Abstract MP50: Effect of Linoleic Acid on Ischemic Stroke: A Mendelian Randomization Study

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
David Wu ◽  
Huijun Huang ◽  
Yu Qian ◽  
Yingying Mao
Keyword(s):  
Ischemic Stroke ◽  
Linoleic Acid ◽  
Mendelian Randomization ◽  
Underlying Mechanism ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Large Artery ◽  
Inverse Association ◽  
Nucleotide Polymorphisms ◽  
Standard Deviation Increase

Background and Purpose: Linoleic acid (LA) is an essential fatty acid involved in eicosanoid synthesis. Epidemiological studies have suggested an inverse association between circulating LA levels and ischemic stroke (IS), however, it is unclear whether the observed association is causal or due to confounding or reverse causation. We conducted a Mendelian randomization (MR) to evaluate the potential causal relationship between circulating LA levels and risk of IS. Methods: Summary statistics for IS were obtained from the MEGASTROKE consortium, including 34,217 IS cases and 404,630 controls of European ancestry. Seventeen single nucleotide polymorphisms (SNPs) associated with circulating LA levels were used as instrumental variables (IVs) in the MR analysis, with another two SNP sets used in sensitivity analyses. We used the inverse-variance weighted method to evaluate the potential causal associations of circulating LA levels with IS, complemented with other MR approaches including weighted-median, weighted-mode, MR Pleiotropy RESidual Sum and Outlier test and MR-Egger regression. Results: Each 1-standard deviation increase of genetically-predicted LA levels was inversely associated with a 2% (95% confidence interval [CI], 1%-3%) reduction in IS incidence. Subgroup analyses showed significant causal associations for large artery stroke (OR, 0.95; 95% CI, 0.92-0.98; P =3.45х10 -4 ), but not for cardioembolic stroke (OR, 0.98; 95% CI, 0.96-1.00; P =0.05) and small vessel stroke (OR, 1.02; 95% CI, 0.99-1.05; P =0.11). Sensitivity analyses using two additional SNP sets as IVs produced consistent findings. Conclusions: Our study provides evidence for an inverse causal association of circulating LA levels with risk of IS, particularly large artery stroke. Further studies are warranted to clarify the underlying mechanism of LA in the prevention of IS.

scholarly journals Association Between Circulating Linoleic Acid and Risk of Ischemic Stroke

2021 ◽  
Vol 11 ◽  
Author(s):  
Ding Ye ◽  
Huijun Huang ◽  
David J. H. Wu ◽  
Wanting Zhang ◽  
Feixiang Zhou ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Linoleic Acid ◽  
Genome Wide Association Study ◽  
Sensitivity Analyses ◽  
Large Artery ◽  
Inverse Association ◽  
Nucleotide Polymorphisms ◽  
Outlier Test ◽  
A Genome ◽  
The Impact

BackgroundObservational studies have shown an inverse association between circulating linoleic acid (LA) and risk of ischemic stroke (IS).ObjectiveThe aim of this study was to explore whether genetic variants predicting levels of circulating LA are associated with IS and its subtypes using a two-sample Mendelian randomization (MR) analysis.MethodsLA-related single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of 8,631 participants, and summary statistics of IS and IS subtypes were obtained from the MEGASTROKE consortium. MR analysis was performed using the inverse-variance weighted (IVW) method complemented with other approaches, including weighted-median, weighted-mode, MR Pleiotropy RESidual Sum and Outlier test and MR-Egger regression, to test for the robustness of the association. Moreover, we conducted bidirectional MR analysis to assess the impact of IS-associated SNPs on circulating LA levels. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated.ResultsWe found that genetically predicted circulating LA levels were inversely associated with the risk of IS by the IVW method (OR = 0.98, 95% CI: 0.97–0.99, and P = 0.003). Subgroup analyses showed a statistically significant association between LA and risk of large artery stroke (LAS; OR = 0.95, 95% CI: 0.92–0.98, and P = 0.004), but not for other IS subtypes. The results were stable in sensitivity analyses, and no evidence of reverse association between LA and risk of IS, or LAS was observed.ConclusionOur study supports a potential inverse association of genetically predicted circulating LA levels with risk of IS, particularly LAS.

