Association of mental health with the risk of coronary artery disease in patients with diabetes: A mendelian randomization study

Background and aimsObservational studies have shown an association between mental health and coronary artery disease (CAD) in patients with diabetes. Nevertheless, whether these associations are causal is still unknown. In this two-sample Mendelian randomization (MR) study, we aimed to assess the causality between mental health and CAD in patients with diabetes.Methods and resultsSingle-nucleotide polymorphisms (SNPs) associated with: depression (807,553 individuals), anxiety (83,556 individuals) and neuroticism (329,821 individuals) were identified from the largest genome-wide association studies (GWAS). Summary-level data for CAD were extracted from the recently published GWAS of 15,666 diabetic patients (3968 CAD cases and 11,696 controls). The inverse-variance weighted (IVW) method was used for the main analysis. Sensitivity analyses included weighted median, maximum likelihood, and the MR-Egger method. Genetic liability to depression was significantly associated with a higher risk of CAD in patients with diabetes (odds ratio [OR], 1.286; 95%CI,1.018–1.621;p = 0.035). For anxiety and neuroticism, no causal association with CAD in patients with diabetes was observed. Consistent results were obtained in most sensitivity analyses.ConclusionsThis MR study provides genetic evidence that depression is a potential risk factor for CAD in patients with diabetes. However, anxiety and neuroticism were not causally associated with CAD in patients with diabetes. Mental health treatments should be enhanced to prevent CAD in patients with diabetes.     

Avoiding Clinical Errors With Bedside Echocardiography: A Randomized Clinical Study

Clinicians have strong opinions about whether they should be provided the clinical history before or after bedside testing. We hypothesized that diagnostic accuracy is improved when a concordant clinical history is provided before a diagnostic test. To investigate whether the timing (before or after) and the consistency (concordant vs discordant) of the clinical history in the setting of focused bedside echocardiography affects clinician diagnostic accuracy and management decisions. Thirty-two cardiology residents were asked to perform a bedside echocardiogram on a Vimedix 3D mannequin. Half of the histories were provided before echocardiography and half after echocardiography. Half were consistent with the echocardiographic diagnosis (concordant), and half were suggestive of a plausible alternative diagnosis (discordant). Participants were asked for a diagnosis and management plan. The primary outcome was the diagnostic accuracy of the echocardiographic images. The secondary outcome was the management plan. Overall diagnostic accuracy was 63%. If the clinical history was provided before the bedside testing, it significantly improved diagnostic accuracy if it was concordant and it diminished accuracy if it was discordant (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.16-0.80; P = 0.001). Clinical history, whether concordant or discordant, had no significant impact if provided after the images were obtained. Appropriate management was chosen 77% of the time and was chosen less often with discordant compared with concordant histories (OR, 0.25; 95% CI, 0.11-0.57; P = 0.001). Our study suggests a significant downside to clinical information received before echocardiography when the information is discordant, raising the possibility that receiving clinical information after echocardiography may be superior for diagnostic accuracy.     

Genetic Risk Score for Coronary Disease Identifies Predispositions to Cardiovascular and Noncardiovascular Diseases

