Effects of blood lead on coronary artery disease and its risk factors: a Mendelian Randomization study.
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ABSTRACT:
SUBMITTER: Schooling CM
PROVIDER: S-EPMC6831655 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
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Project description:Background Elevated blood pressure is a major cause of cardiovascular morbidity and mortality. However, it is not known whether midlife blood pressure affects later life cardiovascular risk independent of later life blood pressure. Methods and Results Using genetic association estimates from the UK Biobank and CARDIoGRAMplusC4D consortium, univariable mendelian randomization was performed to investigate the total effect of genetically predicted mean arterial pressure (MAP) at age ≤55 years on coronary artery disease (CAD) risk, and multivariable mendelian randomization was performed to investigate the effect of genetically predicted MAP on CAD risk after adjusting for genetically predicted MAP at age >55 years. In both univariable and multivariable mendelian randomization analyses, there was consistent evidence of higher genetically predicted MAP at age ≤55 years increasing CAD risk. This association persisted after adjusting for genetically predicted MAP at age >55 years, when considering nonoverlapping populations for the derivation of MAP and CAD risk genetic association estimates, when investigating only incident CAD events after age >55 years, and when restricting the analysis to variants with most heterogeneity in their associations with MAP ≤55 and >55 years. For a 10-mm Hg increase in genetically predicted MAP at age ≤55 years, the odds ratio of later life CAD was 1.43 (95% CI, 1.16-1.77; P=0.001) after adjusting for genetically predicted MAP at age >55 years. Conclusions These mendelian randomization findings support a cumulative lifetime effect of elevated blood pressure on increasing CAD risk. Clinical and public health efforts toward cardiovascular disease reduction should optimize blood pressure control throughout life.
| S-EPMC7660704 | biostudies-literature
Project description:Selecting a set of valid genetic variants is critical for Mendelian randomization (MR) to correctly infer risk factors causing a disease. We here developed a method for selecting genetic variants as valid instrumental variables for inferring risk factors causing coronary artery disease (CAD). Using this method, we selected two sets of single-nucleotide-polymorphism (SNP) genetic variants (SNP338 and SNP363) associated with each of the three potential risk factors for CAD including low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c) and triglycerides (TG) from two independent GWAS datasets. We performed in-depth multivariate MR (MVMR) analyses and the results from both datasets consistently showed that LDL-c was strongly associated with increased risk for CAD (? = 0.396,OR = 1.486 per 1?SD (equivalent to 38?mg/dL), 95CI = (1.38, 1.59) in SNP338; and ? = 0.424, OR = 1.528 per 1?SD, 95%CI = (1.42, 1.65) in SNP363); HDL-c was strongly associated with reduced risk for CAD (? = -0.315, OR = 0.729 per 1?SD (equivalent to 16?mg/dL), 95CI = (0.68, 0.78) in SNP338; and ? = -0.319, OR = 0.726 per 1?SD, 95%CI = (0.66, 0.80), in SNP363). In case of TG, when using the full datasets, an increased risk for CAD (? = 0.184, OR = 1.2 per 1?SD (equivalent to 89?mg/dL), 95%CI = (1.12, 1.28) in SNPP338; and ? = 0.207, OR = 1.222 per 1?SD, 95%CI = (1.10, 1.36) in SNP363) was observed, while using partial datasets that contain shared and unique SNPs showed that TG is not a risk factor for CAD. From these results, it can be inferred that TG itself is not a causal risk factor for CAD, but it's shown as a risk factor due to pleiotropic effects associated with LDL-c and HDL-c SNPs. Large-scale simulation experiments without pleiotropic effects also corroborated these results.
| S-EPMC7280530 | biostudies-literature
Project description:We assessed the associations of genetically instrumented blood sucrose with risk of coronary heart disease (CHD) and its risk factors (i.e., type 2 diabetes, adiposity, blood pressure, lipids, and glycaemic traits), using two-sample Mendelian randomization. We used blood fructose as a validation exposure. Dental caries was a positive control outcome. We selected genetic variants strongly (P < 5 × 10-6) associated with blood sucrose or fructose as instrumental variables and applied them to summary statistics from the largest available genome-wide association studies of the outcomes. Inverse-variance weighting was used as main analysis. Sensitivity analyses included weighted median, MR-Egger and MR-PRESSO. Genetically higher blood sucrose was positively associated with the control outcome, dental caries (odds ratio [OR] 1.04 per log10 transformed effect size [median-normalized standard deviation] increase, 95% confidence interval [CI] 1.002-1.08, P = 0.04), but this association did not withstand allowing for multiple testing. The estimate for blood fructose was in the same direction. Genetically instrumented blood sucrose was not clearly associated with CHD (OR 1.01, 95% CI 0.997-1.02, P = 0.14), nor with its risk factors. Findings were similar for blood fructose. Our study found some evidence of the expected detrimental effect of sucrose on dental caries but no effect on CHD. Given a small effect on CHD cannot be excluded, further investigation with stronger genetic predictors is required.
