A Mendelian randomization study of the effect of calcium on coronary artery disease, myocardial infarction and their risk factors.
ABSTRACT: 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.
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.
Project description:BACKGROUND: Although plasma fibrinogen levels are related to cardiovascular risk, data regarding the role of fibrinogen genetic variation in myocardial infarction (MI) or coronary artery disease (CAD) etiology remain inconsistent. The purpose of the present study was to investigate the effect of fibrinogen A (FGA), fibrinogen B (FGB) and fibrinogen G (FGG) gene SNPs and haplotypes on susceptibility to CAD in a homogeneous Greek population. METHODS: We genotyped for rs2070022, rs2070016, rs2070006 in FGA gene, the rs7673587, rs1800789, rs1800790, rs1800788, rs1800787, rs4681 and rs4220 in FGB gene and for the rs1118823, rs1800792 and rs2066865 SNPs in FGG gene applying an arrayed primer extension-based genotyping method (APEX-2) in a sample of CAD patients (n = 305) and controls (n = 305). Logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), before and after adjustment for potential confounders. RESULTS: None of the FGA and FGG SNPs and FGA, FGB, FGG and FGA-FGG haplotypes was associated with disease occurrence after adjustment. Nevertheless, rs1800787 and rs1800789 SNPs in FGB gene seem to decrease the risk of CAD, even after adjustment for potential confounders (OR = 0.42, 95%CI: 0.19-0.90, p = 0.026 and OR = 0.44, 95%CI:0.21-0.94, p = 0.039, respectively). CONCLUSIONS: FGA and FGG SNPs as well as FGA, FGB, FGG and FGA-FGG haplotypes do not seem to be important contributors to CAD occurrence in our sample. On the contrary, FGB rs1800787 and rs1800789 SNPs seem to confer protection to disease onset lowering the risk by about 50% in homozygotes for the minor alleles.
Project description:Observational studies have reported an association of handgrip strength with risk of cardiovascular disease. However, residual confounding and reverse causation may have influenced these findings. A Mendelian randomization (MR) study was conducted to examine whether handgrip is causally associated with cardiovascular disease. Two single nucleotide polymorphisms (SNPs), rs3121278 and rs752045, were used as the genetic instruments for handgrip. The effect of each SNP on coronary artery disease/myocardial infarction (CAD/MI) was weighted by its effect on handgrip strength, and estimates were pooled to provide a summary measure for the effect of increased handgrip on risk of CAD/MI. MR analysis showed that higher grip strength reduces risk for CAD/MI, with 1-kilogram increase in genetically determined handgrip reduced odds of CAD by 6% (odds ratio (OR)?=?0.94, 95% confidence interval (CI) 0.91-0.99, P?=?0.01), and reduced odds of MI by 7% (OR?=?0.93, 95% CI 0.89-0.98, P?=?0.003). No association of grip strength with type 2 diabetes, body mass index, LDL- and HDL-cholesterol, triglycerides and fasting glucose was found. The inverse causal relationship between handgrip and the risk of CAD or MI suggests that promoting physical activity and resistance training to improve muscle strength may be important for cardiovascular health.
Project description:<h4>Aims</h4>The effect of first-line antianginal agents, ?-blockers, and calcium antagonists on clinical outcomes in stable coronary artery disease (CAD) remains uncertain.<h4>Methods and results</h4>We analysed the use of ?-blockers or calcium antagonists (baseline and annually) and outcomes in 22 006 stable CAD patients (enrolled 2009-2010) followed annually to 5?years, in the CLARIFY registry (45 countries). Primary outcome was all-cause death. Secondary outcomes were cardiovascular death and the composite of cardiovascular death/non-fatal myocardial infarction (MI). After multivariable adjustment, baseline ?-blocker use was not associated with lower all-cause death [1345 (7.8%) in users vs. 407 (8.4%) in non-users; hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.84-1.06; P?=?0.30]; cardiovascular death [861 (5.0%) vs. 262 (5.4%); HR 0.91, 95% CI 0.79-1.05; P?=?0.20]; or cardiovascular death/non-fatal MI [1272 (7.4%) vs. 340 (7.0%); HR 1.03, 95% CI 0.91-1.16; P?=?0.66]. Sensitivity analyses according to ?-blocker use over time and to prescribed dose produced similar results. Among prior MI patients, for those enrolled in the year following MI, baseline ?-blocker use was associated with lower all-cause death [205 (7.0%) vs. 59 (10.3%); HR 0.68, 95% CI 0.50-0.91; P?=?0.01]; cardiovascular death [132 (4.5%) vs. 49 (8.5%); HR 0.52, 95% CI 0.37-0.73; P?=?0.0001]; and cardiovascular death/non-fatal MI [212 (7.2%) vs. 59 (10.3%); HR 0.69, 95% CI 0.52-0.93; P?=?0.01]. Calcium antagonists were not associated with any difference in mortality.<h4>Conclusion</h4>In this contemporary cohort of stable CAD, ?-blocker use was associated with lower 5-year mortality only in patients enrolled in the year following MI. Use of calcium antagonists was not associated with superior mortality, regardless of history of MI.
