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.

scholarly journals Periodontitis and pulmonary function: a Mendelian randomization study

2021 ◽  
Author(s):  
Sebastian-Edgar Baumeister ◽  
Michael Nolde ◽  
Birte Holtfreter ◽  
Hansjörg Baurecht ◽  
Sven Gläser ◽  
...  
Keyword(s):  
Pulmonary Function ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Forced Expiratory Volume ◽  
Sensitivity Analyses ◽  
Observational Research ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
A Genome ◽  
The Uk

Abstract Objectives Observational research suggests that periodontitis affects pulmonary function; however, observational studies are subject to confounding and reverse causation, making causal inference and the direction of these associations difficult. We used Mendelian randomization (MR) to assess the potential causal association between genetic liability to periodontitis and pulmonary function. Materials and methods We used six single-nucleotide polymorphisms (SNPs) associated with periodontitis (P < 5 × 10−6) from a genome-wide association study (GWAS) of 17,353 European descent periodontitis cases and 28,210 controls from the GeneLifestyle Interactions in Dental Endpoints consortium and the UK Biobank, and related these to SNPs from a lung function GWAS including 79,055 study participants of the SpiroMeta Consortium. Results MR analysis suggested no effect of periodontitis on the ratio of forced expiratory volume in one second to lower forced vital capacity (standard deviation increment in outcome per doubling of the odds of the exposure (95% confidence interval) =  − 0.004 (− 0.028; 0.020)). Replication analysis using genetic instruments from two different GWAS and sensitivity analyses to address potential pleiotropy led to no substantial changes in estimates. Conclusions Collectively, these findings do not support a relationship between genetic liability for periodontitis and pulmonary function. Clinical relevance Periodontitis does not seem to be a risk factor for worsening of pulmonary function.

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.

scholarly journals Circulating Vitamin K1 Levels in Relation to Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1575 ◽  
Author(s):  
Susanna Larsson ◽  
Matthew Traylor ◽  
Hugh Markus
Keyword(s):  
Ischemic Stroke ◽  
Mendelian Randomization ◽  
Cardioembolic Stroke ◽  
Small Vessel ◽  
Large Artery ◽  
Vitamin K1 ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Level Data ◽  
Increased Risk

Vitamin K plays a crucial role in blood coagulation, and hypercoagulability has been linked to atherosclerosis-related vascular disease. We used the Mendelian randomization study design to examine whether circulating vitamin K1 (phylloquinone) levels are associated with ischemic stroke. Four single-nucleotide polymorphisms associated with vitamin K1 levels were used as instrumental variables. Summary-level data for large artery atherosclerotic stroke (n = 4373 cases), small vessel stroke (n = 5386 cases), cardioembolic stroke (n = 7193 cases), and any ischemic stroke (n = 34,217 cases and 404,630 non-cases) were available from the MEGASTROKE consortium. Genetically-predicted circulating vitamin K1 levels were associated with large artery atherosclerotic stroke but not with any other subtypes or ischemic stroke as a whole. The odds ratios per genetically predicted one nmol/L increase in natural log-transformed vitamin K1 levels were 1.31 (95% confidence interval (CI) 1.12–1.53; p = 7.0 × 10−4) for large artery atherosclerotic stroke, 0.98 (95% CI 0.85–1.12; p = 0.73) for small vessel stroke, 1.01 (95% CI 0.90–1.14; p = 0.84) for cardioembolic stroke, and 1.05 (95% CI 0.99–1.11; p = 0.11) for any ischemic stroke. These findings indicate that genetic predisposition to higher circulating vitamin K1 levels is associated with an increased risk of large artery atherosclerotic stroke.

scholarly journals An artificial neural network approach integrating plasma proteomics and genetic data identifies PLXNA4 as a new susceptibility locus for pulmonary embolism