| S-EPMC7725802 | biostudies-literature
Project description:Meta-analyses of randomized controlled trials (RCTs) suggest calcium could have adverse effects on cardiovascular disease, although these findings are controversial. To clarify, we assessed whether people with genetically higher calcium had a higher risk of coronary artery disease (CAD), myocardial infarction (MI) and their risk factors. We used a two-sample Mendelian randomization study. We identified genetic variants (single nucleotide polymorphisms (SNPs)) that independently contributed to serum calcium at genome-wide significance which we applied to large extensively genotyped studies of CAD, MI, diabetes, lipids, glycaemic traits and adiposity to obtain unconfounded estimates, with body mass index (BMI) as a control outcome. Based on 4 SNPs each 1?mg/dl increase in calcium was positively associated with CAD (odds ratio (OR) 1.49, 95% confidence interval (CI) 1.02-2.17), MI (OR 1.58, 95% CI 1.06-2.35), LDL-cholesterol (0.21 standard deviations, 95% CI 0.01-0.4), total cholesterol (0.21 standard deviations, 95% CI 0.03-0.38) and possibly triglycerides (0.19 standard deviations, 95% CI -0.1-0.48), but was unlikely related to BMI although the estimate lacked precision. Sensitivity analysis using 13 SNPs showed a higher risk for CAD (OR 1.87, 95% CI 1.14-3.08). Our findings, largely consistent with the experimental evidence, suggest higher serum calcium may increase the risk of CAD.
| S-EPMC5307362 | biostudies-literature
Project description:Observational studies have reported a cardioprotective effect of vitamin E whereas intervention trials failed to confirm its beneficial effects, and even some reported adverse effects of vitamin E supplements on coronary artery disease (CAD). To clarify, we conducted a two-sample mendelian randomization study to investigate causal association of vitamin E with the risk of CAD. Three single nucleotide polymorphisms (SNPs) identified in a genome-wide analysis study including 7781 individuals of European descent, rs964184, rs2108622, and rs11057830 were used as the genetic instruments for vitamin E. Data for CAD/myocardial infarction (MI) were available from Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) plus The Coronary Artery Disease (C4D) Genetics consortium. The effect of each SNP on CAD/myocardial infarction (MI) was weighted by its effect on serum vitamin E (mg/L), and results were pooled to give a summary estimates for the effect of increased vitamin E on risk of CAD/MI. Based on 3 SNPs each 1 mg/L increase in vitamin E was significantly associated with CAD (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.03-1.06), MI (OR 1.04, 95% CI 1.03-1.05), elevated low-density lipoprotein cholesterol (0.021 standard deviations (SD), 95% CI 0.016, 0.027), triglycerides (0.026 SD, 95% CI 0.021, 0.031), and total cholesterol (0.043 SD, 95% CI 0.038, 0.048) and lower levels of high-density lipoprotein cholesterol (-0.019 SD 95% CI -0.024, -0.014). Our findings indicate that higher vitamin E may increase the risk of CAD/MI and the safety and efficacy of vitamin E supplementation use should be reevaluated.
| S-EPMC6770080 | biostudies-literature
Project description:Estimated ?5-desaturase (D5D) and ?6-desaturase (D6D) are key enzymes in metabolism of polyunsaturated fatty acids (PUFA) and have been associated with cardiometabolic risk; however, causality needs to be clarified. We applied two-sample Mendelian randomization (MR) approach using a representative sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study and public data from DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) genome-wide association studies (GWAS). Furthermore, we addressed confounding by linkage disequilibrium (LD) as all instruments from FADS1 (encoding D5D) are in LD with FADS2 (encoding D6D) variants. Our univariable MRs revealed risk-increasing total effects of both, D6D and D5D on type 2 diabetes (T2DM) risk; and risk-increasing total effect of D6D on risk of coronary artery disease (CAD). The multivariable MR approach could not unambiguously allocate a direct causal effect to either of the individual desaturases. Our results suggest that D6D is causally linked to cardiometabolic risk, which is likely due to downstream production of fatty acids and products resulting from high D6D activity. For D5D, we found indication for causal effects on T2DM and CAD, which could, however, still be confounded by LD.
