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Causal association of rheumatoid arthritis with frailty and the mediation role of inflammatory cytokines: A Mendelian randomization study. Archives of gerontology and geriatrics BACKGROUND:Previous observational studies have suggested the association between rheumatoid arthritis (RA) and frailty. However, it remains obscure whether this association is causal. This study aims to investigate the causal association of RA with frailty and the mediation effect of inflammatory cytokines using Mendelian randomization (MR) design. METHODS:Summary-level data for RA (N = 58,284), frailty index (FI) (N = 175,226), Fried frailty score (FFS) (N = 386,565), and 41 inflammatory cytokines (N = 8,293) were obtained from recent genome-wide association studies. Univariable and multivariable MR analyses were conducted to investigate and verify the causal association of RA with frailty. The potential mediation effects of inflammatory cytokines were estimated using two-step MR. RESULTS:Univariable inverse variance weighted MR analysis suggested that genetically determined RA was associated with increased FI (beta=0.021; 95 % CI: 0.012, 0.03; p = 2.2 × 10) and FFS (beta=0.011; 95 %CI: 0.007, 0.015; p = 8.811 × 10). The consistent results were observed in multivariable MR analysis after adjustment for asthma, smoking, BMI, physical activity, telomere length, and depression. Mediation analysis showed evidence of an indirect effect of RA on FI through monokine induced by interferon-gamma (MIG) with a mediated proportion of 9.8 % (95 %CI: 4.76 %, 19.05 %), on FFS via MIG and stromal cell-derived factor-1 alpha with a mediated proportion of 9.6 % (95 %CI: 0 %, 18.18 %) and 8.44 % (95 %CI: 0 %, 18.18 %), respectively. CONCLUSION:This study provided credible evidence that genetically predicted RA was associated with a higher risk of frailty. Additionally, inflammatory cytokines were involved in the mechanism of RA-induced frailty. 10.1016/j.archger.2024.105348
Dissecting the causal relationship between neuroticism and osteoarthritis: a univariable and multivariable Mendelian randomization study. Frontiers in psychiatry Background:Mental health has been found to be associated with risk of osteoarthritis (OA), but the causal relationship was not fully clarified. Methods:Two-sample Mendelian randomization (MR) study was conducted to investigate the causal relationship between neuroticism (n = 329,821) and the two most frequently affected parts of osteoarthritis (OA) (knee OA: case/control =24,955/378,169; hip OA: case/control = 15,704/378,169) using large scale summary genome-wide association study (GWAS) data. Inverse variance weighted (IVW), weighted median, and MR-Egger were used to estimate the causal effects. Multiple sensitivity analyses were conducted to examine the robustness of the causal estimates. Multivariable MR analysis was used to estimate the direct effects of neuroticism on OA after accounting for the other OA risk factors. Two-step MR approach was employed to explore the potential mediators of the causal relationship. Results:Univariable MR analysis indicated that 1-SD increase in genetically predicted neuroticism score was associated with an increased risk of knee OA (IVW: OR, 1.17; 95% CI, 1.087-1.26; p = 2.72E-05) but not with hip OA. The causal effects remained significant after accounting for the effects of BMI, alcohol drinking, and vigorous physical activity but were attenuated with adjustment of smoking. Further mediation analysis revealed that smoking initiation mediated a significant proportion of the causal effects of neuroticism on knee OA (proportion of mediation effects in total effects: 22.3%; 95% CI, 5.9%-38.6%; p = 7.60E-03). Conclusions:Neuroticism has significant causal effects on knee OA risk. Smoking might partly mediate the causal relationship. Further studies were warranted to explore the underlying mechanisms and potential use of neuroticism management for OA treatment. 10.3389/fpsyt.2024.1333528
Causal associations of obstructive sleep apnea with cardiovascular disease: a Mendelian randomization study. Sleep STUDY OBJECTIVES:Obstructive sleep apnea (OSA) had been associated with various cardiovascular diseases (CVDs) in observational studies, but causal inferences have not been confirmed. We used the Mendelian randomization (MR) study to explore the potential causal association between OSA with CVDs in the general population. METHODS:We performed a two-sample MR analysis using five gene-wide significant single-nucleotide polymorphisms associated with OSA at genome-wide significance from the FinnGen study (N = 217 955) and 12 cardiovascular diseases from the UK Biobank and the genetic consortia. The inverse-variance weight was chosen as the primary analysis and was complemented by various sensitivity analyses. The study design applied univariable MR, multivariable MR, and mediation analysis. RESULTS:MR analyses provide evidence of genetically predicted OSA on the risk of heart failure (odds ratio [OR],1.26; 95% confidence interval [CI],1.08 to 1.47), hypertension (OR,1.24; 95%CI, 1.11 to 1.39) and atrial fibrillation (OR,1.21; 95%CI,1.12 to 1.31). Multivariable MR indicated the adverse effect of OSA on heart failure persisted after adjusting BMI, smoking, drinking, and education (IVW OR,1.13; 95%CI, 1.01 to 1.27). However, the significance of hypertension and atrial fibrillation was dampened. Mediation analyses suggest that the causal association between OSA and heart failure is mediated in part by Apolipoprotein B, with a mediated portion of 9%. CONCLUSIONS:This study suggested that genetically predicted OSA is a potential causal risk factor for heart failure based on a large-scale population. Nevertheless, further studies regarding ancestral diversity are needed to confirm the causal association between OSA and CVDs. 10.1093/sleep/zsac298
Leisure Sedentary Behavior and Risk of Lung Cancer: A Two-Sample Mendelian Randomization Study and Mediation Analysis. Frontiers in genetics Leisure sedentary behavior, especially television watching, has been previously reported as associated with the risk of lung cancer in observational studies. This study aims to evaluate the causal association with two-sample Mendelian randomization (MR) analysis. Single nucleotide polymorphisms associated with leisure television watching, computer use, and driving were extracted from genome-wide association studies. Summary-level results of lung cancer overall and histological types were obtained from International Lung Cancer Consortium (ILCCO). In univariable MR using inverse-variance-weighted method, we observed causal effects of television watching on lung cancer [OR, 1.89, 95% confidence interval (CI), 1.41, 2.54; = 2.33 × 10], and squamous cell lung cancer (OR, 2.37, 95% CI, 1.58, 3.55; = 3.02 × 10), but not on lung adenocarcinoma (OR, 1.40, 95% CI, 0.94, 2.09; = 0.100). No causal effects of computer use and driving on lung cancer were observed. Television watching significantly increased the exposure to several common risk factors of lung cancer. The associations of television watching with lung cancer and squamous cell lung cancer were compromised after adjusting for smoking quantity with multivariable MR. Our mediation analyses estimated indirect effects of television watching on lung cancer (beta, 0.31, 95% CI, 0.13, 0.52; = 6.64 × 10) and squamous cell lung cancer (beta, 0.33, 95% CI, 0.14, 0.53, = 4.76 × 10) mediated by smoking quantity. Our findings indicate that television watching is positively correlated with the risk of lung cancer, potentially mediated through affecting smoking quantity. 10.3389/fgene.2021.763626