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Misbah Razzaq ◽  
Maria Jesus Iglesias ◽  
Manal Ibrahim-Kosta ◽  
Louisa Goumidi ◽  
Omar Soukarieh ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Genome Wide Association Study ◽  
Susceptibility Gene ◽  
Biological Traits ◽  
Nucleotide Polymorphisms ◽  
Ann Model ◽  
Neural Network Approach ◽  
A Genome ◽  
Increased Risk ◽  
Artificial Neural

AbstractVenous thromboembolism is the third common cardiovascular disease and is composed of two entities, deep vein thrombosis (DVT) and its potential fatal form, pulmonary embolism (PE). While PE is observed in ~ 40% of patients with documented DVT, there is limited biomarkers that can help identifying patients at high PE risk. To fill this need, we implemented a two hidden-layers artificial neural networks (ANN) on 376 antibodies and 19 biological traits measured in the plasma of 1388 DVT patients, with or without PE, of the MARTHA study. We used the LIME algorithm to obtain a linear approximate of the resulting ANN prediction model. As MARTHA patients were typed for genotyping DNA arrays, a genome wide association study (GWAS) was conducted on the LIME estimate. Detected single nucleotide polymorphisms (SNPs) were tested for association with PE risk in MARTHA. Main findings were replicated in the EOVT study composed of 143 PE patients and 196 DVT only patients. The derived ANN model for PE achieved an accuracy of 0.89 and 0.79 in our training and testing sets, respectively. A GWAS on the LIME approximate identified a strong statistical association peak (rs1424597: p = 5.3 × 10–7) at the PLXNA4 locus. Homozygote carriers for the rs1424597-A allele were then more frequently observed in PE than in DVT patients from the MARTHA (2% vs. 0.4%, p = 0.005) and the EOVT (3% vs. 0%, p = 0.013) studies. In a sample of 112 COVID-19 patients known to have endotheliopathy leading to acute lung injury and an increased risk of PE, decreased PLXNA4 levels were associated (p = 0.025) with worsened respiratory function. Using an original integrated proteomics and genetics strategy, we identified PLXNA4 as a new susceptibility gene for PE whose exact role now needs to be further elucidated.

scholarly journals Iron Status and Cancer Risk in UK Biobank: A Two-Sample Mendelian Randomization Study

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 526 ◽  
Author(s):  
Shuai Yuan ◽  
Paul Carter ◽  
Mathew Vithayathil ◽  
Siddhartha Kar ◽  
Edward Giovannucci ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Brain Cancer ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Nucleotide Polymorphisms ◽  
Uk Biobank ◽  
Odds Ratios ◽  
A Genome

We conducted a two-sample Mendelian randomization study to explore the associations of iron status with overall cancer and 22 site-specific cancers. Single-nucleotide polymorphisms for iron status were obtained from a genome-wide association study of 48,972 European-descent individuals. Summary-level data for breast and other cancers were obtained from the Breast Cancer Association Consortium and UK Biobank. Genetically predicted iron status was positively associated with liver cancer and inversely associated with brain cancer but not associated with overall cancer or the other 20 studied cancer sites at p < 0.05. The odds ratios of liver cancer were 2.45 (95% CI, 0.81, 7.45; p = 0.11), 2.11 (1.16, 3.83; p = 0.02), 10.89 (2.44, 48.59; p = 0.002) and 0.30 (0.17, 0.53; p = 2 × 10−5) for one standard deviation increment of serum iron, transferrin saturation, ferritin and transferrin levels, respectively. For brain cancer, the corresponding odds ratios were 0.69 (0.48, 1.00; p = 0.05), 0.75 (0.59, 0.97; p = 0.03), 0.41 (0.20, 0.88; p = 0.02) and 1.49 (1.04, 2.14; p = 0.03). Genetically high iron status was positively associated with liver cancer and inversely associated with brain cancer.

scholarly journals Circulating antioxidants and Alzheimer disease prevention: a Mendelian randomization study

2018 ◽  
Vol 109 (1) ◽  
pp. 90-98 ◽  
Author(s):  
Dylan M Williams ◽  
Sara Hägg ◽  
Nancy L Pedersen
Keyword(s):  
Alzheimer Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Late Onset ◽  
Association Studies ◽  
Nucleotide Polymorphisms ◽  
Primary Methods ◽  
A Genome ◽  
Β Carotene

ABSTRACT Background Higher circulating antioxidant concentrations are associated with a lower risk of late-onset Alzheimer disease (AD) in observational studies, suggesting that diet-sourced antioxidants may be modifiable targets for reducing disease risk. However, observational evidence is prone to substantial biases that limit causal inference, including residual confounding and reverse causation. Objectives In order to infer whether long-term circulating antioxidant exposure plays a role in AD etiology, we tested the hypothesis that AD risk would be lower in individuals with lifelong, genetically predicted increases in concentrations of 4 circulating antioxidants that are modifiable by diet. Methods Two-sample Mendelian randomization analyses were conducted. First, published genetic association studies were used to identify single-nucleotide polymorphisms (SNPs) that determine variation in circulating ascorbate (vitamin C), β-carotene, retinol (vitamin A), and urate. Second, for each set of SNP data, statistics for genotype associations with AD risk were extracted from data of a genome-wide association study of late-onset AD cases and controls (n = 17,008 and 37,154, respectively). Ratio-of-coefficients and inverse-variance-weighted meta-analyses were the primary methods used to assess the 4 sets of SNP-exposure and SNP-AD associations. Additional analyses assessed the potential impact of bias from pleiotropy on estimates. Results The models suggested that genetically determined differences in circulating ascorbate, retinol, and urate are not associated with differences in AD risk. All estimates were close to the null, with all ORs for AD ≥1 per unit increase in antioxidant exposure (ranging from 1.00 for ascorbate to 1.05 for retinol). There was little evidence to imply that pleiotropy had biased results. Conclusions Our findings suggest that higher exposure to ascorbate, β-carotene, retinol, or urate does not lower the risk of AD. Replication Mendelian randomization studies could assess this further, providing larger AD case-control samples and, ideally, using additional variants to instrument each exposure.

scholarly journals Effects of copper and zinc on ischemic heart disease and myocardial infarction: a Mendelian randomization study

2018 ◽  
Vol 108 (2) ◽  
pp. 237-242 ◽  
Author(s):  
Hanish P Kodali ◽  
Brian T Pavilonis ◽  
C Mary Schooling
Keyword(s):  
Sensitivity Analysis ◽  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Dietary Factors ◽  
Ischemic Heart ◽  
P Value ◽  
Copper And Zinc ◽  
A Genome

ABSTRACTBackgroundDespite great progress in prevention and control, ischemic heart disease (IHD) remains a leading cause of global morbidity and mortality. Diet plays a key role in IHD, but a comprehensive delineation of the role of dietary factors in IHD is not yet quite complete.ObjectiveThe aim of this study was to test the long-standing hypothesis that copper is protective and zinc harmful in IHD.DesignWe used separate-sample instrumental variable analysis with genetic instruments (Mendelian randomization). We obtained single nucleotide polymorphisms (SNPs) from a genome wide association study, strongly (P value < 5 × 10−8) and independently associated with erythrocyte copper and zinc. We applied these genetic predictors of copper and zinc to the largest, most extensively genotyped IHD case (n ≤ 76014)-control (n ≤ 264785) study, based largely on CARDIoGRAMplusC4D 1000 Genomes and the UK Biobank SOFT CAD, to obtain SNP-specific Wald estimates for the effects of copper and zinc on IHD, which were combined through the use of inverse variance weighting. Sensitivity analysis included use of the MR-Egger method, and reanalysis including SNPs independently associated with erythrocyte copper and zinc at P value < 5 × 10−6.ResultsGenetically instrumented copper was negatively associated with IHD (OR: 0.94; 95% CI: 0.90, 0.98). Genetically instrumented zinc was positively associated with IHD (OR: 1.06; 95% CI: 1.02, 1.11). Sensitivity analysis via MR-Egger gave no indication of unknown pleiotropy; less strongly associated SNPs gave similar results for copper.ConclusionGenetic validation of a long-standing hypothesis suggests that further investigation of the effects, particularly of copper, on IHD may provide a practical means of reducing the leading cause of mortality and morbidity.

