Iyas Daghlas | PubMed Health

PubMed2025

Genetic Downregulation of Interleukin-6 Signaling, Coagulation Function, and Risk of Thromboembolic Disease.

BACKGROUND: Although genetic evidence supports IL-6 (interleukin-6) signaling inhibition as protective against atherosclerotic disease, its potential effects on thromboembolic outcomes are not well established. We conducted a Mendelian randomization analysis to investigate the association of genetically proxied IL-6 signaling inhibition with venous thromboembolism, cardioembolic stroke, and coagulation cascade protein levels. METHODS: IL-6 signaling inhibition was proxied using the rs2228145 IL6R missense variant, which impairs classical IL-6 signaling and lowers CRP (C-reactive protein) levels. Genetic associations with thromboembolic disease outcomes were obtained from genome-wide association studies of venous thromboembolism (81 190 cases) and cardioembolic stroke (10 804 cases). As atherosclerotic comparator traits, we included coronary artery disease (181 522 cases) and large-artery atherosclerotic stroke (6399 cases). Genetic associations with 35 coagulation cascade protein levels were obtained from the UK Biobank (n=6218) and deCODE cohorts (n=35 559). Mendelian randomization estimates were derived using the Wald ratio method, scaled per 1-unit decrease in natural log-transformed CRP levels. RESULTS: Genetically proxied IL-6 signaling inhibition was associated with increased risk of venous thromboembolism (odds ratio [OR], 1.31 [95% CI, 1.16-1.47], P=6.5×10-6) but not with cardioembolic stroke (OR, 1.25 [95% CI, 0.73-2.14], P=0.42). Conversely, protective associations were observed for both coronary artery disease and large-artery atherosclerotic stroke. Proteomic analyses demonstrated significant reductions in levels of 5 procoagulant and 7 anticoagulant or antifibrinolytic proteins. CONCLUSIONS: These findings suggest that IL-6 signaling inhibition dysregulates coagulation homeostasis and increases venous thromboembolism risk. Further experimental, translational, and epidemiologic studies are warranted to delineate underlying mechanisms and to evaluate thromboembolic safety in pharmacologic IL-6 signaling inhibition.

Humans↗

PubMed2023

Causal Associations of Sleep Apnea with Alzheimer's Disease and Cardiovascular Disease: a Bidirectional Mendelian Randomization Analysis.

BACKGROUND: Sleep apnea (SA) has been linked to an increased risk of dementia in numerous observational studies; whether this is driven by neurodegenerative, vascular or other mechanisms is not clear. We sought to examine the bidirectional causal relationships between SA, Alzheimer's disease (AD), coronary artery disease (CAD), and ischemic stroke using Mendelian randomization (MR). METHODS: Using summary statistics from four recent, large genome-wide association studies of SA (n=523,366), AD (n=64,437), CAD (n=1,165,690), and stroke (n=1,308,460), we conducted bidirectional two-sample MR analyses. Our primary analytic method was fixed-effects inverse variance weighted MR; diagnostics tests and sensitivity analyses were conducted to verify the robustness of the results. RESULTS: We identified a significant causal effect of SA on the risk of CAD (odds ratio (OR IVW ) =1.35 per log-odds increase in SA liability, 95% confidence interval (CI) =1.25-1.47) and stroke (OR IVW =1.13, 95% CI =1.01-1.25). These associations were somewhat attenuated after excluding single-nucleotide polymorphisms associated with body mass index (BMI) (OR IVW =1.26, 95% CI =1.15-1.39 for CAD risk; OR IVW =1.08, 95% CI =0.96-1.22 for stroke risk). SA was not causally associated with a higher risk of AD (OR IVW =1.14, 95% CI =0.91-1.43). We did not find causal effects of AD, CAD, or stroke on risk of SA. CONCLUSIONS: These results suggest that SA increased the risk of CAD, and the identified causal association with stroke risk may be confounded by BMI. Moreover, no causal effect of SA on AD risk was found. Future studies are warranted to investigate cardiovascular pathways between sleep disorders, including SA, and dementia.

Preprint↗