Rheumatoid arthritis and risk for Alzheimer's disease: a systematic review and meta-analysis and a Mendelian Randomization study.
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ABSTRACT:
SUBMITTER: Policicchio S
PROVIDER: S-EPMC5634412 | biostudies-literature | 2017 Oct
REPOSITORIES: biostudies-literature
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Rheumatoid arthritis and risk for Alzheimer's disease: a systematic review and meta-analysis and a Mendelian Randomization study.
Policicchio Stefania S Ahmad Aminah Noor AN Powell John Francis JF Proitsi Petroula P
Scientific reports 20171009 1
Rheumatoid arthritis (RA) patients have been observed to be at a lower risk of developing Alzheimer's Disease (AD). Clinical trials have showed no relationship between nonsteroidal anti-inflammatory drug (NSAID) use and AD. The aim of this study was to establish if there is a causal link between RA and AD. A systematic literature review on RA incidence and its link to AD was carried out according to the PRISMA guidelines. Eight case-control and two population-based studies were included in a ran ...[more]
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Project description:Alzheimer's disease (AD) is the most common neurodegenerative disease. In recent years, multiple pathway analyses of AD genome-wide association studies (GWAS) have been conducted, and provided strong support for immune pathways in AD. Rheumatoid arthritis (RA) is a chronic autoimmune disease. It is reported that antirheumatic drugs had protective effect on dementia in RA patients. However, observational studies have reported a controversial inverse relationship between AD and RA. In addition, Mendelian randomization studies have also been performed to evaluate the association of RA with AD. However, these studies reported inconsistent association of RA with AD. Until now, it is still unclear that AD is a causally associated with RA. Here, we performed a Mendelian randomization study to investigate the causal association of AD with RA. We analyzed the large-scale AD GWAS dataset (74,046 individuals) and RA GWAS dataset (58,284 individuals) from the European descent. However, we did not identify any significant association of AD with RA using inverse-variance weighted meta-analysis (IVW), weighted median regression and MR-Egger regression.
| S-EPMC6143656 | 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:Significant genetic association exists between rheumatoid arthritis (RA) and cardiovascular disease. The associated mechanisms include common inflammatory mediators, changes in lipoprotein composition and function, immune responses, etc. However, the causality of RA and vascular/heart problems remains unknown. Herein, we performed Mendelian randomization (MR) analysis using a large-scale RA genome-wide association study (GWAS) dataset (462,933 cases and 457,732 controls) and six cardio-cerebrovascular disease GWAS datasets, including age angina (461,880 cases and 447,052 controls), hypertension (461,880 cases and 337,653 controls), age heart attack (10,693 cases and 451,187 controls), abnormalities of heartbeat (461,880 cases and 361,194 controls), stroke (7,055 cases and 454,825 controls), and coronary heart disease (361,194 cases and 351,037 controls) from United Kingdom biobank. We further carried out heterogeneity and sensitivity analyses. We confirmed the causality of RA with age angina (OR = 1.17, 95% CI: 1.04-1.33, p = 1.07E-02), hypertension (OR = 1.45, 95% CI: 1.20-1.75, p = 9.64E-05), age heart attack (OR = 1.15, 95% CI: 1.05-1.26, p = 3.56E-03), abnormalities of heartbeat (OR = 1.07, 95% CI: 1.01-1.12, p = 1.49E-02), stroke (OR = 1.06, 95% CI: 1.01-1.12, p = 2.79E-02), and coronary heart disease (OR = 1.19, 95% CI: 1.01-1.39, p = 3.33E-02), contributing to the understanding of the overlapping genetic mechanisms and therapeutic approaches between RA and cardiovascular disease.