scholarly journals GWAS of Post-Orthodontic Aggressive External Apical Root Resorption Identified Multiple Putative Loci at X-Y Chromosomes

2020 ◽  
Vol 10 (4) ◽  
pp. 169
Author(s):  
Paula Iber-Díaz ◽  
Raquel Senen-Carramolino ◽  
Alejandro Iglesias-Linares ◽  
Pablo Fernández-Navarro ◽  
Carlos Flores-Mir ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Root Resorption ◽  
Genetic Model ◽  
Nucleotide Polymorphisms ◽  
Apical Root Resorption ◽  
A Genome ◽  
Increased Risk ◽  
External Apical Root Resorption

Personalized dental medicine requires from precise and customized genomic diagnostic. To conduct an association analysis over multiple putative loci and genes located at chromosomes 2, 4, 8, 12, 18, X, and Y, potentially implicated in an extreme type of external apical root resorption secondary to orthodontic forces (aEARR). A genome-wide association study of aEARR was conducted with 480 patients [ratio~1:3 case/control]. Genomic DNA was extracted and analyzed using the high-throughput Axiom platform with the GeneTitan® MC Instrument. Up to 14,377 single nucleotide polymorphisms (SNPs) were selected at candidate regions and clinical/diagnostic data were recorded. A descriptive analysis of the data along with a backward conditional binary logistic regression was used to calculate odds ratios, with 95% confidence intervals [p < 0.05]. To select the best SNP candidates, a logistic regression model was fitted assuming a log-additive genetic model using R software [p < 0.0001]. In this sample the top lead genetic variants associated with aEARR were two novel putative genes located in the X chromosome, specifically, STAG 2 gene, rs151184635 and RP1-30E17.2 gene, rs55839915. These variants were found to be associated with an increased risk of aEARR, particularly restricted to men [OR: 6.09; 95%CI: 2.6–14.23 and OR: 6.86; 95%CI: 2.65–17.81, respectively]. Marginal associations were found at previously studied variants such as SSP1: rs11730582 [OR: 0.54; 95%CI: 0.34–0.86; p = 0.008], P2RX7: rs1718119 [OR: 0.6; 95%CI: 0.36–1.01; p = 0.047], and TNFRSF11A: rs8086340 [OR: 0.6; 95%CI: 0.38–0.95; p = 0.024]), found solely in females. Multiple putative genetic variants located at chromosomes X and Y are potentially implicated in an extreme phenotype of aEARR. A gender-linked association was noted.

Evidence for Genetic Association of CARD9 and SNAPC4 with Ankylosing Spondylitis in a Chinese Han Population

2013 ◽  
Vol 41 (2) ◽  
pp. 318-324 ◽  
Author(s):  
Xiaochun Ma ◽  
Yongchao Liu ◽  
Hua Zhang ◽  
Rongfang Qiu ◽  
Hailing Zhao ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
Mrna Expression ◽  
Genome Wide Association Study ◽  
Chinese Han Population ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Chinese Han ◽  
Han Population ◽  
A Genome ◽  
Increased Risk

