A Mendelian Randomization Study of Plasma Homocysteine Levels and Cerebrovascular and Neurodegenerative Diseases.
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ABSTRACT:
SUBMITTER: Liu W
PROVIDER: S-EPMC8047106 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12-6.38; P = 2.7 × 10(-2)). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs).
| S-EPMC4850434 | biostudies-other
Project description:BackgroundAlthough several observational studies have suggested an association of elevated plasma homocysteine (Hcy) levels with increased risk of atrial fibrillation (AF), it remains unclear whether this association reflects causality. In this study, we aimed to investigate the causal association of plasma Hcy levels with AF risk.MethodsA two-sample Mendelian randomization (MR) study was designed to investigate the causal association of Hcy with AF. Summary data on association of single nucleotide polymorphisms (SNPs) with Hcy were extracted from the hitherto largest genome-wide association study (GWAS) with up to 44,147 individuals, and statistics data on association of SNPs with AF were obtained from another recently published GWAS with up to 1,030,836 individuals. SNPs were selected at a genome-wide significance threshold (p < 5 × 10-8). Fixed-effect inverse variance weighting (IVW) method was used to calculate the causal estimate. Other statistical methods and leave-one-out analysis were applied in the follow-up sensitivity analyses. MR-Egger intercept test was conducted to detect the potential directional pleiotropy.ResultsIn total, nine SNPs were identified as valid instrumental variables in our two-sample MR analysis. Fixed-effect IVW analysis indicated no evidence of causal association of genetically predicted Hcy with AF. The odds ratio (OR) and 95% confidence interval (CI) of AF per standard deviation (SD) increase in Hcy were 1.077 (0.993, 1.168), p = 0.075. Similar results were observed in the sensitivity analyses. MR-Egger intercept test suggested no evidence of potential horizonal pleiotropy.ConclusionsThis two-sample MR analysis found no evidence to support causal association of Hcy with AF.
| S-EPMC8189424 | biostudies-literature
Project description:ObjectiveTo systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease.MethodsWe used summary statistics from genome-wide association studies for body mass index (BMI), waist-to-hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2-sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively.ResultsGenetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44-113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29-91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59-457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (β = 0.11, 95% CI = 0.01-0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one-tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4-20%), but no evidence of mediation was found for average blood glucose.InterpretationAbdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. ANN NEUROL 2020;87:516-524.
| S-EPMC7392199 | biostudies-literature
Project description:BackgroundPhysical activity has been hypothesized to play a protective role in neurodegenerative diseases. However, effect estimates previously derived from observational studies were prone to confounding or reverse causation.MethodsWe performed a two-sample Mendelian randomization (MR) analysis to explore the causal association of accelerometer-measured physical activity with 3 common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We selected genetic instrumental variants reaching genome-wide significance (p < 5 × 10-8) from 2 largest meta-analyses of about 91,100 UK Biobank participants. Summary statistics for AD, PD, and ALS were retrieved from the up-to-date studies in European ancestry led by the international consortia. The random-effect, inverse-variance weighted MR was employed as the primary method, while MR pleiotropy residual sum and outlier (MR-PRESSO), weighted median, and MR-Egger were implemented as sensitivity tests. All statistical analyses were performed using the R programming language (Version 3.6.1; R Foundation for Statistical Computing, Vienna, Austria).ResultsPrimary MR analysis and replication analysis utilized 5 and 8 instrumental variables, which explained 0.2% and 0.4% variance in physical activity, respectively. In each set, one variant at 17q21 was significantly associated with PD, and MR sensitivity analyses indicated them it as an outlier and source of heterogeneity and pleiotropy. Primary results with the removal of outlier variants suggested odds ratios (ORs) of neurodegenerative diseases per unit increase in objectively measured physical activity were 1.52 for AD (95% confidence interval (95%CI): 0.88-2.63, p = 0.13) and 3.35 for PD (95%CI: 1.32-8.48, p = 0.01), while inconsistent results were shown in the replication set for AD (OR = 1.06, 95%CI: 1.01-1.12, p = 0.02) and PD (OR = 0.99, 95%CI: 0.88-0.12, p = 0.97). Similarly, the beneficial effect of physical activity on ALS (OR = 0.51, 95%CI: 0.29-0.91, p = 0.02) was not confirmed in the replication analysis (OR = 0.96, 95%CI: 0.91-1.02, p = 0.22).ConclusionGenetically predicted physical activity was not robustly associated with risk of neurodegenerative disorders. Triangulating evidence across other studies is necessary in order to elucidate whether enhancing physical activity is an effective approach in preventing the onset of AD, PD, or ALS.
