Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study.
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ABSTRACT:
SUBMITTER: Georgakis MK
PROVIDER: S-EPMC7299212 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
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Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study.
Georgakis Marios K MK Malik Rainer R Gill Dipender D Franceschini Nora N Sudlow Cathie L M CLM Dichgans Martin M
Circulation. Genomic and precision medicine 20200512 3
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Project description:IntroductionPrevious epidemiological studies have found an increased risk for ischemic stroke in patients with migraine; however, the evidence for a causal relationship between migraine and ischemic stroke is scarce. This study aims to explore the potential causal relationship between migraine and ischemic stroke and its subtypes [including large artery stroke (LAS), small vessel stroke (SVS), and cardioembolic stroke (CES)].MethodsWe used data on genetic variants associated with migraine identified from a genome-wide association study (GWAS) meta-analysis among 889,018 European ancestries. Summary data for ischemic stroke and its subtypes were obtained from the MEGASTROKE consortium including up to 438,847 participants. We performed two-sample Mendelian randomization (MR) analyses using the inverse-variance-weighted method as the primary approach. The MR-Egger, weighted median, simple median, simple mode, and weighted mode methods were also conducted as sensitivity analyses to determine the robustness of our results.ResultsWe failed to detect statistically significant associations between migraine and ischemic stroke (OR, 0.935; 95% CI 0.851-1.027; P = 0.159) and its subtypes (LAS: OR, 0.818; 95% CI 0.692-0.967; P = 0.018) (SVS: OR, 0.935; 95% CI 0.781-1.119; P = 0.460) (CES: OR, 1.015; 95% CI 0.867-1.189; P = 0.850). The results were consistent with the sensitivity analyses.ConclusionsBy conducting a series of causal inference approaches, this study supports no causal effect of migraine on ischemic stroke and its subtypes.
| S-EPMC8857343 | biostudies-literature
Project description:Observational studies have evaluated the potential association of socioeconomic factors such as higher education with the risk of stroke but reported controversial findings. The objective of our study was to evaluate the potential causal association between higher education and the risk of stroke. Here, we performed a Mendelian randomization analysis to evaluate the potential association of educational attainment with ischemic stroke (IS) using large-scale GWAS datasets from the Social Science Genetic Association Consortium (SSGAC, 293,723 individuals), UK Biobank (111,349 individuals), and METASTROKE consortium (74,393 individuals). We selected three Mendelian randomization methods including inverse-variance-weighted meta-analysis (IVW), weighted median regression, and MR-Egger regression. IVW showed that each additional 3.6-year increase in years of schooling was significantly associated with a reduced IS risk (OR = 0.54, 95% CI: 0.41-0.71, and p = 1.16 × 10-5). Importantly, the estimates from weighted median (OR = 0.49, 95% CI: 0.33-0.73, and p = 1.00 × 10-3) and MR-Egger estimate (OR = 0.18, 95% CI: 0.06-0.60, and p = 5.00 × 10-3) were consistent with the IVW estimate in terms of direction and magnitude. In summary, we provide genetic evidence that high education could reduce IS risk.
| S-EPMC8876515 | biostudies-literature
Project description:BackgroundUnfavorable sleep habits have been linked with ischemic stroke in observational studies, but the causality remains unclear. The aim of this study is to investigate the potential causal role of three sleep traits, including sleep duration, insomnia, and chronotype, in ischemic stroke and its subtypes.MethodsWe conducted two-sample Mendelian randomization (MR) analysis using single nucleotide polymorphisms associated with sleep duration, insomnia, and chronotype as instruments to estimate causal associations with ischemic stroke and its subtypes, among 34,217 ischemic stroke cases and 406,111 controls from the MEGASTROKE consortium. Inverse-variance weighted method was used as the main analyses. Alternative MR methods and sensitivity analyses were further performed.ResultsWe found suggestive evidence that per doubling of genetic liability for short sleep duration (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.01-1.58) and frequent insomnia symptoms (OR, 1.19; 95% CI, 1.00-1.41) were associated with a modest increase in risk of large artery stroke (LAS) but not with small vessel stroke, cardioembolic stroke, or any ischemic stroke. The association of frequent insomnia symptoms with LAS was stronger after the exclusion of the outlier (OR, 1.25; 95% CI, 1.04-1.50). No significant association was observed for chronotype with any ischemic stroke subtype. Results were overall robust to sensitivity analyses, and there was little evidence of horizontal pleiotropy.ConclusionWe provided suggestive evidence for a potential causal role of short sleep duration and insomnia symptoms in LAS. Future researches are required to investigate whether improved sleep habits could help to mitigate LAS risk.
| S-EPMC7585859 | biostudies-literature
Project description:ObjectiveTo examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach.MethodsWe undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity.ResultsA 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68, p = 1.1 × 10-8). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 × 10-3) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 × 10-3) when compared with that for CHD.ConclusionsIn contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.
