Platelet indices and the risk of pulmonary arterial hypertension: a two-sample and multivariable Mendelian randomization study
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ABSTRACT:
SUBMITTER: Li Y
PROVIDER: S-EPMC11338760 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundPlatelet indices are blood-based parameters reflecting the activation of platelets. Previous studies have identified an association between platelet indices and blood pressure (BP). However, causal inferences are prone to bias by confounding effects and reverse causation. We performed a Mendelian randomization (MR) study to compare the causal roles between genetically determined platelet indices and BP levels.MethodsSingle-nucleotide polymorphisms (SNPs) associated with platelet count (PLT), plateletcrit (PCT), mean platelet volume (MPV), platelet distribution width (PDW), and BP at the level of genome-wide significance (p < 5 × 10- 8) in the UK Biobank were used as instrumental variables. In bidirectional univariable MR analyses, inverse variance-weighted (IVW), MR‒Egger, and weighted median methods were used to obtain estimates for individual causal power. In addition, heterogeneity and sensitivity analyses were performed to examine the pleiotropy of effect estimates. Finally, multivariable MR analyses were undertaken to disentangle the comparative effects of four platelet indices on BP.ResultsIn the univariable MR analyses, increased levels of PLT and PCT were associated with higher BP, and PDW was associated with higher DBP alone. In the reverse direction, SBP had a minor influence on PLT and PCT. In multivariable MR analysis, PDW and PLT revealed an independent effect, whereas the association for PCT and MPV was insignificant after colinear correction.ConclusionThese findings suggest that platelets and BP may affect each other. PDW and PLT are independent platelet indices influencing BP. Increased platelet activation and aggregation may be involved in the pathogenesis of hypertension, which may provide insights into evaluating thromboembolic events in people with high BP. The necessity of initiating antiplatelet therapy among hypertension groups needs further investigation.
| S-EPMC10026509 | biostudies-literature
Project description:BackgroundHypertension poses a significant global health challenge, warranting exploration of novel preventive measures. This study aimed to investigate the role of circulating concentrations of various micronutrients in hypertension using a Mendelian randomization (MR) approach.MethodsData on hypertension were obtained from FinnGen, comprising 55,917 cases and 162,837 controls of European ancestry. Fifteen micronutrients were evaluated and selected based on genome-wide association studies (GWAS) data. Instrumental single nucleotide polymorphisms (SNPs) were chosen according to strict criteria. Univariable Mendelian randomization (UVMR) analysis was conducted using the inverse variance weighted (IVW) method, supplemented by sensitivity analyses. Multivariate Mendelian randomization (MVMR) analysis was performed to assess interactions between micronutrients.ResultsIn UVMR analysis, the IVW method revealed a potential influence of copper (OR = 1.052, 95% CI: 1.006-1.099, P = 0.025) and zinc (OR = 1.083, 95% CI: 1.007-1.165, P = 0.031) on hypertension. Sensitivity analyses supported these findings. MVMR analysis confirmed a direct positive effect of zinc on hypertension (OR = 1.087, 95% CI: 1.026-1.151, P = 0.005), while adjusting for zinc attenuated the effect of copper on hypertension (OR = 1.026, 95% CI: 0.987-1.066, P = 0.193).ConclusionCirculating zinc levels may be a potential risk factor for hypertension, while the association with other micronutrients remains inconclusive. These findings suggest that reducing zinc intake within a healthy range may help lower hypertension risk. Future research should further explore the role of zinc and nonlinear associations for a more comprehensive understanding.