EXPRESS: Effect of genetic liability to visceral adiposity on stroke and its subtypes: a Mendelian randomization study

2021 ◽  
pp. 174749302110062
Author(s):  
Bin Yan ◽  
Jian Yang ◽  
Li Qian ◽  
Fengjie Gao ◽  
Ling Bai ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Ischemic Stroke ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Visceral Adiposity ◽  
Large Artery ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
A Genome ◽  
Increased Risk

Background: Observational studies have found an association between visceral adiposity and stroke. Aims: The purpose of this study was to investigate the role and genetic effect of visceral adipose tissue (VAT) accumulation on stroke and its subtypes. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants (221 single nucleotide polymorphisms; P<5×10-8) using as instrumental variables for MR analysis was obtained from a genome-wide association study (GWAS) of VAT. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium (up to 67,162 cases and 453,702 controls). MR standard analysis (inverse variance weighted method) was conducted to investigate the effect of genetic liability to visceral adiposity on stroke and its subtypes. Sensitivity analysis (MR-Egger, weighted median, MR-PRESSO) were also utilized to assess horizontal pleiotropy and remove outliers. Multi-variable MR analysis was employed to adjust potential confounders. Results: In the standard MR analysis, genetically determined visceral adiposity (per 1 SD) was significantly associated with a higher risk of stroke (odds ratio [OR] 1.30; 95% confidence interval [CI] 1.21-1.41, P=1.48×10-11), ischemic stroke (OR 1.30; 95% CI 1.20-1.41, P=4.01×10-10), and large artery stroke (OR 1.49; 95% CI 1.22-1.83, P=1.16×10-4). The significant association was also found in sensitivity analysis and multi-variable MR analysis. Conclusions: Genetic liability to visceral adiposity was significantly associated with an increased risk of stroke, ischemic stroke, and large artery stroke. The effect of genetic susceptibility to visceral adiposity on the stroke warrants further investigation.

P6231Iron status and risk of cardio-metabolic diseases in European adults: a Mendelian randomization study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
W Gan ◽  
D Bennett ◽  
A Mahajan ◽  
H Du ◽  
Z Chen ◽  
...  
Keyword(s):  
Serum Iron ◽  
Metabolic Diseases ◽  
Mendelian Randomization ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Research Centre ◽  
Inverse Association ◽  
Total N

Abstract Background Observational studies have reported conflicting results about the associations of iron status with risk of cardio-metabolic diseases but such studies are constrained by confounding and reverse causality. Purpose To assess the causal relevance of iron status biomarkers (transferrin, serum iron, and ferritin) for risk of coronary artery diseases (CAD), ischaemic stroke (IS), and type 2 diabetes (T2D), using Mendelian randomization (MR). Methods Effect size estimates for genetic variants associated with iron status biomarkers were obtained from the Genetics of Iron Status consortium (transferrin saturation, serum iron, and ferritin: n=48,972). The corresponding effects of these variants on the risk of CAD, IS and T2D were obtained from a meta-analysis of unrelated participants of European ancestry in the UK Biobank (UKB), together with previously recruited participants in CARDIOGRAMplusC4D (total n=90,377 CAD cases), MEGASTROKE (total n=43,381 IS cases) and DIAGRAM (total n=74,124 T2D cases), respectively. The main analysis used a two-sample inverse-variance weighted MR, while the sensitivity analyses used weighted-median, weighted-mode, MR-PRESSO, and MR-Egger approaches. Results MR analysis demonstrated significant inverse association of each of the three genetically-instrumented iron status biomarker with risk of CAD (transferrin saturation OR=0.96 [95% CI: 0.92–0.99], p=0.02; serum iron OR=0.93 [0.89–0.97], p=0.001; and ferritin OR=0.86 (0.79–0.94), p=0.001, per 1 SD higher level). In contrast, these iron status biomarkers showed positive associations with risk of T2D (transferrin saturation OR=1.06 [1.01–1.11], p=0.01; serum iron OR=1.06 [0.99–1.13], p=0.07; and ferritin OR=1.12 [0.99–1.26], p=0.06, per 1 SD higher level). There was positive, but non-significant, association of IS with each of the iron status biomarker analysed. Sensitivity analyses using several different MR approaches yielded concordant results. Conclusions Among European adults, iron status appeared to have causal associations, but in opposite directions, with the risk of CHD and T2D. Our findings highlight the need for caution about strategies for advocating iron supplementation in individuals with normal haemoglobin levels for prevention of CAD. Acknowledgement/Funding British Heart Found, Medical Research Council, Wellcome Trust, NIHR Biomedical Research Centre, Oxford

scholarly journals Coffee consumption and risk of breast cancer: a Mendelian Randomization study

2020 ◽  
Author(s):  
Merete Ellingjord-Dale ◽  
Nikos Papadimitriou ◽  
Michalis Katsoulis ◽  
Chew Yee ◽  
Niki Dimou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Random Effects ◽  
Mendelian Randomization ◽  
Coffee Consumption ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Inverse Association ◽  
Er Positive

AbstractBackgroundObservational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer.MethodsWe conducted a two-sample Mendelian randomization randomization (MR) analysis to evaluate the relationship between coffee consumption and breast cancer risk using 33 single-nucleotide polymorphisms (SNPs) associated with coffee consumption from a genome-wide association (GWA) study on 212,119 female UK Biobank participants of White British ancestry. Risk estimates for breast cancer were retrieved from publicly available GWA summary statistics from the Breast Cancer Association Consortium (BCAC) on 122,977 cases (of which 69,501 were estrogen receptor (ER)-positive, 21,468 ER-negative) and 105,974 controls of European ancestry. Random-effects inverse variance weighted (IVW) MR analyses were performed along with several sensitivity analyses to assess the impact of potential MR assumption violations.ResultsOne cup per day increase in genetically predicted coffee consumption in women was not associated with risk of total (IVW random-effects; odds ratio (OR): 0.91, 95% confidence intervals (CI): 0.80-1.02, P: 0.12, P for instrument heterogeneity: 7.17e-13), ER-positive (OR=0.90, 95% CI: 0.79-1.02, P: 0.09) and ER-negative breast cancer (OR: 0.88, 95% CI: 0.75-1.03, P: 0.12). Null associations were also found in the sensitivity analyses using MR-Egger (total breast cancer; OR: 1.00, 95% CI: 0.80-1.25), weighted median (OR: 0.97, 95% CI: 0.89-1.05) and weighted mode (OR: 1.00, CI: 0.93-1.07).ConclusionsThe results of this large MR study do not support an association of genetically predicted coffee consumption on breast cancer risk, but we cannot rule out existence of a weak inverse association.

scholarly journals Large differences in adiponectin levels have no clear effect on multiple sclerosis risk: A Mendelian randomization study

2016 ◽  
Vol 23 (11) ◽  
pp. 1461-1468 ◽  
Author(s):  
Julia Devorak ◽  
Lauren E Mokry ◽  
John A Morris ◽  
Vincenzo Forgetta ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Body Mass ◽  
Mendelian Randomization ◽  
Strong Support ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Standard Deviation Increase ◽  
Clear Effect ◽  
Genome Wide ◽  
Unit Increase

Background: Mendelian randomization (MR) studies have demonstrated strong support for an association between genetically increased body mass index and risk of multiple sclerosis (MS). The adipokine adiponectin may be a potential mechanism linking body mass to risk of MS. Objective: To evaluate whether genetically increased adiponectin levels influence risk of MS. Methods: Using genome-wide significant single nucleotide polymorphisms (SNPs) for adiponectin, we undertook an MR study to estimate the effect of adiponectin on MS. This method prevents bias due to reverse causation and minimizes bias due to confounding. Sensitivity analyses were performed to evaluate the assumptions of MR. Results: MR analyses did not support a role for genetically elevated adiponectin in risk of MS (odds ratio (OR) = 0.93 per unit increase in natural-log-transformed adiponectin, equivalent to a two-standard deviation increase in adiponectin on the absolute scale; 95% confidence interval (CI) = 0.66–1.33; p = 0.61). Further MR analysis suggested that genetic variation at the adiponectin gene, which influences adiponectin level, does not impact MS risk. Sensitivity analyses, including MR-Egger regression, suggested no bias due to pleiotropy. Conclusion: Lifelong genetically increased adiponectin levels in humans have no clear effect on risk of MS. Other biological factors driving the association between body mass and MS should be investigated.

scholarly journals Diet‐Derived Antioxidants Do Not Decrease Risk of Ischemic Stroke: A Mendelian Randomization Study in 1 Million People

2021 ◽  
Author(s):  
Leon G. Martens ◽  
Jiao Luo ◽  
Ko Willems van Dijk ◽  
J. Wouter Jukema ◽  
Raymond Noordam ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Lower Risk ◽  
Mendelian Randomization ◽  
Association Studies ◽  
European Ancestry ◽  
Blood Levels ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Blood Concentrations ◽  
Vitamins E And C

Background Dietary intake and blood concentrations of vitamins E and C, lycopene, and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot be inferred from these associations. Here, we investigated causality by analyzing the associations between genetically influenced antioxidant levels in blood and ischemic stroke using Mendelian randomization. Methods and Results For each circulating antioxidant (vitamins E and C, lycopene, β‐carotene, and retinol), which were assessed as either absolute blood levels and/or high‐throughput metabolite levels, independent genetic instrumental variables were selected from earlier genome‐wide association studies ( P <5×10 −8 ). We used summary statistics for single‐nucleotide polymorphisms–stroke associations from 3 European‐ancestry cohorts (cases/controls): MEGASTROKE (60 341/454 450), UK Biobank (2404/368 771), and the FinnGen study (8046/164 286). Mendelian randomization analyses were performed on each exposure per outcome cohort using inverse variance–weighted analyses and subsequently meta‐analyzed. In a combined sample of 1 058 298 individuals (70 791 cases), none of the genetically influenced absolute antioxidants or antioxidant metabolite concentrations were causally associated with a lower risk of ischemic stroke. For absolute antioxidants levels, the odds ratios (ORs) ranged between 0.94 (95% CI, 0.85–1.05) for vitamin C and 1.04 (95% CI, 0.99–1.08) for lycopene. For metabolites, ORs ranged between 1.01 (95% CI, 0.98–1.03) for retinol and 1.12 (95% CI, 0.88–1.42) for vitamin E. Conclusions This study did not provide evidence for a causal association between dietary‐derived antioxidant levels and ischemic stroke. Therefore, antioxidant supplements to increase circulating levels are unlikely to be of clinical benefit to prevent ischemic stroke.

scholarly journals Carnitine and COVID-19 Susceptibility and Severity: A Mendelian Randomization Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Chunyu Li ◽  
Ruwei Ou ◽  
Qianqian Wei ◽  
Huifang Shang
Keyword(s):  
Causal Relationship ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Carnitine Level ◽  
Standard Deviation Increase ◽  
Inverse Variance ◽  
Weighted Median ◽  
Genetically Determined

Background: Carnitine, a potential substitute or supplementation for dexamethasone, might protect against COVID-19 based on its molecular functions. However, the correlation between carnitine and COVID-19 has not been explored yet, and whether there exists causation is unknown.Methods: A two-sample Mendelian randomization (MR) analysis was conducted to explore the causal relationship between carnitine level and COVID-19. Significant single nucleotide polymorphisms from genome-wide association study on carnitine (N = 7,824) were utilized as exposure instruments, and summary statistics of the susceptibility (N = 1,467,264), severity (N = 714,592) and hospitalization (N = 1,887,658) of COVID-19 were utilized as the outcome. The causal relationship was evaluated by multiplicative random effects inverse variance weighted (IVW) method, and further verified by another three MR methods including MR Egger, weighted median, and weighted mode, as well as extensive sensitivity analyses.Results: Genetically determined one standard deviation increase in carnitine amount was associated with lower susceptibility (OR: 0.38, 95% CI: 0.19–0.74, P: 4.77E−03) of COVID-19. Carnitine amount was also associated with lower severity and hospitalization of COVID-19 using another three MR methods, though the association was not significant using the IVW method but showed the same direction of effect. The results were robust under all sensitivity analyses.Conclusions: A genetic predisposition to high carnitine levels might reduce the susceptibility and severity of COVID-19. These results provide better understandings on the role of carnitine in the COVID-19 pathogenesis, and facilitate novel therapeutic targets for COVID-19 in future clinical trials.

scholarly journals Association of Fibroblast Growth Factor 23 With Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study

2020 ◽  
Vol 11 ◽  
Author(s):  
Kai Zheng ◽  
Lingmin Lin ◽  
Pan Cui ◽  
Tao Liu ◽  
Lin Chen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Mendelian Randomization ◽  
Fibroblast Growth Factor 23 ◽  
Large Artery ◽  
Fibroblast Growth ◽  
Causal Association ◽  
Standard Deviation Increase ◽  
A Genome

