scholarly journals Inflammatory Cytokines and Risk of Ischemic Stroke: A Mendelian Randomization Study

2022 ◽  
Vol 12 ◽  
Author(s):  
Yalan Li ◽  
Jun Lu ◽  
Jie Wang ◽  
Peizhi Deng ◽  
Changjiang Meng ◽  
...  

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.

2020 ◽  
Vol 8 (1) ◽  
pp. e920
Author(s):  
Adil Harroud ◽  
J. Brent Richards ◽  
Sergio E. Baranzini

ObjectiveTo examine whether lifelong genetically increased serum urate levels, a potent antioxidant, contribute to MS susceptibility using Mendelian randomization (MR).MethodsThis 2-sample MR study included 25 independent genetic variants strongly associated with serum urate levels in a genome-wide association study meta-analysis of 140,949 individuals. Effects on the risk of MS were assessed with summary statistics from 3 large-scale MS genetic data sets totaling 61,667 MS cases and 86,806 controls from the International MS Genetic Consortium. Multiple sensitivity analyses were performed to evaluate the assumptions of MR and remove potentially pleiotropic variants.ResultsUsing inverse-variance weighted MR, we found no evidence for a causal effect of serum urate level on the risk of MS in any of the cohorts (MS1: OR 0.99 per each mg/dL unit increase in urate, 95% CI 0.89–1.08, p = 0.76; MS2: OR = 0.99, 95% CI 0.89–1.11, p = 0.90; MS3: OR = 1.00, 95% CI 0.98–1.2, p = 0.91). Pleiotropy robust MR methods yielded consistent estimates.ConclusionThis MR study does not support a clinically relevant causal effect of serum urate levels on the risk of MS.


2021 ◽  
Vol 8 ◽  
Author(s):  
Zixian Wang ◽  
Shiyu Chen ◽  
Qian Zhu ◽  
Yonglin Wu ◽  
Guifeng Xu ◽  
...  

Background: Heart failure (HF) is the main cause of morbidity and mortality worldwide, and metabolic dysfunction is an important factor related to HF pathogenesis and development. However, the causal effect of blood metabolites on HF remains unclear.Objectives: Our chief aim is to investigate the causal relationships between human blood metabolites and HF risk.Methods: We used an unbiased two-sample Mendelian randomization (MR) approach to assess the causal relationships between 486 human blood metabolites and HF risk. Exposure information was obtained from Sample 1, which is the largest metabolome-based genome-wide association study (mGWAS) data containing 7,824 Europeans. Outcome information was obtained from Sample 2, which is based on the results of a large-scale GWAS meta-analysis of HF and contains 47,309 cases and 930,014 controls of Europeans. The inverse variance weighted (IVW) model was used as the primary two-sample MR analysis method and followed the sensitivity analyses, including heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis.Results: We observed that 11 known metabolites were potentially related to the risk of HF after using the IVW method (P < 0.05). After adding another four MR models and performing sensitivity analyses, we found a 1-SD increase in the xenobiotics 4-vinylphenol sulfate was associated with ~22% higher risk of HF (OR [95%CI], 1.22 [1.07–1.38]).Conclusions: We revealed that the 4-vinylphenol sulfate may nominally increase the risk of HF by 22% after using a two-sample MR approach. Our findings may provide novel insights into the pathogenesis underlying HF and novel strategies for HF prevention.


2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahao Cai ◽  
Xiong Chen ◽  
Hongxuan Wang ◽  
Zixin Wei ◽  
Mei Li ◽  
...  

BackgroundObservational studies have shown an association of increased iron status with a higher risk of amyotrophic lateral sclerosis (ALS). Iron status might be a novel target for ALS prevention if a causal relationship exists. We aimed to reveal the causality between iron status and ALS incidence using a large two-sample Mendelian randomization (MR).MethodsSingle nucleotide polymorphisms (SNPs) for iron status were identified from a genome-wide association study (GWAS) on 48,972 individuals. The outcome data came from the largest ALS GWAS to date (20,806 cases; 59,804 controls). We conducted conservative analyses (using SNPs with concordant change of biomarkers of iron status) and liberal analyses (using SNPs associated with at least one of the biomarkers of iron status), with inverse variance weighted (IVW) method as the main analysis. We then performed sensitivity analyses including weighted median, MR-Egger and MR-pleiotropy residual sum and outlier, as well as leave-one-out analysis to detect pleiotropy.ResultsIn the conservative analyses, we found no evidence of association between four biomarkers of iron status and ALS using IVW method with odds ratio (OR) 1.00 [95% confidence interval (CI): 0.90–1.11] per standard deviation (SD) increase in iron, 0.96 (95% CI: 0.77–1.21) in ferritin, 0.99 (95% CI: 0.92–1.07) in transferrin saturation, and 1.04 (95% CI: 0.93–1.16) in transferrin. Findings from liberal analyses were similar, and sensitivity analyses suggested no pleiotropy detected (all p > 0.05).ConclusionOur findings suggest no causal effect between iron status and risk of ALS. Efforts to change the iron status to decrease ALS incidence might be impractical.