Objective.A genome-wide association study and 2 replication studies identified 2 single-nucleotide polymorphisms (SNP) of caspase recruitment domain-containing protein 9 (CARD9) and small nuclear RNA-activating complex polypeptide 4 (SNAPC4) at Chr 9q34.3 associated with ankylosing spondylitis (AS) in whites. We explored a possible association of SNP in CARD9 and SNAPC4 and AS in a Chinese Han population from Shandong.Methods.The study included 1150 patients with AS and 1120 healthy controls who underwent genotyping for 4 SNP of CARD9 and 2 of SNAPC4; we replicated the results in another 490 patients and 380 healthy controls of Ningxia Han Chinese during the same time. We used quantitative real-time PCR (qRT-PCR) to measure CARD9 and SNAPC4 mRNA expression in peripheral leukocytes from 44 patients and 36 controls and allele-specific mRNA expression of CARD9 and SNAPC4 in leukocytes from 130 controls.Results.We validated that an SNP in SNAPC4, rs11145835, was significantly associated with AS in our Chinese Han population (p = 0.001) and replicated the association in samples from the Chinese Ningxia Han population (p = 0.002). Carrying the G allele of rs11145835 was associated with increased risk of AS (OR 1.34, 95% CI 1.12–1.59) and with decreased expression of CARD9 (p = 0.001) and SNAPC4 (p = 0.02) in leukocytes. SNAPC4 mRNA expression was lower in leukocytes from patients than from controls (p = 0.0002).Conclusion.Our study confirmed that an SNP rs11145835 in 9q34.3 that harbors CARD9 and SNAPC4 is associated with AS in a Chinese Han population, and rs11145835 in SNAPC4 is a potential causal variant.

scholarly journals Homocysteine, B vitamins, and cardiovascular disease: a Mendelian randomization study

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shuai Yuan ◽  
Amy M. Mason ◽  
Paul Carter ◽  
Stephen Burgess ◽  
Susanna C. Larsson
Keyword(s):  
Cardiovascular Disease ◽  
Ischemic Stroke ◽  
Subarachnoid Hemorrhage ◽  
Vitamin B12 ◽  
Vitamin B6 ◽  
Mendelian Randomization ◽  
Nucleotide Polymorphisms ◽  
Multiple Testing Correction ◽  
Increased Risk ◽  
B Vitamin

Abstract Background Whether a modestly elevated homocysteine level is causally associated with an increased risk of cardiovascular disease remains unestablished. We conducted a Mendelian randomization study to assess the associations of circulating total homocysteine (tHcy) and B vitamin levels with cardiovascular diseases in the general population. Methods Independent single nucleotide polymorphisms associated with tHcy (n = 14), folate (n = 2), vitamin B6 (n = 1), and vitamin B12 (n = 14) at the genome-wide significance level were selected as instrumental variables. Summary-level data for 12 cardiovascular endpoints were obtained from genetic consortia, the UK Biobank study, and the FinnGen consortium. Results Higher genetically predicted circulating tHcy levels were associated with an increased risk of stroke. For each one standard deviation (SD) increase in genetically predicted tHcy levels, the odds ratio (OR) was 1.11 (95% confidence interval (CI), 1.03, 1.21; p = 0.008) for any stroke, 1.26 (95% CI, 1.05, 1.51; p = 0.013) for subarachnoid hemorrhage, and 1.11 (95% CI, 1.03, 1.21; p = 0.011) for ischemic stroke. Higher genetically predicted folate levels were associated with decreased risk of coronary artery disease (ORSD, 0.88; 95% CI, 0.78, 1.00, p = 0.049) and any stroke (ORSD, 0.86; 95% CI, 0.76, 0.97, p = 0.012). Genetically predicted increased vitamin B6 levels were associated with a reduced risk of ischemic stroke (ORSD, 0.88; 95% CI, 0.81, 0.97, p = 0.009). None of these associations persisted after multiple testing correction. There was no association between genetically predicted vitamin B12 and cardiovascular disease. Conclusions This study reveals suggestive evidence that B vitamin therapy and lowering of tHcy may reduce the risk of stroke, particularly subarachnoid hemorrhage and ischemic stroke.

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