Project description:<h4>Background</h4>Psychological stress is an independent risk factor for cardiovascular disease (CVD), but the mechanism by which stress is associated with CVD is not entirely understood. Although genetic factors are implied in both stress responsivity and cardiovascular reactivity, no studies to date have investigated their interactions with stress for cardiovascular end points. The objective was to elucidate the association and interactions between a genetic risk score (GRS), individual genetic variants and stress for three cardiovascular end points: coronary artery disease (CAD), fatal myocardial infarction (MI), non-fatal MI, and cardiovascular death.<h4>Methods and findings</h4>18,559 participants from the Malmö Diet Cancer Study, a population-based prospective study, were included in the analyses. Cox proportional hazards regression models were used and adjusted for a large number of known predictors of cardiovascular end points. Mean follow-up time in years was 14.6 (CAD; n = 1938), 14.8 (fatal MI; n = 436), 14.8 (non-fatal MI; n = 1108), and 15.1 (cardiovascular death; n = 1071) respectively. GRS was significantly associated with increased risks of CAD (top quartile hazard ratio [HR], 1.72; 95% confidence interval [CI], 1.51-1.96), fatal MI (top quartile HR, 1.62; 95%CI, 1.23-2.15), non-fatal MI (top quartile HR, 1.55; 95%CI, 1.31-1.84), and cardiovascular death (top quartile HR, 1.29; 95%CI, 1.08-1.53). Stress was not independently associated with any end point and did not interact with GRS. Four individual genetic variants interacted unfavorably with stress for end points with mortality outcomes.<h4>Conclusion</h4>A GRS composed of 50 SNPs and predictive of CAD was found for the first time to also strongly predict fatal MI, non-fatal MI and cardiovascular death. A stress-sensitive component of the GRS was isolated on the basis of individual genetic variants that interacted unfavorably with stress.
Project description:Although numerous single-nucleotide polymorphisms (SNPs) in chromosome 9p21 have been associated with coronary artery disease (CAD) and incident myocardial infarction (MI) in whites, there are limited and conflicting reports on the association of this locus with prognosis in whites with existing CAD and no reports in blacks or Hispanics. We investigated the hypothesis that 9p21 polymorphisms are associated with increased risk for adverse cardiovascular outcomes in patients with documented CAD.We studied the association of 155 chromosome 9p21 SNPs with adverse outcomes among hypertension patients with CAD of multiple races/ethnicities in INVEST-GENES (the International Verapamil SR Trandolapril Study Genetic Substudy) (n=1460 and n=5979 for 2 SNPs) with replication testing of 4 SNPs in the INFORM (Investigation of Outcomes From Acute Coronary Syndrome) study (n=714) of patients with acute coronary syndromes. In INVEST, the haplotype comprising the risk allele for the widely reported 9p21 SNPs was associated with better prognosis in whites (odds ratio [OR], 0.72; 95% CI, 0.57 to 0.92; P=0.0085) but not in blacks (OR, 1.21; 95% CI, 0.68 to 1.24; P=0.52) or Hispanics (OR, 0.96; 95% CI, 0.65 to 1.44; P=0.86). A less commonly reported linkage disequilibrium block was associated with worse prognosis in INVEST in both whites (OR, 1.52; 95% CI, 1.20 to 1.93; P=0.0006) and blacks (OR, 4.11; 95% CI, 1.55 to 10.88; P=0.004).Our findings suggest that previously reported chromosome 9p21 SNPs, which predict incident CAD, are not associated with higher risk for adverse outcomes in patients with established CAD. The less commonly reported linkage disequilibrium block warrants further investigation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00133692.
Project description:Risk stratification among patients with coronary artery disease (CAD) is of considerable interest to potentially guide secondary preventive therapies. Cardiac troponins as well as C-reactive protein (hsCRP) and natriuretic peptides have emerged as biomarkers for risk stratification. The question remains if one of these biomarkers is superior in predicting adverse outcomes. Thus, we perform a head-to-head comparison between high-sensitivity troponin I (hsTnI), hsCRP, and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with CAD. Plasma levels were measured in a cohort of 2193 patients with documented CAD. The main outcome measures were cardiovascular (CV) death and/or nonfatal myocardial infarction (MI). During a median follow-up of 3.8 years, all three biomarkers were associated with cardiovascular death and/or MI. After adjustments for conventional cardiovascular risk factors, the hazard ratio (HR) per standard deviation (SD) for the prediction of CV death and/or nonfatal MI was 1.39 [95% CI: 1.24-1.57, p < 0.001] for hsTnI, 1.41 [95% CI: 1.24-1.60, p < 0.001] for hsCRP, and 1.64 [95% CI: 1.39-1.92, p < 0.001] for NT-proBNP. However, upon further adjustments for the other two biomarkers, only NT-proBNP was still associated with the combined endpoint with an HR of 1.47 [95% CI: 1.19-1.82, p < 0.001]. Conclusively, NT-proBNP is reliably linked to CV death and MI in patients with CAD and provides incremental value beyond hsCRP and hsTnI.