| S-EPMC8343066 | biostudies-literature
Project description:Homocysteine (Hcy) is well known to be increased in the metabolic syndrome (MetS) incidence. However, it remains unclear whether the relationship is causal or not. Recently, Mendelian Randomization (MR) has been popularly used to assess the causal influence. In this study, we adopted MR to investigate the causal influence of Hcy on MetS in adults using three independent cohorts. We considered one-sample MR and two-sample MR. We analyzed one-sample MR in 5902 individuals (2090 MetS cases and 3812 controls) from the KARE and two-sample MR from the HEXA (676 cases and 3017 controls) and CAVAS (1052 cases and 764 controls) datasets to evaluate whether genetically increased Hcy level influences the risk of MetS. In observation studies, the odds of MetS increased with higher Hcy concentrations (odds ratio (OR) 1.17, 95%CI 1.12-1.22, p < 0.01). One-sample MR was performed using two-stage least-squares regression, with an MTHFR C677T and weighted Hcy generic risk score as an instrument. Two-sample MR was performed with five genetic variants (rs12567136, rs1801133, rs2336377, rs1624230, and rs1836883) by GWAS data as the instrumental variables. For sensitivity analysis, weighted median and MR-Egger regression were used. Using one-sample MR, we found an increased risk of MetS (OR 2.07 per 1-SD Hcy increase). Two-sample MR supported that increased Hcy was significantly associated with increased MetS risk by using the inverse variance weighted (IVW) method (beta 0.723, SE 0.119, and p < 0.001), the weighted median regression method (beta 0.734, SE 0.097, and p < 0.001), and the MR-Egger method (beta 2.073, SE 0.843, and p = 0.014) in meta-analysis. The MR-Egger slope showed no evidence of pleiotropic effects (intercept -0.097, p = 0.107). In conclusion, this study represented the MR approach and elucidates the significant relationship between Hcy and the risk of MetS in the Korean population.
| S-EPMC8308555 | biostudies-literature
Project description:BackgroundWhether 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.MethodsIndependent 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.ResultsHigher 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.ConclusionsThis study reveals suggestive evidence that B vitamin therapy and lowering of tHcy may reduce the risk of stroke, particularly subarachnoid hemorrhage and ischemic stroke.
| S-EPMC8063383 | biostudies-literature
Project description:BACKGROUND:Several observational studies have shown an association between increased circulating homocysteine and risk of type 2 diabetes (T2D). We aimed to assess whether this relation is causal using genetic data from large populations of individuals of European descent. METHODS:We investigated the association between homocysteine concentrations and blood glucose, plasma insulin, T2D in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort (n?=?1,016). A score of five previously published single nucleotide polymorphisms (SNPs) from genes involved in homocysteine metabolism were utilized as genetic instrument for homocysteine concentrations. The effect estimate of this genetic score with T2D was determined using results from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (including 34,840 cases and 114,981 controls). Further, the effects of the genetic score with fasting glucose and insulin were determined using results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (up to 38,238 non-diabetic participants). RESULTS:The genetic score provided a strong instrument for homocysteine concentrations (P?=?2.7?×?10(-143), F?=?650). In the PIVUS cohort, we found an association of homocysteine with fasting insulin [??=?0.056 (95% CI 0.021, 0.090), P?=?0.001], but not with incident diabetes. We did not find any evidence of a causal effect of homocysteine on fasting glucose, fasting insulin, or T2D (P?>?0.05 for all analyses) when using data from DIAGRAM or MAGIC studies. CONCLUSION:No evidence of a causal relationship of levels of plasma homocysteine with fasting glucose, fasting insulin, or T2D was observed.
| S-EPMC4671343 | biostudies-literature
Project description:Significant genetic association exists between rheumatoid arthritis (RA) and cardiovascular disease. The associated mechanisms include common inflammatory mediators, changes in lipoprotein composition and function, immune responses, etc. However, the causality of RA and vascular/heart problems remains unknown. Herein, we performed Mendelian randomization (MR) analysis using a large-scale RA genome-wide association study (GWAS) dataset (462,933 cases and 457,732 controls) and six cardio-cerebrovascular disease GWAS datasets, including age angina (461,880 cases and 447,052 controls), hypertension (461,880 cases and 337,653 controls), age heart attack (10,693 cases and 451,187 controls), abnormalities of heartbeat (461,880 cases and 361,194 controls), stroke (7,055 cases and 454,825 controls), and coronary heart disease (361,194 cases and 351,037 controls) from United Kingdom biobank. We further carried out heterogeneity and sensitivity analyses. We confirmed the causality of RA with age angina (OR = 1.17, 95% CI: 1.04–1.33, p = 1.07E−02), hypertension (OR = 1.45, 95% CI: 1.20–1.75, p = 9.64E−05), age heart attack (OR = 1.15, 95% CI: 1.05–1.26, p = 3.56E−03), abnormalities of heartbeat (OR = 1.07, 95% CI: 1.01–1.12, p = 1.49E−02), stroke (OR = 1.06, 95% CI: 1.01–1.12, p = 2.79E−02), and coronary heart disease (OR = 1.19, 95% CI: 1.01–1.39, p = 3.33E−02), contributing to the understanding of the overlapping genetic mechanisms and therapeutic approaches between RA and cardiovascular disease.
| S-EPMC8567962 | biostudies-literature
Project description:BackgroundSeveral studies have reported a protective role of circulating α-Klotho on cardiovascular diseases (CVD); however, the causality remains unclear. We aim to elucidate whether genetically predicted circulating α-Klotho levels were causally associated with the risk of coronary artery disease (CAD), atrial fibrillation (AF), heart failure (HF), stroke, ischemic stroke (IS), and IS subtypes.MethodsA two-sample Mendelian randomization (MR) study was designed, with 5 single-nucleotide polymorphisms associated with circulating α-Klotho levels utilized as instrumental variables. MR estimates on each CVD outcome derived from the fixed-effects inverse-variance weighted (IVW) approach in different data sources were combined by the fixed-effects meta-analysis approach, complemented by several sensitivity analyses including the simple median, the weighed median, MR-Egger regression, and MR-pleiotropy residual sum and outlier.ResultsIn the meta-analysis combining different data sources, suggestive inverse causal association of circulating α-Klotho concentrations with CAD [Odds ratio (OR), 0.97; 95% confidence interval (CI), 0.94, 1.00; P = 0.044] and significant inverse association of circulating α-Klotho concentrations with AF (OR, 0.96; 95% CI, 0.93, 0.99; P = 0.005) was observed. However, there was no causal association of α-Klotho with HF, any stroke, IS, or IS subtypes neither in different data sources nor in the meta-analysis. Complementary sensitivity analyses showed consistent and robust results in general.ConclusionEvidence was found for a protective effect of circulating α-Klotho on the prevention of AF risk. However, no significant causal association between genetically predicted circulating α-Klotho levels and risk of CAD, HF, stroke, IS, or IS subtypes was found.
| S-EPMC8859151 | biostudies-literature
Project description:An understanding of whether homocysteine is a cause or a marker of increased blood pressure is relevant because blood homocysteine can be effectively lowered by safe and inexpensive interventions (e.g., vitamin B-6, B-9, and B-12 supplementation).The aim was to assess the causal influence of homocysteine on systolic and diastolic blood pressure (SBP and DBP, respectively) in adults with the use of Mendelian randomization (MR).Data from the 1982 Pelotas Birth Cohort (Brazil) were used. A total of 4297 subjects were evaluated in 2004-2005 (mean age: 22.8 y). The association of homocysteine concentration with SBP and DBP was assessed by conventional ordinary least-squares (OLS) linear regression and 2-stage least-squares (2SLS) regression (MR analysis). The single nucleotide polymorphism (SNP) methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) was used as proxy for homocysteine concentration. We also applied MR to data from the International Consortium for Blood Pressure (ICBP) genomewide association studies (>69,000 participants) using rs1801133 and additional homocysteine-associated SNPs as instruments.In OLS regression, a 1-SD unit increase in log homocysteine concentration was associated with an increase of 0.9 (95% CI: 0.4, 1.4) mm Hg in SBP and of 1.0 (95% CI: 0.6, 1.4) mm Hg in DBP. In 2SLS regression, for the same increase in homocysteine, the coefficients were -1.8 mm Hg for SBP (95% CI: -3.9, 0.4 mm Hg; P = 0.01) and 0.1 mm Hg for DBP (95% CI: -1.5, 1.7 mm Hg; P = 0.24). In the MR analysis of ICBP data, homocysteine concentration was not associated with SBP (? = 0.6 mm Hg for each 1-SD unit increase in log homocysteine; 95% CI: -0.8, 1.9 mm Hg) but was positively associated with DBP (? = 1.1 mm Hg; 95% CI: 0.2, 1.9 mm Hg). The association of genetically increased homocysteine with DBP was not consistent across different SNPs.Overall, the present findings do not corroborate the hypothesis that homocysteine has a causal role in blood pressure, especially in SBP.
| S-EPMC4691668 | biostudies-other