Fibroblast growth factor 23 (FGF23), which is involved in the regulation of vitamin D, is an emerging independent risk factor for cardiovascular diseases. Previous studies have demonstrated a positive association between FGF23 and stroke. In this study, we aimed to assess the association of FGF23 with ischemic stroke and its subtypes by applying a Mendelian randomization (MR) framework. Five genetic variants obtained from a genome-wide association study involving 16,624 European subjects were used as valid instruments of circulating FGF23 levels. MR was applied to infer the causality of FGF23 levels and the risk of ischemic stroke using data from the MEGASTROKE consortium. Subsequently, several MR analyses, including inverse-variance weighted meta-analysis, MR-Egger, weighted median estimate (WME), MR Pleiotropy Residual Sum and Outlier were performed. The heterogeneity test analysis, including Cochran’s Q, I2 test and leave-one-out analysis were also applied. Furthermore, potential horizontal/vertical pleiotropy was assessed. Lastly, the power of MR analysis was tested. Three validated variants were found to be associated with circulating FGF23 levels and were used for further investigation. We found that high expression level of FGF23 was not associated with any ischemic stroke. However, a causal association between genetically predicted FGF23 levels and the risk of large-artery atherosclerotic stroke (LAS) was significant, with an odds ratio of 1.74 (95% confidence interval = 1.08–2.81) per standard deviation increase in circulating FGF23 levels. Our findings provide support for the causal association between FGF23 and LAS, and therefore, offer potential therapeutic targets for LAS. The specific roles of FGF23 in LAS and associated molecules require further investigation.

scholarly journals Educational Attainment Decreases the Risk of COVID-19 Severity in the European Population: A Two-Sample Mendelian Randomization Study

2021 ◽  
Vol 9 ◽  
Author(s):  
Masahiro Yoshikawa ◽  
Kensuke Asaba
Keyword(s):  
Educational Attainment ◽  
Lower Risk ◽  
Mendelian Randomization ◽  
European Population ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Standard Deviation Increase ◽  
Summary Data ◽  
Years Of Schooling

Observational studies have reported that the severity of COVID-19 depends not only on physical conditions but also on socioeconomic status, including educational level. Because educational attainment (EA), which measures the number of years of schooling, is moderately heritable, we investigated the causal association of EA on the risk of COVID-19 severity using the Mendelian randomization (MR) approach. A two-sample MR analysis was performed using publicly available summary-level data sets of genome-wide association studies (GWASs). A total of 235 single-nucleotide polymorphisms (SNPs) were extracted as instrumental variables for the exposure of EA from the Social Science Genetic Association Consortium GWAS summary data of 766,345 participants of European ancestry. The effect of each SNP on the outcome of COVID-19 severity risk was obtained from the GWAS summary data of 1,059,456 participants of European ancestry gathered from the COVID-19 Host Genetics Initiative. Using inverse variance weighted method, our MR study shows that EA was significantly associated with a lower risk of COVID-19 severity (odds ratio per one standard deviation increase in years of schooling, 0.540; 95% confidence interval, 0.376–0.777, P = 0.0009). A series of sensitivity analyses showed little evidence of bias. In conclusion, we show for the first time using a two-sample MR approach the associations between higher EA and the lower risk of COVID-19 severity in the European population. However, the genetic or epidemiological mechanisms underlying the association between EA and the risk of COVID-19 severity remain unknown, and further studies are warranted to validate the MR findings and investigate underlying mechanisms.

scholarly journals A Mendelian randomization of γ′ and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke

Blood ◽  
2020 ◽  
Vol 136 (26) ◽  
pp. 3062-3069
Author(s):  
Jillian Maners ◽  
Dipender Gill ◽  
Nathan Pankratz ◽  
Michael A. Laffan ◽  
Alisa S. Wolberg ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Venous Thromboembolism ◽  
Protective Effect ◽  
Stroke Risk ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Coagulation Cascade ◽  
Large Artery ◽  
Inverse Variance ◽  
Genetic Instruments

Abstract Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ′) fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied 2-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ′ fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ′ fibrinogen and total fibrinogen were selected, and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ′ fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ′ fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ′ fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ′ fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects and their clinical applications.

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