BackgroundThe taxonomy of cardiovascular (CV) diseases is divided into a broad spectrum of clinical entities. Many such diseases coincide in specific patient groups and suggest shared predisposition.ObjectivesThis study focused on coronary artery disease (CAD) and investigated the genetic relationship to CV and non-CV diseases with reported CAD comorbidity.MethodsThis study examined 425,196 UK Biobank participants to determine a genetic risk score (GRS) based on 300 CAD associated variants (CAD-GRS). This score was associated with 22 traits, including risk factors, diseases secondary to CAD, as well as comorbid and non-CV conditions. Sensitivity analyses were performed in individuals free from CAD or stable angina diagnosis.ResultsHypercholesterolemia (odds ratio [OR]: 1.27; 95% CI: 1.26 to 1.29) and hypertension (OR: 1.11; 95% CI: 1.10 to 1.12) were strongly associated with the CAD-GRS, which indicated that the score contained variants predisposing to these conditions. However, the CAD-GRS was also significant in patients with CAD who were free of CAD risk factors (OR: 1.37; 95% CI: 1.30 to 1.44). The study observed significant associations between the CAD-GRS and peripheral arterial disease (OR: 1.28; 95% CI: 1.23 to 1.32), abdominal aortic aneurysms (OR: 1.28; 95% CI: 1.20 to 1.37), and stroke (OR: 1.08; 95% CI: 1.05 to 1.10), which remained significant in sensitivity analyses that suggested shared genetic predisposition. The score was also associated with heart failure (OR: 1.25; 95% CI: 1.22 to 1.29), atrial fibrillation (OR: 1.08; 95% CI: 1.05 to 1.10), and premature death (OR: 1.04; 95% CI: 1.02 to 1.06). These associations were abolished in sensitivity analyses that indicated that they were secondary to prevalent CAD. Finally, an inverse association was observed between the score and migraine headaches (OR: 0.94; 95% CI: 0.93 to 0.96).ConclusionsA wide spectrum of CV conditions, including premature death, might develop consecutively or in parallel with CAD for the same genetic roots. In conditions like heart failure, the study found evidence that the CAD-GRS could be used to stratify patients with no or limited genetic overlap with CAD risk. Increased genetic predisposition to CAD was inversely associated with migraine headaches.     

Determining the Optimal Systolic Blood Pressure for Hypertensive Patients: A Network Meta-analysis

Background

There is clinical trial evidence that lowering systolic blood pressure (SBP) to < 120 mm Hg is beneficial, and this has influenced the latest American guideline on hypertension. We therefore used network meta-analysis to study the association between SBP and cardiovascular outcomes.

Can We Eliminate Low-Density Lipoprotein Cholesterol-Related Cardiovascular Events Through More Aggressive Primary Prevention Therapy?

Intravascular levels of low-density lipoprotein cholesterol (LDL-C) at approximately ≤ 0.6 mmol/L are likely to minimize, and perhaps eliminate, LDL-C-related vascular toxicity while having no effect on essential, intracellular cholesterol homeostatic pathways, according to accumulated knowledge from basic science. Randomized clinical trials, observational reports, and Mendelian randomization trials are also forcing a reconsideration of what “normal” LDL-C means. Recent trials of secondary prevention have substantiated that such levels are safe and associated with a decreased risk of cardiovascular events (CVEs) compared with patients with higher levels of LDL-C. Similarly, treatment to this low range is associated with regression and stabilization of established atherosclerosis. Primary prevention trials also show that low levels of LDL-C are safe and associated with decreased risk of CVEs through cholesterol-lowering in adults with LDL-C ≥ 3.5 mmol/L or when levels are < 3.5 mmol/L in association with other cardiovascular risks. Although there are no randomized clinical outcome trials of familial hypercholesterolemia patients, such patients have very high, lifetime risk of CVE, and registry studies show that LDL-C reduction has nearly normalized their CVE rates. The possibility of familial hypercholesterolemia should be considered if LDL-C is > 4.5 and > 4.0 mmol/L at ages 18-39 years and younger than 18 years, respectively. On the basis of these convergent and internally consistent lines of evidence, in this article we speculate on a translational paradigm aimed at eliminating LDL-C-related CVEs through aggressive primary prevention strategies that are already proven and well accepted in principle.     

The net clinical benefits of febuxostat versus allopurinol in patients with gout or asymptomatic hyperuricemia – A systematic review and meta-analysis