| S-EPMC11523844 | biostudies-literature
Project description:BackgroundThere is accumulating evidence that allergy is a risk factor for keratoconus. Nonetheless the association between allergic disease and keratoconus remains controversial. We performed a two-sample Mendelian randomization (MR) study to determine the putative causal association of 4 allergic diseases (allergic conjunctivitis, allergic asthma, allergic rhinitis and atopic dermatitis) with keratoconus.MethodsSummary statistics were obtained from genome-wide association studies (GWAS) of allergic conjunctivitis (AC) (20,958 cases and 356,319 controls), allergic asthma (AA) (9631 cases and 210,122 controls), allergic rhinitis (AR) (11,009 cases and 359,149 controls), atopic dermatitis (AD) (13,473 cases and 336,589 controls), keratoconus (KC) (2116 cases and 24,626 controls) and 91 circulating inflammatory cytokines (n = 14,824). Two-sample univariable and multivariable MR analyses were performed. A two-step MR was then applied to determine whether systemic inflammatory cytokines mediated the effect of allergic disease on keratoconus.ResultsThe causal odds ratio (OR) estimate of genetically determined KC was 1.66 (95% CI: 1.32-2.08; P < 0.001) for AC, 1.29 (95% CI: 1.10-1.51, P = 0.0014) for AA, 1.39 (95% CI: 1.15-1.68; P < 0.001) for AR and 1.30 (95% CI: 1.17-1.45, P < 0.001) for AD. Multivariable MR indicated a suggestive association between AC and KC after conditioning on other allergic diseases (OR 1.61; 95% CI: 1.10-2.34; P adjusted = 0.054). Two-step MR revealed that the effect was not mediated by systemic inflammatory cytokines.ConclusionsOur findings provide evidence of a potential causal relationship between AC and KC. The effect of AC on KC may be mediated via other systemic inflammatory cytokines not included in the present study, or by alternative mechanisms. These findings may offer insight for prevention and intervention strategies to lower the risk of KC in patients with AC.
| S-EPMC11621933 | biostudies-literature
Project description:Purpose: To investigate the potential causal relationship between coffee consumption and osteoarthritis (OA), and to disentangle whether body mass index (BMI) and Bone mineral density (BMD) mediate this relationship. Methods: We performed two-sample and two-step Mendelian randomization (MR) analyses utilizing publicly available genome-wide association studies (GWAS) summary statistics to estimate the association between coffee intake and OA risk (including knee OA, hip OA, knee or hip OA, and total OA), as well as the possible mediating effects of BMI and BMD. In addition, data of different coffee types (decaffeinated coffee, instant coffee, ground coffee-including espresso, filter, etc., and other coffee types) were used to explore the effect of coffee type on the risk of OA. Results: In two-sample MR, coffee intake increased the risk of OA in various sites, with the most significant impact observed in knee osteoarthritis (KOA) (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.57-2.61, p < 0.001). The effect on self-reported OA was minimal (OR 1.03, 95% CI 1.01-1.05, p = 0.006). Further analysis of different types of coffee revealed that only decaffeinated coffee was causally associated with both KOA (OR 4.40, 95% CI 1.71-11.33, p = 0.002) and self-reported OA (OR 1.13, 95% CI 1.02-1.26, p = 0.022). In two-step MR, BMI explained over half of the coffee intake-all OA risk association, while BMD accounted for less than 5% of the mediation effect. Conclusion: Our study suggests that coffee intake increase the risk of OA, with BMI playing a significant mediating role. Decaffeinated coffee appears to have the greatest impact on OA risk compared to other types of coffee. Therefore, managing BMI and selecting appropriate types of coffee should be included in the health management of individuals who frequently consume coffee.
| S-EPMC10867243 | biostudies-literature
Project description:BackgroundMendelian randomization (MR) is a powerful tool in epidemiology that can be used to estimate the causal effect of an exposure on an outcome in the presence of unobserved confounding, by utilizing genetic variants that are instrumental variables (IVs) for the exposure. This has been extended to multivariable MR (MVMR) to estimate the effect of two or more exposures on an outcome.Methods and resultsWe use simulations and theory to clarify the interpretation of estimated effects in a MVMR analysis under a range of underlying scenarios, where a secondary exposure acts variously as a confounder, a mediator, a pleiotropic pathway and a collider. We then describe how instrument strength and validity can be assessed for an MVMR analysis in the single-sample setting, and develop tests to assess these assumptions in the popular two-sample summary data setting. We illustrate our methods using data from UK Biobank to estimate the effect of education and cognitive ability on body mass index.ConclusionMVMR analysis consistently estimates the direct causal effect of an exposure, or exposures, of interest and provides a powerful tool for determining causal effects in a wide range of scenarios with either individual- or summary-level data.