| S-EPMC8567962 | 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:Background Rheumatoid arthritis (RA) and Parkinson's disease (PD) are two common chronic diseases worldwide, and any potential link between the two would significantly impact public health practice. Considering the current inconsistent evidence, we conducted a meta-analysis and systematic review to examine the risk of PD in patients with RA. Methods Two investigators (DL and XH) conducted a comprehensive search of PubMed, Embase, and Web of Science using medical subject headings terms combined with free words to identify relevant papers published from inception through December 31, 2021. All studies that explored the relationship between RA and PD were included for quantitative analysis and qualitative review. Random- and fixed-effects models were used to pool the risk ratios (RRs) of PD in patients with RA. The Newcastle-Ottawa scale was used to assess the quality of included studies. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guideline. Results Four population-based studies involving 353,246 patients and one Mendelian randomized study were included in our study. The pooled result showed a significantly reduced risk of PD in patients with RA than in the general population (RR = 0.74, 95% CI: 0.56-0.98, P = 0.034). No apparent effects of gender, age, region, follow-up time, or study design on PD risk were observed. Sensitivity analysis showed that pooled results were relatively stable, and no publication bias was detected. The Mendelian randomization study indicated a significant inverse association between RA and PD (genetic correlation: −0.10, P = 0.0033) and that each one standard deviation increase in the risk of RA was significantly associated with a lower risk of PD. Of note, the current study is limited by the relatively small number of included studies and unmeasured confounding factors, especially for RA-related anti-inflammatory agents. Conclusions This study supports that people with RA had a lower PD risk than those without RA. Further studies are needed to explore the underlying molecular mechanisms of the interaction between the two diseases.
| S-EPMC9130734 | biostudies-literature
Project description:ObjectThough 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.MethodWe 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.ResultsThe 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.ConclusionThe 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.
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Project description:BackgroundCoronary artery disease (CAD) remains one of the leading causes of mortality worldwide. We aimed to summarize what is currently known with regard to causal modifiable risk factors associated with CAD in populations of diverse ancestries through conducting a systematic review and meta-analysis of Mendelian randomization (MR) studies on CAD.MethodsThe databases Embase, Medline, Cochrane Library and Web of Science were searched on the 19th and 20th of December 2022 for MR studies with CAD as a primary outcome; keywords of the search strategy included "coronary artery disease" and "mendelian randomization". Studies were included if they were published in the English language, included only human participants, employed Mendelian randomization as the primary methodology and studied CAD as the outcome of interest. The exclusion criteria resulted in the removal of studies that did not align with the predefined inclusion criteria, as well as studies which were systematic reviews themselves, and used the same exposure and outcome source as another study. An ancestry-specific meta-analysis was subsequently conducted on studies which investigated either body mass index, lipid traits, blood pressure or type 2 diabetes as an exposure variable. Assessment of publication bias and sensitivity analyses was conducted for risk of bias assessment in the included studies.ResultsA total of 1781 studies were identified through the database searches after de-duplication was performed, with 47 studies included in the quantitative synthesis after eligibility screening. Approximately 80% of all included study participants for MR studies on CAD were of European descent irrespective of the exposure of interest, while no study included individuals of African ancestry. We found no evidence of differences in terms of direction of causation between ancestry groups; however, the strength of the respective relationships between each exposure and CAD were different, with this finding most evident when blood pressure was the exposure of interest.ConclusionsFindings from this review suggest that patterns regarding the causational relationship between modifiable risk factors and CAD do not differ in terms of direction when compared across diverse ancestry populations. Differences in the observed strengths of the respective relationships however are indicative of the value of increasing representation in non-European populations, as novel genetic pathways or functional SNPs relating to CAD may be uncovered through a more global analysis.Systematic review registrationThe protocol for this systematic review was registered to the International Prospective Register of Systematic Reviews (PROSPERO) and is publicly available online (CRD42021272726).
| S-EPMC10790478 | biostudies-literature
Project description:Many observation studies have demonstrated a close relationship between rheumatoid arthritis (RA) and osteoporosis (OP). However, the causal genetic correlation between RA and OP remains unclear. In this study, we performed bi-directional Mendelian randomization (MR) analyses to explore causal inference between these two traits. The instrumental variables for RA were selected from a large-scale genome-wide association study (GWAS) (1,523 cases and 461,487 controls). Bone mineral density (BMD) at five different sites (heel (n=265,627), forearm (FA) (n=8,143), femoral neck (FN) (n=32,735), lumbar spine (LS) (n=28,498), and total body (n=28,498)) were used as phenotypes for OP. The inverse variance weighted (IVW) method did not detect any causal effect of BMDs on RA except heel BMD (beta = -7.57 × 10-4, p = 0.02). However, other methods (MR-Egger, weighted median, weighted mode, MR-PRESSO, and MR-RAPS) showed no causal association between heel BMD and RA. Likewise, we did not find a causal effect of RA on BMD at any sites. In conclusion, we found no evidence that RA is causally associated with OP/BMD, or vice versa. We suggested that the associations found in previous observational studies between RA and OP/BMD are possibly related to secondary effects such as antirheumatic treatment and reduced physical activity.