Background and aimsSystemic reviews and meta-analyses suggest hyperuricemia is a cardiovascular risk factor. The effects of xanthine oxidase inhibitors on cardiac outcomes remain unclear. We assessed the effects of febuxostat and allopurinol on mortality and adverse reactions in adult patients with hyperuricemia.Methods and resultsPubMed and EMBASE were searched to retrieve randomized controlled trials of febuxostat and allopurinol from January 2005 to July 2018. The meta-analysis consisted of 13 randomized controlled trials with a combined sample size of 13,539 patients. Febuxostat vs. allopurinol was not associated with an increased risk of cardiac-related mortality in the overall population (OR: 0.72, 95% CI: 0.24–2.13, P = 0.55). Regarding adverse skin reactions, the patients receiving febuxostat had significantly fewer adverse skin reactions than those receiving allopurinol treatment (OR: 0.50, 95% CI: 0.30–085, P = 0.01). Compared with allopurinol, febuxostat was associated with an improved safety outcome of cardiac-related mortality and adverse skin reactions (OR: 0.72, 95% CI: 0.55–0.96, P = 0.02). The net clinical outcome, composite of incident gout and the safety outcome, was not different significantly in the patients receiving febuxostat or allopurinol (OR: 1.04, 95% CI: 0.76–0.1.42, P = 0.79). In sensitivity analyses, a borderline significance was found in the patients randomized to febuxostat vs. allopurinol regarding cardiac-related mortality (OR: 1.29, 95% CI: 1.00–1.67, P = 0.05) after the CARES study was included.ConclusionFebuxostat vs. allopurinol was associated with the improved safety outcome and have comparable mortality and net clinical outcome in patients with hyperuricemia.Registration numberPROSPERO(CRD42018091657).     

Contribution of metabolic risk factors and lifestyle behaviors to cardiovascular disease: A mendelian randomization study

Background and aimsEtiologic associations between some modifiable factors (metabolic risk factors and lifestyle behaviors) and cardiovascular disease (CVD) remain unclear. To identify targets for CVD prevention, we evaluated the causal associations of these factors with coronary artery disease (CAD) and ischemic stroke using a two-sample Mendelian randomization (MR) method.Methods and resultsPreviously published genome-wide association studies (GWASs) for blood pressure (BP), glucose, lipids, overweight, smoking, alcohol intake, sedentariness, and education were used to identify instruments for 15 modifiable factors. We extracted effects of the genetic variants used as instruments for the exposures on coronary artery disease (CAD) and ischemic stroke from large GWASs (N = 60 801 cases/123 504 controls for CAD and N = 40 585 cases/406 111 controls for ischemic stroke). Genetically predicted hypertension (CAD: OR, 5.19 [95% CI, 4.21–6.41]; ischemic stroke: OR, 4.92 [4.12–5.86]), systolic BP (CAD: OR, 1.03 [1.03–1.04]; ischemic stroke: OR, 1.03 [1.03–1.03]), diastolic BP (CAD: OR, 1.05 [1.05–1.06]; ischemic stroke: OR, 1.05 [1.04–1.05]), type 2 diabetes (CAD: OR, 1.11 [1.08–1.15]; ischemic stroke: OR, 1.07 [1.04-1.10]), smoking initiation (CAD: OR, 1.26 [1.18–1.35]; ischemic stroke: OR, 1.24 [1.16–1.33]), educational attainment (CAD: OR, 0.62 [0.58–0.66]; ischemic stroke: OR, 0.68 [0.63–0.72]), low-density lipoprotein cholesterol (CAD: OR, 1.55 [1.41–1.71]), high-density lipoprotein cholesterol (CAD: OR, 0.82 [0.74–0.91]), triglycerides (CAD: OR, 1.29 [1.14–1.45]), body mass index (CAD: OR, 1.25 [1.19–1.32]), and alcohol dependence (OR, 1.04 [1.03–1.06]) were causally related to CVD.ConclusionThis systematic MR study identified 11 modifiable factors as causal risk factors for CVD, indicating that these factors are important targets for preventing CVD.     

Genetically predicted serum uric acid levels and the risk of coronary artery disease in patients with diabetes: A Mendelian randomization study