| S-EPMC6511103 | biostudies-literature
Project description:Background: Previous observational studies have shown that circulating selenium levels are inversely associated with ischemic stroke (IS). Our aims were to evaluate the causal links between selenium levels and IS, and its subtypes by Mendelian randomization (MR) analysis. Methods: We used the two-sample Mendelian randomization (MR) method to determine whether the circulating selenium levels are causally associated with the risk of stroke. We extracted the genetic variants (SNPs) associated with blood and toenail selenium levels from a large genome-wide association study (GWAS) meta-analysis. Inverse variance-weighted (IVW) method was used as the determinant of the causal effects of exposures on outcomes. Results: A total of 4 SNPs (rs921943, rs6859667, rs6586282, and rs1789953) significantly associated with selenium levels were obtained. The results indicated no causal effects of selenium levels on ischemic stroke by MR analysis (OR = 0.968, 95% CI 0.914-1.026, p = 0.269). Meanwhile, there was no evidence of a causal link between circulating selenium levels and subtypes of IS. Conclusion: The MR study indicated no evidence to support the causal links between genetically predicted selenium levels and IS. Our results also did not support the use of selenium supplementation for IS prevention at the genetic level.
| S-EPMC9043360 | biostudies-literature
Project description:Background: Observational studies have revealed the association between some inflammatory cytokines and the occurrence of ischemic stroke, but the causal relationships remain unclear. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effects of thirty inflammatory cytokines and the risk of ischemic stroke. For exposure data, we collected genetic variants associated with inflammatory cytokines as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis from Finland (sample size up to 8,293). For the outcome data, we collected summary data of ischemic stroke from a large-scale GWAS meta-analysis involved 17 studies (34,217 cases and 406,111 controls). We further performed a series of sensitivity analyses as validation of primary MR results. Results: According to the primary MR estimations and further sensitivity analyses, we established one robust association after Bonferroni correction: the odds ratio (95% CI) per unit change in genetically increased IL-4 was 0.84 (0.89-0.95) for ischemic stroke. The chemokine MCP3 showed a nominally significant association with ischemic stroke risk (OR: 0.93, 95% CI: 0.88-0.99, unadjusted p < 0.05). There was no evidence of a causal effect of other inflammatory cytokines and the risk of ischemic stroke. Conclusions: Our study suggested that genetically increased IL-4 levels showed a protective effect on the risk of ischemic stroke, which provides important new insights into the potential therapeutic target for preventing ischemic stroke.
| S-EPMC8801801 | biostudies-literature
Project description:IntroductionRecent observational studies have reported the association between ischemic stroke (IS) and cerebral microbleeds (CMBs). Whether this reflects a causal association remains to be established. Herein, we adopted a two-sample bidirectional Mendelian randomization (MR) analysis to comprehensively evaluate the causal association of IS and CMBs.MethodsThe summary-level genome-wide association studies (GWASs) data of IS were obtained from the GIGASTROKE consortium (62,100 European ancestry cases and 1,234,808 European ancestry controls). All IS cases could be further divided into large-vessel atherosclerosis stroke (LVS, n = 6399), cardio-embolic stroke (CES, n = 10,804) and small-vessel occlusion stroke (SVS, n = 6811). Meanwhile, we used publicly available summary statistics from published GWASs of CMBs (3556 of the 25,862 European participants across 2 large initiatives). A bidirectional MR analysis was conducted using inverse-variance weighting (IVW) as the major outcome, whereas MR-Egger and weighted median (WM) were used to complement the IVW estimates as they can provide more robust estimates in a broader set of scenarios but are less efficient (wider CIs). A Bonferroni-corrected threshold of p < 0.0125 was considered significant, and p values between 0.0125 and 0.05 were considered suggestive of evidence for a potential association.ResultsWe detected that higher risk of IS [IVW odds ratio (OR) 1.47, 95% confidence interval (CI) 1.04-2.07, p = 0.03] and SVS (IVW OR 1.62, 95% CI 1.07-2.47, p = 0.02) were significantly associated with CMBs. Reverse MR analyses found no significant evidence for a causal effect of CMBs on IS and its subtypes.ConclusionsOur study provides potential evidence that IS and SVS are causally linked to increased risk of CMBs. Further research is needed to determine the mechanisms of association between IS and CMBs.