Project description:Little is known about cardiac adverse events among patients with nonobstructive coronary artery disease (CAD).To compare myocardial infarction (MI) and mortality rates between patients with nonobstructive CAD, obstructive CAD, and no apparent CAD in a national cohort.Retrospective cohort study of all US veterans undergoing elective coronary angiography for CAD between October 2007 and September 2012 in the Veterans Affairs health care system. Patients with prior CAD events were excluded.Angiographic CAD extent, defined by degree (no apparent CAD: no stenosis >20%; nonobstructive CAD: ?1 stenosis ?20% but no stenosis ?70%; obstructive CAD: any stenosis ?70% or left main [LM] stenosis ?50%) and distribution (1, 2, or 3 vessel).The primary outcome was 1-year hospitalization for nonfatal MI after the index angiography. Secondary outcomes included 1-year all-cause mortality and combined 1-year MI and mortality.Among 37,674 patients, 8384 patients (22.3%) had nonobstructive CAD and 20,899 patients (55.4%) had obstructive CAD. Within 1 year, 845 patients died and 385 were rehospitalized for MI. Among patients with no apparent CAD, the 1-year MI rate was 0.11% (n?=?8, 95% CI, 0.10%-0.20%) and increased progressively by 1-vessel nonobstructive CAD, 0.24% (n?=?10, 95% CI, 0.10%-0.40%); 2-vessel nonobstructive CAD, 0.56% (n?=?13, 95% CI, 0.30%-1.00%); 3-vessel nonobstructive CAD, 0.59% (n?=?6, 95% CI, 0.30%-1.30%); 1-vessel obstructive CAD, 1.18% (n?=?101, 95% CI, 1.00%-1.40%); 2-vessel obstructive CAD, 2.18% (n?=?110, 95% CI, 1.80%-2.60%); and 3-vessel or LM obstructive CAD, 2.47% (n?=?137, 95% CI, 2.10%-2.90%). After adjustment, 1-year MI rates increased with increasing CAD extent. Relative to patients with no apparent CAD, patients with 1-vessel nonobstructive CAD had a hazard ratio (HR) for 1-year MI of 2.0 (95% CI, 0.8-5.1); 2-vessel nonobstructive HR, 4.6 (95% CI, 2.0-10.5); 3-vessel nonobstructive HR, 4.5 (95% CI, 1.6-12.5); 1-vessel obstructive HR, 9.0 (95% CI, 4.2-19.0); 2-vessel obstructive HR, 16.5 (95% CI, 8.1-33.7); and 3-vessel or LM obstructive HR, 19.5 (95% CI, 9.9-38.2). One-year mortality rates were associated with increasing CAD extent, ranging from 1.38% among patients without apparent CAD to 4.30% with 3-vessel or LM obstructive CAD. After risk adjustment, there was no significant association between 1- or 2-vessel nonobstructive CAD and mortality, but there were significant associations with mortality for 3-vessel nonobstructive CAD (HR, 1.6; 95% CI, 1.1-2.5), 1-vessel obstructive CAD (HR, 1.9; 95% CI, 1.4-2.6), 2-vessel obstructive CAD (HR, 2.8; 95% CI, 2.1-3.7), and 3-vessel or LM obstructive CAD (HR, 3.4; 95% CI, 2.6-4.4). Similar associations were noted with the combined outcome.In this cohort of patients undergoing elective coronary angiography, nonobstructive CAD, compared with no apparent CAD, was associated with a significantly greater 1-year risk of MI and all-cause mortality. These findings suggest clinical importance of nonobstructive CAD and warrant further investigation of interventions to improve outcomes among these patients.
Project description:Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction.To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization.The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide association meta-analysis of serum calcium levels (N = up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium's 1000 genomes-based genome-wide association meta-analysis (N = up to 184 305 individuals) that included cases (individuals with CAD and myocardial infarction) and noncases, with baseline data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD and myocardial infarction was weighted by its association with serum calcium, and estimates were combined using an inverse-variance weighted meta-analysis.Genetic risk score based on genetic variants related to elevated serum calcium levels.Co-primary outcomes were the odds of CAD and myocardial infarction.Among the mendelian randomized analytic sample of 184 305 individuals (60 801 CAD cases [approximately 70% with myocardial infarction] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weighted meta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically predicted serum calcium levels were 1.25 (95% CI, 1.08-1.45; P = .003) for CAD and 1.24 (95% CI, 1.05-1.46; P = .009) for myocardial infarction.A genetic predisposition to higher serum calcium levels was associated with increased risk of CAD and myocardial infarction. Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medium-term calcium supplementation is unknown.
Project description:In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial.Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication.Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; P(interaction) = .038), which was not observed in women without history of NMSC.Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation.