Interleukins and rheumatoid arthritis: bi-directional Mendelian randomization investigation

Abstract Background Ample observational evidence indicates that patients with rheumatoid arthritis (RA) are at increased risk of developing comorbid conditions, in particular cardiovascular disease. The pathogenesis of these comorbidities is still largely unknown. For effective preventive measures, it would however be important to discriminate between those that are causally linked with rheumatoid arthritis and those that are the results of concomitant treatments or other confounding factors. Purpose Our objective was to explore whether genetically determined manifestation of RA was associated with any comorbidities, in particular cardiovascular disease, by conducting a 2-sample Mendelian randomization (MR) study on publicly available summary statistics from genome-wide association study (GWAS) consortia. Methods Genetic instruments for RA were obtained from a GWAS of 14,361 autoantibody-positive individuals with RA and 43,923 controls of European descent (Okada et al. 2014). The CARDIoGRAMplusC4D consortium comprising 60,801 cases with coronary artery disease and 123,504 controls was used to evaluate the associations with cardiovascular outcomes applying inverse variance–weighted meta-analysis, weighted-median analysis, Mendelian randomization–Egger regression, and multivariable Mendelian randomization. Genetic instruments for RA were further tested for association with other etiologically related traits by using publicly available GWAS data. Results Genetic predisposition to RA was not associated with higher risk of coronary artery disease (beta coefficient [b] ± standard error [se] = 0.02±0.03; P=0.4913), and myocardial infarction (b ± se = 0.03±0.03; P=0.3338). In contrast, IgA nephropathy (b ± se = 0.47±0.18; P=0.0225) and triglyceride levels were significantly related as outcomes to genetically determined RA as exposure. Other significantly related outcomes were the manifestation of squamous cell lung cancer (b ± se = 0.17±0.08; P=0.0496), serous ovarian cancer (b ± se = 0.13±0.05; P=0.0202), and prostate cancer (b ± se = 0.06±0.02; P=0.0041). Conclusions Despite the high prevalence of coronary artery disease and myocardial infarction among RA patients in observational studies, cardiovascular outcomes were not significantly associated with RA by Mendelian randomization. This paradox might partly be explained by the traits such as IgA nephropathy and elevated triglyceride levels that could act as mediators for the increased cardiovascular risk by their causal link with genetically determined RA. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Medical University of Vienna, Austria

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Rheumatoid arthritis decreases risk for Parkinson’s disease: a Mendelian randomization study

npj Parkinson s Disease ◽

10.1038/s41531-021-00166-x ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

ChunYu Li ◽

RuWei Ou ◽

HuiFang Shang

Keyword(s):

Rheumatoid Arthritis ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Genetic Correlation ◽

Mendelian Randomization ◽

Association Studies ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Standard Deviation Increase ◽

Rheumatoid Arthritis Risk

AbstractEpidemiological and clinical studies have suggested comorbidity between rheumatoid arthritis and Parkinson’s disease (PD), but whether there exists a causal association and the effect direction of rheumatoid arthritis on PD is controversial and elusive. To evaluate the causal relationship, we first estimated the genetic correlation between rheumatoid arthritis and PD, and then performed a two-sample Mendelian randomization analysis based on summary statistics from large genome-wide association studies of rheumatoid arthritis (N = 47,580) and PD (N = 482,703). We identified negative and significant correlation between rheumatoid arthritis and PD (genetic correlation: −0.10, P = 0.0033). Meanwhile, one standard deviation increase in rheumatoid arthritis risk was associated with a lower risk of PD (OR: 0.904, 95% CI: 0.866–0.943, P: 2.95E–06). The result was robust under all sensitivity analyses. Our results provide evidence supporting a protective role of rheumatoid arthritis on PD. A deeper understanding of the inflammation and immune response is likely to elucidate the potential pathogenesis of PD and identify therapeutic targets for PD.

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Mendelian randomization indicates that TNF is not causally associated with Alzheimer’s disease

10.1101/673749 ◽

2019 ◽

Cited By ~ 1

Author(s):

Shea J Andrews ◽

Alison Goate

Keyword(s):

Rheumatoid Arthritis ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tumor Necrosis Factor ◽

Causal Relationship ◽

Tumor Necrosis ◽

Mendelian Randomization ◽

Potential Treatment ◽

Tnf Α ◽

Necrosis Factor

AbstractINTRODUCTIONEpidemiological research has suggested that inhibition of tumor necrosis factor (TNF)-α in patients with rheumatoid arthritis (RA) reduces the overall risk of Alzheimer’s disease (AD). TNF-α antagonists have been suggested as a potential treatment for AD.METHODSWe used a two-sample Mendelian randomization design to examine the causal relationship between blood TNF expression, serum TNF-α levels, and RA on AD risk.RESULTSOur results do not support a causal relationship between TNF expression, serum TNF-α levels or RA on AD risk.DISCUSSIONThese results suggest that TNF-α antagonists are unlikely to reduce the risk of AD.

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Genetic liability to rheumatoid arthritis on autism and autistic traits: polygenic risk score and Mendelian randomization analyses

Translational Psychiatry ◽

10.1038/s41398-021-01772-2 ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Amanda Ly ◽

Beate Leppert ◽

Dheeraj Rai ◽

Hannah Jones ◽

Christina Dardani ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mendelian Randomization ◽

Causal Effect ◽

Autistic Traits ◽

Causal Effects ◽

Risk Scores ◽

Polygenic Risk Score ◽

Genetic Liability ◽

Polygenic Risk ◽

Genome Wide

AbstractHigher prevalence of autism in offspring born to mothers with rheumatoid arthritis has been reported in observational studies. We investigated (a) the associations between maternal and offspring’s own genetic liability for rheumatoid arthritis and autism-related outcomes in the offspring using polygenic risk scores (PRS) and (b) whether the effects were causal using Mendelian randomization (MR). Using the latest genome-wide association (GWAS) summary data on rheumatoid arthritis and individual-level data from the Avon Longitudinal Study of Parents and Children, United Kingdom, we constructed PRSs for maternal and offspring genetic liability for rheumatoid arthritis (single-nucleotide polymorphism [SNP] p-value threshold 0.05). We investigated associations with autism, and autistic traits: social and communication difficulties, coherence, repetitive behaviours and sociability. We used modified Poisson regression with robust standard errors. In two-sample MR analyses, we used 40 genome-wide significant SNPs for rheumatoid arthritis and investigated the causal effects on risk for autism, in 18,381 cases and 27,969 controls of the Psychiatric Genetics Consortium and iPSYCH. Sample size ranged from 4992 to 7849 in PRS analyses. We found little evidence of associations between rheumatoid arthritis PRSs and autism-related phenotypes in the offspring (maternal PRS on autism: RR 0.89, 95%CI 0.73–1.07, p = 0.21; offspring’s own PRS on autism: RR 1.11, 95%CI 0.88–1.39, p = 0.39). MR results provided little evidence for a causal effect (IVW OR 1.01, 95%CI 0.98–1.04, p = 0.56). There was little evidence for associations between genetic liability for rheumatoid arthritis on autism-related outcomes in offspring. Lifetime risk for rheumatoid arthritis has no causal effects on autism.

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