| S-EPMC6734942 | biostudies-literature
Project description:Multivariable Mendelian randomization (MVMR) is a form of instrumental variable analysis which estimates the direct effect of multiple exposures on an outcome using genetic variants as instruments. Mendelian randomization and MVMR are frequently conducted using two-sample summary data where the association of the genetic variants with the exposures and outcome are obtained from separate samples. If the genetic variants are only weakly associated with the exposures either individually or conditionally, given the other exposures in the model, then standard inverse variance weighting will yield biased estimates for the effect of each exposure. Here, we develop a two-sample conditional F-statistic to test whether the genetic variants strongly predict each exposure conditional on the other exposures included in a MVMR model. We show formally that this test is equivalent to the individual level data conditional F-statistic, indicating that conventional rule-of-thumb critical values of F> 10, can be used to test for weak instruments. We then demonstrate how reliable estimates of the causal effect of each exposure on the outcome can be obtained in the presence of weak instruments and pleiotropy, by repurposing a commonly used heterogeneity Q-statistic as an estimating equation. Furthermore, the minimized value of this Q-statistic yields an exact test for heterogeneity due to pleiotropy. We illustrate our methods with an application to estimate the causal effect of blood lipid fractions on age-related macular degeneration.
| S-EPMC9479726 | biostudies-literature
Project description:BackgroundObservational studies show an association between reduced lung function and impaired cognition. Cognitive dysfunction influences important health outcomes and is a precursor to dementia, but treatments options are currently very limited. Attention has therefore focused on identifying modifiable risk factors to prevent cognitive decline and preserve cognition. Our objective was to determine if lung function or risk of COPD causes reduced cognitive function using Mendelian randomization (MR).MethodsSingle nucleotide polymorphisms from genome wide association studies of lung function and COPD were used as exposures. We examined their effect on general cognitive function in a sample of 132,452 individuals. We then performed multivariable MR (MVMR), examining the effect of lung function before and after conditioning for covariates.ResultsWe found only weak evidence that reduced lung function (Beta - 0.002 (SE 0.02), p-value 0.86) or increased liability to COPD (- 0.008 (0.008), p-value 0.35) causes lower cognitive function. MVMR found both reduced FEV1 and FVC do cause lower cognitive function, but that after conditioning for height (- 0.03 (0.03), p-value 0.29 and - 0.01 (0.03) p-value 0.62, for FEV1 and FVC respectively) and educational attainment (- 0.03 (0.03) p-value 0.33 and - 0.01 (0.02), p-value 0.35) the evidence became weak.ConclusionWe did not find evidence that reduced lung function or COPD causes reduced cognitive function. Previous observational studies are probably affected by residual confounding. Research efforts should focus on shared risk factors for reduced lung function and cognition, rather than lung function alone as a modifiable risk factor.