Background and aimsSerum uric acid (SUA) levels have been reported to be associated with an increased risk of coronary artery disease (CAD) among patients with diabetes in observational study. Whether this relationship is causal remains unclear. The current study aimed to explore the causal association between SUA and the risk of CAD in patients with diabetes.Methods and resultsA two-sample Mendelian randomization (MR) approach was employed to evaluate the causal effect of SUA on the risk of CAD in patients with diabetes. A total of 28 single nucleotide polymorphisms (SNPs) related to SUA were identified as instruments. Genetic association with CAD were obtained from a recently published genome-wide association study (GWAS) of 15,666 patients with diabetes (3968 CAD cases and 11,696 controls). The fixed-effects inverse variance-weighted method was employed to estimate the causal effect for the primary analysis, and other robust methods were employed for sensitivity analyses. In addition, the whole analyses were repeated using 9 non-pleiotropic SNPs. Genetic determined SUA levels were not significantly associated with the risk of CAD in patients with diabetes in the primary analysis (odds ratio = 1.13, 95% confidence interval: 0.98–1.16, P = 0.09). Consistent results were observed in the sensitivity analyses using various robust methods. In addition, this finding was confirmed by the repeated analyses using 9 non-pleiotropic SNPs.ConclusionsThis two-sample MR study does not support a causal effect of genetically predicted SUA levels on the risk of CAD in patients with diabetes.     

No association between alcohol consumption and risk of atrial fibrillation: A two-sample Mendelian randomization study

Background and aimsAlthough many observational studies have suggested that alcohol intake was associated with incident atrial fibrillation (AF), controversy remains. This study aimed to examine the causal association of alcohol intake with the risk of AF.Methods and resultsTwo-sample Mendelian randomization (MR) analysis was performed to estimate the causal effects of alcohol consumption, alcohol dependence, or alcohol use disorder identification test (AUDIT) scores on AF. Summary data on single nucleotide polymorphisms (SNPs) associated with AF were obtained from a genome-wide association study (GWAS) with up to 1,030,836 participants. The fixed- and random-effect inverse-variance weighted (IVW) methods were used to calculate the overall causal effects. MR analysis revealed nonsignificant association of genetically predicted alcohol consumption with risk of AF using fixed- and random-effect IVW approaches (odds ratio (OR) [95% confidence interval (CI)] = 1.004 [0.796–1.266], P = 0.975; OR [95% CI] = 1.004 [0.766–1.315], P = 0.979). Genetically predicted alcohol dependence was also not causally associated with AF in the fixed- and random-effect IVW analyses (OR [95% CI] = 1.012 [0.978–1.048], P = 0.490; OR [95% CI] = 1.012 [0.991–1.034], P = 0.260). There was no significantly causal association between AUDIT and AF in the fixed- and random-effect IVW analyses (OR [95% CI] = 0.889 [0.433–1.822], P = 0.748; OR [95% CI] = 0.889 [0.309–2.555], P = 0.827). Sensitivity analyses indicated no evidence of pleiotropy and heterogeneity in statistical models.ConclusionsThis MR study did not find evidence of a causal association between alcohol intake and AF.     

Does Early Coronary Angiography Improve Survival After out-of-Hospital Cardiac Arrest? A Systematic Review With Meta-Analysis

Background

In patients with out-of-hospital cardiac arrest who achieve return of spontaneous circulation, coronary angiography (CAG) might improve outcomes. We conducted a systematic review and meta-analysis to elucidate the benefit and optimal timing of early CAG in comatose out-of-hospital cardiac arrest patients with return of spontaneous circulation.

Geographical Differences in Comorbidity Burden and Outcomes in Adults With Syncope Hospitalizations in Canada

A recent study found that rates of hospitalization for syncope vary across provinces; however, it is unknown whether differences in comorbidity burden and outcomes also exist. The Canadian Institute for Health Information Discharge Abstract Database was used to identify primary syncope hospitalizations (ICD-10 code R55) from 2004 to 2013 for all provinces (except Quebec). Charlson comorbidity score was calculated from comorbidities at the time of hospitalization. Outcomes were defined as in-hospital mortality, 30-day readmission for any cause, and syncope. Logistic regression models were constructed for odds ratios (ORs) and 95% confidence intervals (CIs) to estimate interprovincial differences in outcomes. The interprovincial range (IPR) for mean age was 61.1 ± 17.5 to 73.7 ± 16.3 years, and at least half were male patients. There were significant differences in comorbidity burden across provinces (P < 0.01); however, the majority of patients had a Charlson comorbidity score = 0 (IPR, 53.9%- 71.9%). In multivariable analysis, compared with Ontario, in-hospital mortality was higher for British Columbia (OR, 1.59; 95% CI, 1.22-2.06), Nova Scotia (OR, 1.67; 95% CI, 1.05-2.65), and Newfoundland (OR, 2.27; 95% CI, 1.29-4.00); 30-day readmission for any cause was higher for British Columbia (OR, 1.15; 95% CI, 1.06-1.26), Alberta (OR, 1.19; 95% CI, 1.07-1.31), Manitoba (OR, 1.36; 95% CI, 1.18-1.56), and Prince Edward Island (OR, 1.38; 95% CI, 1.0-1.89), and all outcomes were higher in Saskatchewan. There is significant interprovincial heterogeneity in comorbidity burden and outcomes for hospitalizations for syncope. Future research evaluating whether standardized practices for management of syncope reduce variability and improve healthcare utilization and costs is needed.     