2020 ◽  
Author(s):  
Gunn-Helen Moen ◽  
Robin N Beaumont ◽  
Christine Sommer ◽  
Beverley M. Shields ◽  
Deborah A Lawlor ◽  
...  

AbstractLower maternal serum vitamin B12 (B12) and folate levels have been associated with lower offspring birthweight in observational studies. The aim of this study was to investigate whether this relationship is causal.We performed two-sample Mendelian Randomization (MR) using summary data on associations between genotype-B12 (10 genetic variants) or genotype-folate (4 genetic variants) levels from a genome-wide association study of 45,576 individuals (sample 1) and maternal-specific genetic effects on offspring birthweight from the latest EGG consortium meta-analysis with 297,356 individuals reporting their own birthweight and 210,248 women reporting their offspring’s birthweight (sample 2). To investigate the effect of offspring’s own B12 or folate levels on their own birthweight, we performed two-sample MR using the fetal-specific genetic effects from the latest EGG consortium meta-analysis. We used the inverse variance weighted method, and sensitivity analyses to account for pleiotropy, in addition to sensitivity analyses excluding a potentially pleiotropic variant in the FUT2 gene for B12.We did not find evidence for a causal effect of maternal B12 on offspring birthweight, nor evidence for an effect of offspring B12 on their own birthweight using the fetal-specific genetic effect. The results were consistent across the different methods and in sensitivity analyses excluding the FUT2 variant. We found a positive effect of maternal folate on offspring birthweight (0.146 [0.065, 0.227], which corresponds to an increase in birthweight of 71g per 1SD higher folate). We found some evidence for a small inverse effect of fetal folate on their own birthweight (−0.051 [−0.100, −0.003]).In conclusion, our results are consistent with evidence from randomized controlled trials that increased maternal folate levels increase offspring birthweight. We did not find evidence for a causal effect of B12 on offspring birthweight, suggesting previous observational studies may have been due to confounding.


Rheumatology ◽  
2019 ◽  
Vol 59 (5) ◽  
pp. 940-947 ◽  
Author(s):  
Zhen Zeng ◽  
Wanting Zhang ◽  
Yu Qian ◽  
Huijun Huang ◽  
David J H Wu ◽  
...  

Abstract Objective To evaluate the telomere length (TL) in patients with RA relative to that in controls and to test whether TL is causally associated with risk of RA. Methods Systematic review and meta-analysis of relevant literature was conducted to evaluate the association between TL and RA. Standardized mean differences with 95% CIs of TL in RA patients relative to controls were pooled using fixed or random-effects models. TL-related single-nucleotide polymorphisms were selected from a genome-wide association study of 37 684 individuals, and summary statistics of RA were obtained from a genome-wide association study meta-analysis including 14 361 RA patients and 43 923 controls. Mendelian randomization was performed using the inverse-variance weighted, weighted-median and likelihood-based methods. Sensitivity analyses were performed to test the robustness of the association. Results In the meta-analysis of 911 RA patients and 2498 controls, we found that patients with RA had a significantly shorter TL compared with controls (standardized mean differences = −0.50; 95% CI −0.88, −0.11; P = 0.012). In the Mendelian randomization analysis, we found that genetically predicted longer TL was associated with a reduced risk of RA [odds ratio = 0.68; 95% CI 0.54, 0.86; P = 0.002 using the inverse-variance weighted method]. Sensitivity analyses using alternative Mendelian randomization approaches yielded similar findings, suggesting the robustness of the causal association. Conclusion Our study provides evidence for a negative causal association of TL with risk of RA. Further studies are warranted to elucidate the underlying mechanism for the role of telomeres in the development of RA.


Author(s):  
Gunn-Helen Moen ◽  
Robin N Beaumont ◽  
Niels Grarup ◽  
Christine Sommer ◽  
Beverley M Shields ◽  
...  