| S-EPMC7469057 | biostudies-literature
Project description:ObjectiveObservational studies show that higher hemoglobin A1c (A1C) predicts coronary artery disease (CAD). It remains unclear whether this association is driven entirely by glycemia. We used Mendelian randomization (MR) to test whether A1C is causally associated with CAD through glycemic and/or nonglycemic factors.Research design and methodsTo examine the association of A1C with CAD, we selected 50 A1C-associated variants (log10 Bayes factor ≥6) from an A1C genome-wide association study (GWAS; n = 159,940) and performed an inverse-variance weighted average of variant-specific causal estimates from CAD GWAS data (CARDIoGRAMplusC4D; 60,801 CAD case subjects/123,504 control subjects). We then replicated results in UK Biobank (18,915 CAD case subjects/455,971 control subjects) and meta-analyzed all results. Next, we conducted analyses using two subsets of variants, 16 variants associated with glycemic measures (fasting or 2-h glucose) and 20 variants associated with erythrocyte indices (e.g., hemoglobin [Hb]) but not glycemic measures. In additional MR analyses, we tested the association of Hb with A1C and CAD.ResultsGenetically increased A1C was associated with higher CAD risk (odds ratio [OR] 1.61 [95% CI 1.40, 1.84] per %-unit, P = 6.9 × 10-12). Higher A1C was associated with increased CAD risk when using only glycemic variants (OR 2.23 [1.73, 2.89], P = 1.0 × 10-9) and when using only erythrocytic variants (OR 1.30 [1.08, 1.57], P = 0.006). Genetically decreased Hb, with concomitantly decreased mean corpuscular volume, was associated with higher A1C (0.30 [0.27, 0.33] %-unit, P = 2.9 × 10-6) per g/dL and higher CAD risk (OR 1.19 [1.04, 1.37], P = 0.02).ConclusionsGenetic evidence supports a causal link between higher A1C and higher CAD risk. This relationship is driven not only by glycemic but also by erythrocytic, glycemia-independent factors.
| S-EPMC6609962 | biostudies-literature
Project description:BackgroundMenarche timing may not be directly associated with the risk of coronary artery disease (CAD). Therefore, we investigated the roles of metabolic factors in explaining the effect of age at menarche on CAD risk.MethodsWe identified women with age at menarche and CAD by using three analytical methods: Mendelian randomization (MR), logistic regression analysis, and Cox proportional hazard regression. The first two analyses were performed in the Taiwan Biobank (N = 71,923) study, and the last analysis was performed in the Chin-Shan Community Cardiovascular Cohort study (N = 1,598). We further investigated the role of metabolic factors in mediating the effect of age at menarche on CAD risk by using three complementary methods with mediation analyses.ResultsOne standard deviation of earlier age at menarche was associated with a 2% higher CAD risk [odds ratio = 1.02, 95% confidence interval (CI) = 1.001-1.03] in the MR analysis, an 11% higher risk (odds ratio = 1.11, 95% CI = 1.02-1.21) in the logistic regression analysis, and a 57% higher risk (hazard ratio = 1.57, 95% CI = 1.12-2.19) in the Cox proportional hazard regression. All the analyses consistently supported the role of systolic blood pressure in mediating this effect. The MR results indicated that 29% (95% CI = 26%-32%) of the effect of genetically predicted earlier age at menarche on CAD risk was mediated by genetically predicted systolic blood pressure.ConclusionThe results obtained using different analytical methods suggest that interventions aimed at lowering systolic blood pressure can reduce the cases of CAD attributable to earlier age at menarche.
| S-EPMC9868731 | biostudies-literature
Project description:Mendelian randomization (MR) of lipid traits in coronary artery disease (CAD) has provided evidence for causal associations of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) in CAD, but many lipid trait genetic variants have pleiotropic effects on other cardiovascular risk factors that may bias MR associations. The goal of this study was to evaluate pleiotropic effects of lipid trait genetic variants and to account for these effects in MR of lipid traits in CAD. We performed multivariable MR using inverse variance-weighted (IVW) and MR-Egger methods in large (n ≥ 300,000) GWAS datasets. We found that 30% of lipid trait genetic variants have effects on metabolic syndrome traits, including body mass index (BMI), type 2 diabetes (T2D), and systolic blood pressure (SBP). Nonetheless, in multivariable MR analysis, LDL-C, high-density lipoprotein cholesterol (HDL-C), TG, BMI, T2D, and SBP are independently associated with CAD, and each of these associations is robust to adjustment for directional pleiotropy. MR at loci linked to direct effects on HDL-C and TG suggests locus- and mechanism-specific causal effects of these factors on CAD.
| S-EPMC7933489 | biostudies-literature
Project description:Previous Mendelian randomization (MR) studies have yielded a conflicting causal relationship between sarcopenia and coronary artery disease (CAD), and lack the association of CAD with sarcopenia. We performed a bi-directional MR approach to clarify the causality and causal direction between sarcopenia-related traits and CAD. In stage 1 analysis, estimates of inverse variance weighting (IVW) and several sensitivity analyses were obtained by applying genetic variants that predict sarcopenia-related traits to CAD. Conversely, we also applied genetic variants that predict CAD to sarcopenia-related traits in stage 2 analyses. IVW analysis showed that higher handgrip strength reduces risk for CAD: A 1-kilogram (kg) increase in genetically determined left handgrip strength reduced odds of CAD by 36% [odds ratio (OR) = 0.64, 95% confidence interval (CI) 0.498 - 0.821, p = 4.56E-04], and right handgrip strength reduced odds of CAD by 41.1% (OR = 0.599, 95% CI 0.476 - 0.753, p = 1.10E-05). However, genetically predicted CAD did not show any causal association with handgrip strength, and no significant causal relationship was detected between genetically instrumented body lean mass and CAD. Our results suggest that decreased muscle strength but not decreased muscle mass leads to the increased risk of CAD in sarcopenia.
| S-EPMC7066916 | biostudies-literature