Genetically Predicted Adiposity,Diabetes, and Lifestyle Factors in Relation to Diverticular Disease

Background & AimsAdiposity, type 2 diabetes, alcohol and coffee consumption, and smoking have been examined in relation to diverticular disease in observational studies. We conducted a Mendelian randomization study to assess the causality of these associations.MethodsIndependent genetic instruments associated with the studied exposures at genome-wide significance were obtained from published genome-wide association studies. Summary-level data for the exposure-associated single nucleotide polymorphisms with diverticular disease were available in the FinnGen consortium (10,978 cases and 149,001 noncases) and the UK Biobank study (12,662 cases and 348,532 noncases).ResultsHigher genetically predicted body mass index and genetic liability to type 2 diabetes and smoking initiation were associated with an increased risk of diverticular disease in meta-analyses of results from the two studies. The combined odds ratio of diverticular disease was 1.23 (95% confidence interval [CI], 1.14–1.33; P < .001) for a 1-standard deviation (~4.8 kg/m²) increase in body mass index, 1.04 (95% CI, 1.01–1.07; P = .007) for a 1-unit increase in log-transformed odds ratio of type 2 diabetes, and 1.21 (95% CI, 1.12–1.30; P < .001) for a 1-standard deviation increase in prevalence of smoking initiation. Coffee consumption was not associated with diverticular disease, whereas the association for alcohol consumption largely differed between the 2 studies.ConclusionsThis study strengthens the causal associations of higher body mass index, type 2 diabetes, and smoking with an increased risk of diverticular disease. Coffee consumption is not associated with diverticular disease. Whether alcohol consumption affects the risk of diverticular disease needs further investigation.     

Preterm birth and risk of type 1 and type 2 diabetes: systematic review and meta‐analysis

Preterm birth is suggested to play an important role in the development of diabetes. However, results have been inconsistent. We conducted a systematic review and meta‐analysis to clarify the relationship between preterm birth and type 1 and type 2 diabetes. PubMed, Embase and ISI Web of Science were searched. A total of 18 studies (including 2,176,480 participants and 22,073 cases) for type 1 diabetes and five studies (including 31,478 participants and 1,898 cases) for type 2 diabetes were included in the current meta‐analyses. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) using fixed‐effects model to evaluate the relations between preterm birth and type 1 and type 2 diabetes. The results suggested that preterm birth was significantly associated with increased risk of type 1 diabetes (OR = 1.18, 95% CI = 1.11–1.25), with no evidence of between‐study heterogeneity (I² = 13.2%, P = 0.296). Preterm birth was also significantly associated with increased risk of type 2 diabetes (OR = 1.51, 95% CI = 1.32–1.72), with no evidence of (I² = 0.0%, P = 0.557). Subgroup analyses suggested that there was significant association in both case‐control studies (OR = 1.16, 95% CI = 1.06–1.26) and cohort studies (relative risk = 1.20, 95% CI = 1.11–1.29) for type 1 diabetes, and similar results were found for type 2 diabetes. The results suggested that preterm birth was a significant and independent risk factor for both type 1 and type 2 diabetes.     

Improving Prenatal Diagnosis of Coarctation of the Aorta

Background

The purpose of the study was to evaluate the association between fetal echocardiographic measurements and the need for intervention (primary coarctation repair, staged coarctation repair, or catheter intervention) in prenatally diagnosed coarctation of the aorta.