| S-EPMC8202858 | biostudies-literature
Project description:BackgroundMeta-analysis of genome-wide association studies (GWAS) data showed that the relationship between hypothyroidism and rheumatoid arthritis (RA) risk remains under debate. This study is conducted to test the causal relationship of hypothyroidism and RA.MethodsA two-sample Mendelian randomization (TSMR) analysis was employed to estimate the causality of hypothyroidism and rheumatoid arthritis in European ancestry and Asian ancestry. Integrating the effects generated by TSMR, functional annotations and noncoding variant prediction framework were applied to analyze and interpret the functional instrument variants (IVs).ResultsThe results of the inverse variance weighted method showed a strong significant causal relationship between hypothyroidism and risk of RA in European ancestry [odds ratio (OR) = 1.96; 95% confidence interval (CI) 1.49, 2.58; p < 0.001]. The outcomes of MR-Egger, weighted median, weighted mode, and simple mode also showed that hypothyroidism was significantly associated with increased risk of RA in European ancestry. The MR-PRESSO method also showed significant results [Outlier-corrected Causal Estimate = 0.70; standard error (SE) = 0.06; p < 0.001]. An independent dataset and an Asian ancestry dataset were applied to estimate and obtain the coincident results. Furthermore, we integrated the effect of variants in TSMR analysis, functional annotations, and prediction methods to pinpoint the single-nucleotide polymorphism (SNP) rs4409785 as one of the causal variants, which suggested that this variant could impact the binding of CTCF-cohesin and play a vital role in immune cells.ConclusionIn this study, we prove that hypothyroidism is significantly causally associated with increased RA risk, which has not been shown in previous studies. Furthermore, we pinpoint the potential causal variants in RA.
| S-EPMC10262846 | biostudies-literature
Project description:BackgroundAlthough observational epidemiological studies have found that smoking is positively associated with risk of rheumatoid arthritis (RA), assessing the causality of this relationship has remained elusive because conventional observational studies are susceptible to bias such as confounding and reverse causation. Here, we applied the Mendelian randomization (MR) approach to examine the potential causal relationship between smoking and risk of RA.MethodsSummary statistics data for RA were obtained from a meta-analysis of genome-wide association studies (GWAS), including 14,361 RA cases and 43,923 controls of European ancestry. The instrumental variables (IV) and the genetic association estimates for smoking initiation and lifetime smoking were obtained from a GWAS meta-analysis including 1,232,091 individuals and a GWAS of 462,690 individuals of European ancestry, respectively. MR analyses were performed using the inverse-variance weighted (IVW) method and supplemented with the weighted-median method. Potential pleiotropy was assessed using the MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test and MR-Egger regression. Sensitivity analyses were further performed to test the robustness of the association.ResultsWe found that compared with never smokers, genetic predisposition to smoking initiation was positively associated with risk of RA (odds ratio (OR)?=?1.32, 95% confidence interval (CI)?=?1.15-1.52, P?=?9.17?×?10-5 using the IVW method). Similarly, genetically predicted lifetime smoking was associated with an increased risk of RA (OR?=?1.55, 95% CI?=?1.13-2.14, P?=?0.007). Sensitivity analyses using alternative MR methods and different sets of IVs produced similar results, suggesting the robustness of our findings.ConclusionsThese results provide support for a causal association between smoking and increased risk of RA. Further studies are warranted to explain the underlying mechanisms of smoking in the development of RA.
| S-EPMC7060545 | biostudies-literature