Abstract Background Lower maternal serum vitamin B12 (B12) and folate levels have been associated with lower offspring birthweight, in observational studies. The aim of this study was to investigate whether this relationship is causal. Methods We performed two-sample Mendelian randomization (MR) using summary data on associations between genotype-B12 (10 genetic variants) or genotype-folate (four genetic variants) levels from: a genome-wide association study of 45 576 individuals (sample 1); and both maternal- and fetal-specific genetic effects on offspring birthweight from the latest Early Growth Genetics consortium meta-analysis with 297 356 individuals reporting their own birthweight and 210 248 women reporting their offspring's birthweight (sample 2). We used the inverse variance weighted method, and sensitivity analyses to account for pleiotropy, in addition to excluding a potentially pleiotropic variant in the FUT2 gene for B12 levels. Results We did not find evidence for a causal effect of maternal or fetal B12 levels on offspring birthweight. The results were consistent across the different methods. We found a positive causal effect of maternal folate levels on offspring birthweight [0.146 (0.065, 0.227), which corresponds to an increase in birthweight of 71 g per 1 standard deviation higher folate]. We found some evidence for a small inverse effect of fetal folate levels on their own birthweight [−0.051 (−0.100, −0.003)]. Conclusions Our results are consistent with evidence from randomized controlled trials that higher maternal folate levels increase offspring birthweight. We did not find evidence for a causal effect of B12 levels on offspring birthweight, suggesting previous observational studies may have been confounded.


2021 ◽  
pp. 174749302110062
Author(s):  
Bin Yan ◽  
Jian Yang ◽  
Li Qian ◽  
Fengjie Gao ◽  
Ling Bai ◽  
...  

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.


2019 ◽  
Vol 4 ◽  
pp. 113 ◽  
Author(s):  
Venexia M Walker ◽  
Neil M Davies ◽  
Gibran Hemani ◽  
Jie Zheng ◽  
Philip C Haycock ◽  
...  

Mendelian randomization (MR) estimates the causal effect of exposures on outcomes by exploiting genetic variation to address confounding and reverse causation. This method has a broad range of applications, including investigating risk factors and appraising potential targets for intervention. MR-Base has become established as a freely accessible, online platform, which combines a database of complete genome-wide association study results with an interface for performing Mendelian randomization and sensitivity analyses. This allows the user to explore millions of potentially causal associations. MR-Base is available as a web application or as an R package. The technical aspects of the tool have previously been documented in the literature. The present article is complementary to this as it focuses on the applied aspects. Specifically, we describe how MR-Base can be used in several ways, including to perform novel causal analyses, replicate results and enable transparency, amongst others. We also present three use cases, which demonstrate important applications of Mendelian randomization and highlight the benefits of using MR-Base for these types of analyses.


Blood ◽  
2019 ◽  
Vol 133 (9) ◽  
pp. 967-977 ◽  
Author(s):  
Paul S. de Vries ◽  
Maria Sabater-Lleal ◽  
Jennifer E. Huffman ◽  
Jonathan Marten ◽  
Ci Song ◽  
...  

Abstract Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.


2020 ◽  
Vol 105 (11) ◽  
Author(s):  
Zihao Qu ◽  
Fangkun Yang ◽  
Jianqiao Hong ◽  
Wei Wang ◽  
Shigui Yan

Abstract Purpose Accumulating evidence implicates parathyroid hormone (PTH) in the development of osteoporosis. However, the causal effect of PTH on bone mineral density (BMD) remains unclear. Thus, this study is aimed at exploring the association between the concentrations of serum PTH and BMD. Methods The instrumental variables for PTH were selected from a large-scale genome-wide association study (GWAS; n = 29 155). Outcomes included BMD of the forearm (FA; n = 8143), femoral neck (FN; n = 33 297), lumbar spine (LS; n = 32 735), heel (HL; n = 394 929), and risk of fractures in these bones (n = 361 194). Furthermore, the BMD of 5 different age groups: 15 years or younger (n = 11 807), 15–30 (n = 4180), 30–45 (n = 10 062), 45–60 (n = 18 805), and 60 years or older (n = 22 504) were extracted from a GWAS meta-analysis study. The analyses were performed using the 2-sample Mendelian randomization method. Results Mendelian randomization analysis revealed that the level of serum PTH was inversely associated with BMD of FA (95% CI: -0.763 to -0.016), FN (95% CI: -0.669 to -0.304), and LS (95% CI: -0.667 to -0.243). A causal relationship between serum PTH levels and BMD was observed in individuals aged 30–45 (95% CI: -0.888 to -0.166), 45–60 (95% CI: -0.758 to -0.232), and over 60 years (95% CI: -0.649 to -0.163). Main Conclusions This study demonstrated that the concentrations of serum PTH is inversely associated with BMD of several bones. Further analysis revealed site- and age-specific correlations between serum PTH levels and BMD, which implies that the levels of serum PTH contribute to the development of osteoporosis.


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