Association of heart rate and diabetes among 0.5 million adults in the China Kadoorie biobank: Results from observational and Mendelian randomization analyses

Background and aimsObservational studies have associated resting heart rate with incident diabetes. Whether the associations are causal remains unclear. We aimed to examine the shape and strength of the associations and assessed the causal relevance of such associations in Chinese adults.Methods and resultsThe China Kadoorie Biobank enrolled 512,891 adults in China. Cox proportional hazard regression models was conducted to estimate hazard ratios (HRs) for the associations of resting heart rate with type 2 diabetes and total diabetes. Among 92,724 participants, 36 single-nucleotide polymorphisms (SNPs) related to resting heart rate were used to construct genetic risk score. We used Mendelian randomization analyses to make the causal inferences. During a median follow-up of 9 years, 7872 incident type 2 diabetes and 13,349 incident total diabetes were documented. After regression dilution bias adjustment, each 10 bpm higher heart rate was associated with about a 26% higher risk of type 2 diabetes (HR, 1.26 [95% CI, 1.23, 1.29]) and 23% higher risk of total diabetes (HR, 1.23 [95% CI, 1.20, 1.26]). Instrumental variable analyses showed participants at top quintile compared with those at bottom quintile had 30% higher risk for type 2 diabetes (HR, 1.30 [95% CI, 1.17, 1.43]), and 10% higher risk for total diabetes (HR, 1.10 [95% CI, 1.02, 1.20]).ConclusionsThis study provides evidence that resting heart rate is an important risk factor for diabetes risk. The results suggest that novel treatment approaches targeting reduction of high heart rate for incidence of diabetes may be worth further investigation.     

The adiponectin gene SNP+45 is associated with coronary artery disease in Type 2 (non-insulin-dependent) diabetes mellitus.

BACKGROUND: The ACRP30/adiponectin gene on chromosome 3q27, a region linked to the metabolic syndrome, encodes for the abundant adipocyte-specific secreted protein. Consistent rodent and human studies suggested that this adipokine may be a molecular link between metabolic and cardiovascular diseases. AIMS: In order to investigate the role of single nucleotide polymorphisms (SNPs) within the APM1 gene in the susceptibility to coronary artery disease (CAD), we performed a case-control study on Caucasian Type 2 (non-insulin-dependent) diabetic patients, a population at high-risk for CAD. METHODS: Five APM1 SNPs were genotyped in 162 Type 2 diabetic French and Swiss subjects with CAD and in 315 Type 2 diabetic French and Swiss subjects without CAD. RESULTS: In univariate analysis, SNP+45 T>G was associated with CAD (OR 1.9 95% CI 1.2-2.9 P = 0.0036). In multivariate analysis, SNP+45 T>G remained associated with CAD (OR 1.2 95% CI 0.8-1.9 P = 0.017), independently of classical cardiovascular risk factors including components of the metabolic syndrome. SNP haplotype analyses revealed a CAD protective combination of all SNP wild-type alleles (OR 0.5 95% CI 0.3-0.7 P = 0.0006). CONCLUSIONS: Our study, performed in diabetic subjects, revealed an association between individual SNP+45 in the APM1 gene and CAD. Furthermore, the susceptibility for CAD due to SNP+45 was independent of classic cardiovascular risk factors. Further studies will be necessary to confirm the role of SNP+45 in the development of CAD. However, ACRP30/adiponectin may contribute to atherosclerosis susceptibility in high-risk populations such as Type 2 diabetic subjects.     

Prothrombotic State in Atrial Fibrillation Patients With One Additional Risk Factor of the CHA2DS2-VASc Score (Beyond Sex)

Background

It is unclear whether a prothrombotic state occurs in atrial fibrillation (AF) with low stroke risk.