| S-EPMC10310681 | biostudies-literature
Project description:ObjectiveWe conducted a Mendelian randomization (MR) study to disentangle causal associations between women's reproductive behaviors and ischemic stroke (IS) and investigate the roles of two modifiable risk factors (body mass index (BMI) and educational attainment (EA)) in these associations.MethodsUsing summary-level data from large-scale genome-wide association studies, we performed univariable MR to examine whether there is genetic evidence that women's reproductive traits are causally associated with IS and its subtypes. Multivariable MR and MR mediation analysis were used to investigate whether BMI and EA are common mechanisms or mediators for these associations. A set of sensitivity analyses were conducted to test valid MR assumptions.ResultsWe observed consistent and statistically significant associations across female and sex-combined analyses for earlier age at first birth (AFB) and age at first sexual intercourse (AFS) with a higher risk of IS and large-artery atherosclerotic stroke (LAS) risk in the primary analysis. The odds ratios of IS per 1 SD increase in genetically predicted early AFB and AFS were 0.93 (95% CI, 0.86-0.99; p = 0.046) and 0.83 (95% CI, 0.70-0.97, p = 0.020), respectively. Further analyses indicated that BMI played a shared role in AFS and IS/LAS while EA played a shared role in AFS/AFB and IS/LAS as well as a mediator in the path from AFS to IS/LAS.InterpretationThese findings may inform prevention strategies and interventions directed toward relative women's reproductive behaviors and IS. Future studies are warranted to explore other factors related to EA which are responsible for these causalities.
| S-EPMC9852390 | biostudies-literature
Project description:Background: Heart failure (HF) is a potential cause of ischemic stroke (IS), and previous studies have reported an association between HF and IS. This study aimed to analyze the causal link between HF and IS using bidirectional and multivariable Mendelian randomization (MR) studies. Methods: Genetic variants significantly associated with HF and IS were selected in the MR analysis from two large genome-wide association studies. Bidirectional and multivariable MR analyses were performed to evaluate the effect of HF on IS or the effect of IS on HF. Results: Two-sample MR analysis showed causal effects of HF on IS of all causes [odds ratio (OR) = 1.555, 95% confidence interval (CI): 1.343-1.799, p = 3.35 × 10-9] and large artery atherosclerosis stroke (LAS) (OR = 1.678, 95% CI: 1.044-2.696, p = 3.03 × 10-5), while there was a suggestive effect of HF on cardioembolic stroke (CES) (OR = 3.355, 95% CI: 1.031-10.919, p = 0.044). Genetically predicted HF was not associated with small artery occlusion stroke. Bidirectional MR analysis showed causal effects of IS of all causes (OR = 1.211, 95% CI: 1.040-1.410, p = 0.014) and CES (OR = 1.277, 95% CI: 1.213-1.344, p = 6.73 × 10-21) on HF, while there were no causal effects of LAS on HF. Conclusion: This MR analysis provided evidence of the causal links between genetically predicted HF and IS. Subgroup analysis highlighted the causal or suggestive relationship between genetically predicted HF and LAS or CES. The potential causal links need further investigation with genetic information about other ancestries or etiologies of HF.
| S-EPMC8666512 | biostudies-literature
Project description:BackgroundPrevious studies have shown that gut microbiota dysbiosis could affect clinical prognosis through an unknown mechanism. However, the causal relationship between the gut microbiota and the functional outcome after ischemic stroke remains unclear. We aimed to investigate the causal association between the gut microbiota and the functional outcome after ischemic stroke using Mendelian randomization (MR).MethodsGenetic instrumental variables associated with 211 bacterial traits were obtained from the MiBioGen consortium (N = 18,340). Data from genome-wide association studies (GWAS) for functional outcome after ischemic stroke were obtained from two phenotypes (i.e., overall stroke outcome and motor recovery). The inverse variance weighted method was used to estimate the causal association. Enrichment analysis was conducted based on the results of the MR analyses.ResultsThe genetically predicted family Peptostreptococcaceae (OR = 0.63, 95% CI = 0.41-0.98, p = 0.038) and the genera LachnospiraceaeNK4A136 group (OR = 0.65, 95% CI = 0.43-1.00, p = 0.048), LachnospiraceaeUCG004 (OR = 0.54, 95% CI = 0.33-0.90, p = 0.017), and Odoribacter (OR = 0.40, 95% CI = 0.21-0.77, p = 0.006) presented a suggestive association with favorable functional outcome, while the genera Eubacterium oxidoreducens group (OR = 1.77, 95% CI = 1.11-2.84, p = 0.018) and RuminococcaceaeUCG005 (OR = 1.85, 95% CI = 1.15-2.96, p = 0.010) were associated with unfavorable functional outcome. The genetically predicted family Oxalobacteraceae (OR = 2.12, 95% CI = 1.10-4.11, p = 0.025) and the genus RuminococcaceaeUCG014 (OR = 4.17, 95% CI = 1.29-13.52, p = 0.017) showed a suggestive association with motor recovery, while the order Enterobacteriales (OR = 0.14, 95% CI = 0.02-0.87, p = 0.035) and the family Enterobacteriaceae (OR = 0.14, 95% CI = 0.02-0.87, p = 0.035) were associated with motor weakness. Enrichment analysis revealed that regulation of the synapse structure or activity may be involved in the effect of the gut microbiota on the functional outcome after ischemic stroke.ConclusionsThis study provides genetic support that the gut microbiota, especially those associated with short-chain fatty acids, could affect stroke prognosis by mediating synapse function. Our findings suggest that modifying the composition of the gut microbiota could improve the prognosis of ischemic stroke.
| S-EPMC11456476 | biostudies-literature