| S-EPMC8296721 | biostudies-literature
Project description:ObjectivesTo examine whether educational attainment and intelligence have causal effects on risk of Alzheimer's disease (AD), independently of each other.DesignTwo-sample univariable and multivariable Mendelian randomization (MR) to estimate the causal effects of education on intelligence and vice versa, and the total and independent causal effects of both education and intelligence on AD risk.Participants17 008 AD cases and 37 154 controls from the International Genomics of Alzheimer's Project (IGAP) consortium.Main outcome measureOdds ratio (OR) of AD per standardized deviation increase in years of schooling (SD = 3.6 years) and intelligence (SD = 15 points on intelligence test).ResultsThere was strong evidence of a causal, bidirectional relationship between intelligence and educational attainment, with the magnitude of effect being similar in both directions [OR for intelligence on education = 0.51 SD units, 95% confidence interval (CI): 0.49, 0.54; OR for education on intelligence = 0.57 SD units, 95% CI: 0.48, 0.66]. Similar overall effects were observed for both educational attainment and intelligence on AD risk in the univariable MR analysis; with each SD increase in years of schooling and intelligence, odds of AD were, on average, 37% (95% CI: 23-49%) and 35% (95% CI: 25-43%) lower, respectively. There was little evidence from the multivariable MR analysis that educational attainment affected AD risk once intelligence was taken into account (OR = 1.15, 95% CI: 0.68-1.93), but intelligence affected AD risk independently of educational attainment to a similar magnitude observed in the univariate analysis (OR = 0.69, 95% CI: 0.44-0.88).ConclusionsThere is robust evidence for an independent, causal effect of intelligence in lowering AD risk. The causal effect of educational attainment on AD risk is likely to be mediated by intelligence.
| S-EPMC7660137 | biostudies-literature
Project description:Immunity and inflammation in pulmonary arterial hypertension (PAH) has gained more attention. This research aimed to investigate the potential causal connections between 731 immunophenotypes and the likelihood of developing PAH. We obtained immunocyte data and PAH from openly accessible database and used Mendelian randomization (MR) analysis to evaluate the causal association between each immunophenotype and PAH. Various statistical methods were employed: the MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode. In the study of 731 different types of immune cells, it was found that 9 showed a potential positive connection (IVW P < .05) with increased risk of PAH, while 19 had a possible negative link to decreased risk. Following false discovery rate (FDR) adjustment, the analysis using the IVW method demonstrated that 5 immune phenotypes were significantly associated with PAH (FDR < 0.05, OR > 1). Conversely, there was a negative correlation between PAH and 4 immune cell types (FDR < 0.05, OR < 1). Sensitivity analyses suggested the robustness of all MR findings. This research, for the first time, has revealed indicative evidence of a causal link between circulating immune cell phenotypes and PAH through genetic mechanisms. These results underscore the importance of immune cells in the pathogenesis of PAH.
| S-EPMC11404942 | biostudies-literature
Project description:BackgroundSeveral recent investigations have posited that distinct metabolites in the bloodstream may be correlated with the pathogenesis of Pulmonary Hypertension (PH). Nonetheless, the interrelationship between the pathogenesis of PH and metabolite fluctuations remains incompletely elucidated, and findings may differ across studies.MethodsIn the extant research, data from 486 metabolite-and PH-related genetic variants in human subjects were procured based on Genome-Wide Association Studies (GWAS) and Finnish databases. Univariate Mendelian Randomization analyses were deployed to evaluate the causal relationships between them. The utilization of the randomized Inverse Variance weighted(IVW) method served as the primary analytic framework in this Mendelian Randomization (MR) study. Additionally, four alternative computational strategies, encompassing MR-Egger, were employed as auxiliary methods. A myriad of tests, including Cochran's Q Test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and linkage disequilibrium score were incorporated to assess the robustness of the study outcomes. Metabolite pathway analysis was also executed to identify potential metabolic pathways.ResultsAfter a series of validations and corrected for False discovery rate (FDR), we found a significant association between 1,5-anhydroglucitol (OR = 2.00, 95% CI: 1.39-2.89, P = 0.0002) and PH, and a significant association between pyridoxalate (OR = 0.59, 95% CI: 0.43-0.81, P = 0.0009) and 1-a achidonoylglycerophosphocholine (OR = 1.78, 95% CI: 1.22-2.58, P = 0.0026) had a suggested association with PH. In addition, the vitamin B6 metabolic pathway was also determined to be associated with PH.ConclusionConclusively, we isolated 1,5-anhydroglucitol, 1-arachidonoylglycerophosphocholine, and pyridoxate as causally implicated in PH, thereby proffering substantial theoretical substantiation for the formulation of future PH prevention and screening paradigms.
| S-EPMC11518716 | biostudies-literature