma and psychiatric disorders remains uncertain because of the susceptibility of observational studies to confounding and reverse causation. This study aims to explore the potential causal association between glaucoma and three highly related psychiatric disorders (Depression, Insomnia, and Schizophrenia) in the European and East Asian populations using a two-sample Mendelian randomization analysis. Methods: Instrumental variables (IVs) of depression, insomnia, and schizophrenia in the European population were obtained after strict filtering. Summary-level data for glaucoma and glaucoma subtypes (primary open-angle glaucoma and primary closed-angle glaucoma) were obtained as outcomes. The inverse variance weighting (IVW) method was used as the primary method. Additionally, the causal effect was evaluated in the East Asian population using the same methods to validate analysis results. The robustness of these results was confirmed using heterogeneity, pleiotropy, and Steiger directionality test. Results: The primary MR results indicated that genetically driven psychiatric disorders were not causally associated with glaucoma (Depression: odds ratio (OR): 1.15, 95% confidence interval (CI): 0.93-1.42, p = 0.20; Insomnia: OR: 1.14, 95% CI: 0.63-2.05, p = 0.66; Schizophrenia: OR: 1.00, 95% CI: 0.93-1.08, p = 0.95), either with the risk of glaucoma subtypes in the European population. Meanwhile, results in the East Asian population were consistent with the results among the European population (Depression: OR = 1.38, CI 0.75-2.53, p = 0.30; Insomnia: OR = 0.99, CI 0.83-1.18, p = 0.93; Schizophrenia: OR = 1.06, CI 0.94-1.20, p = 0.34) with similar causal estimates in direction. Consistency was obtained by corroborating with other supporting methods. Besides, the robustness of the results was proved and the directionality test confirmed our estimation of potential causal direction (p < 0.001). Conclusion: This study found a non-causal association between psychiatric disorders and the risk of glaucoma in the European and East Asian populations, which contradicts many existing observational reports, indicating that increased psychiatric disorders in glaucoma patients were more likely modifiable rather not inheritable.
| S-EPMC10954835 | biostudies-literature
Project description:Background: Rheumatoid arthritis (RA) is associated with diverse extra-articular manifestations, including interstitial lung disease (ILD). No previous studies have examined the bidirectional relationship between RA and ILD using the Mendelian randomization (MR) analyses. Therefore, we aimed to investigate this subject using a two-sample bidirectional MR method. Methods: We performed bidirectional two-sample MR using summary statistics from genome-wide association studies (GWASs). The data are publicly available, de-identified, and from European (EUR) and East Asian (EAS) ancestries. Results: A total of 474,450 EUR participants and 351,653 EAS participants were included for either forward or reverse MR analysis. In our primary analysis, we found significant evidence of an increased risk of ILD associated with RA among individuals of EUR ancestry (ORMR-cML = 1.08; 95% confidence interval [CI] = 1.03-1.14; p = 0.003) and EAS ancestry (ORMR-cML = 1.37; 95% CI = 1.23-1.54; p < 0.001). Additionally, the reverse MR showed significant evidence of an increased risk of RA associated with ILD among those of EUR ancestry (ORMR-cML = 1.12; 95% CI = 1.05-1.19; p < 0.001). However, only one instrumental variable was selected in the EAS ILD GWAS, and there was no increased risk of RA associated with ILD in those of EAS ancestry (ORMR-cML = 1.02; 95% CI = 0.91-1.14; p = 0.740). Conclusions: Our findings indicate that RA and ILD have a bidirectional causal inference when using the MR analysis of GWAS datasets. The findings are only relevant for genetic predisposition; thus, further research is needed to determine the impact of non-genetic predispositions.
| S-EPMC11508725 | biostudies-literature
Project description:BackgroundRheumatoid arthritis (RA) has been associated with atrial fibrillation (AF) in observational studies, yet the causal relationship remains elusive. In this study, we employed Mendelian randomization (MR) to investigate the impact of RA on AF risk specifically in East Asian populations.MethodsUtilizing genome-wide association study (GWAS) data on RA (n = 212,453) and AF (n = 36,792), we applied the following five MR methods: inverse variance weighted (IVW), MR-RAPS, maximum likelihood, weighted median (WM), and Bayesian weighted Mendelian randomization (BWMR). We evaluated heterogeneity, sensitivity, and pleiotropy.ResultsFive genetic instrumental variants for RA were identified. All MR methods consistently indicated a causal association between RA and AF (IVW: OR = 1.20, 95% CI: 1.01-1.41, p < 0.03; MR-RAPS: OR = 1.21, 95% CI: 1.03-1.42, p < 0.02; maximum likelihood: OR = 1.20, 95% CI: 1.04-1.39, p < 0.01; WM: OR = 1.25, 95% CI: 1.03-1.52, p < 0.03; and BWMR: OR = 1.20, 95% CI: 1.02-1.42, p < 0.03). Sensitivity and pleiotropy analyses confirmed the robustness and validity of the results.ConclusionsThis study establishes a causal link between RA and AF in East Asians. Our results underscore the need for in-depth mechanistic investigations to unravel the underlying pathways. Clinicians should consider AF risk in RA management, emphasizing collaborative care between rheumatologists and cardiologists. Moving forward, future research should explore therapeutic interventions and address the shared biological mechanisms.
| S-EPMC11262875 | biostudies-literature
Project description:ObjectiveTo investigate the causal relationship between rheumatoid arthritis (RA) and pregnancy loss and intrauterine growth retardation (IUGR) using Mendelian randomization (MR).MethodsGenetic variants associated with RA (12,555 cases and 240,862 controls), miscarriage (1475 cases and 149,622 controls), and IUGR (3558 cases and 207,312 controls) were obtained from the FinnGen consortium, and supplementary data on RA (5201 cases and 457,732 controls) and miscarriage (7069 cases and 250,492 controls) were obtained from the Medical Research Council Integrated Epidemiology Unit (MRC-IEU). 47 Single nucleotide polymorphisms (SNPs) associated with RA were screened as instrumental variables (IV). The causal relationship between RA and pregnancy loss and IUGR were assessed by 5 MR methods, mainly inverse variance weighting (IVW). Sensitivity analyses were also performed to test the stability of the results.ResultsBidirectional MR showed that genetically predicted RA was causally associated with pregnancy loss and IUGR in forward MR analyses, and that RA significantly increased pregnancy loss [odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.00-1.33, P = .03] and IUGR (OR = 1.08, 95% CI: 1.01-1.15, P = .019). In the reverse MR, there was no causal association between pregnancy loss (P = .15) and IUGR (P = .87) and RA.ConclusionThis study found a significant genetic association between RA and pregnancy loss and IUGR. RA is considered to be a high-risk factor for adverse maternal outcomes. Pre-pregnancy prophylaxis and intra-pregnancy control of patients should be emphasized to reduce the incidence of adverse pregnancy outcomes such as pregnancy loss and IUGR.
| S-EPMC10783369 | biostudies-literature