The homocysteine controversy

Mild to moderate hyperhomocysteinemia has been identified as a strong predictor of cardiovascular disease, independent from classical atherothrombotic risk factors. In the last decade, a number of large intervention trials using B vitamins have been performed and have shown no benefit of homocysteine-lowering therapy in high-risk patients. In addition, Mendelian randomization studies failed to convincingly demonstrate that a genetic polymorphism commonly associated with higher homocysteine levels (methylenetetrahydrofolate reductase 677 C>T) is a risk factor for cardiovascular disease. Together, these findings have cast doubt on the role of homocysteine in cardiovascular disease pathogenesis, and the homocysteine hypothesis has turned into a homocysteine controversy. In this review, we attempt to find solutions to this controversy. First, we explain that the Mendelian randomization analyses have limitations that preclude final conclusions. Second, several characteristics of intervention trials limit interpretation and generalizability of their results. Finally, the possibility that homocysteine lowering is in itself beneficial but is offset by adverse side effects of B vitamins on atherosclerosis deserves serious attention. As we explain, such side effects may relate to direct adverse effects of the B-vitamin regimen (in particular, the use of high-dose folic acid) or to proinflammatory and proproliferative effects of B vitamins on advanced atherosclerotic lesions.     

Diet-Derived Circulating Antioxidants and Risk of Coronary Heart Disease: A Mendelian Randomization Study

BackgroundPreviously, observational studies have identified associations between higher levels of dietary-derived antioxidants and lower risk of coronary heart disease (CHD), whereas randomized clinical trials showed no reduction in CHD risk following antioxidant supplementation.ObjectivesThe purpose of this study was to investigate possible causal associations between dietary-derived circulating antioxidants and primary CHD risk using 2-sample Mendelian randomization (MR).MethodsSingle-nucleotide polymorphisms for circulating antioxidants (vitamins E and C, retinol, β-carotene, and lycopene), assessed as absolute levels and metabolites, were retrieved from the published data and were used as genetic instrumental variables. Summary statistics for gene-CHD associations were obtained from 3 databases: the CARDIoGRAMplusC4D consortium (60,801 cases; 123,504 control subjects), UK Biobank (25,306 cases; 462,011 control subjects), and FinnGen study (7,123 cases; 89,376 control subjects). For each exposure, MR analyses were performed per outcome database and were subsequently meta-analyzed.ResultsAmong an analytic sample of 768,121 individuals (93,230 cases), genetically predicted circulating antioxidants were not causally associated with CHD risk. For absolute antioxidants, the odds ratio for CHD ranged between 0.94 (95% confidence interval [CI]: 0.63 to 1.41) for retinol and 1.03 (95% CI: 0.97 to 1.10) for β-carotene per unit increase in ln-transformed antioxidant values. For metabolites, the odds ratio ranged between 0.93 (95% CI: 0.82 to 1.06) for γ-tocopherol and 1.01 (95% CI: 0.95 to 1.08) for ascorbate per 10-fold increase in metabolite levels.ConclusionsEvidence from our study did not support a protective effect of genetic predisposition to high dietary-derived antioxidant levels on CHD risk. Therefore, it is unlikely that taking antioxidants to increase blood antioxidants levels will have a clinical benefit for the prevention of primary CHD.     

Individual or familial diabetes in relation to eight cardiovascular diseases: A two-sample Mendelian randomization study

Background and aimsDiabetes is associated with increased risk of certain cardiovascular diseases, yet the causality remains to be determined. Meanwhile, given that first-degree relatives share 50% of genes, the effect of familial diabetes is also worthy of attention. Therefore, we sought to investigate the causal relations of individual or familial diabetes with eight cardiovascular diseases, including myocardial infarction, hypertension, atrial fibrillation, heart failure, cardiac death, pulmonary embolism, transient ischemic attack, and ischemic stroke.Methods and resultsApplying two-sample Mendelian randomization, we selected instruments for genetic predisposition to individual or familial diabetes based on published genome-wide association studies. The primary analyses were conducted using the random-effects inverse-variance weighted method. We found that genetically predicted individual diabetes was causally associated with higher risks of myocardial infarction (odd ratio [OR] = 1.09; 95% confidence interval [CI]: 1.05–1.13; P < 0.0001), hypertension (OR = 1.08; 95% CI: 1.03–1.13; P = 0.0006), and ischemic stroke (OR = 1.10; 95% CI: 1.05–1.15; P < 0.0001). Genetically predicted paternal diabetes could increase the risk of ischemic stroke (OR = 1.16; 95% CI: 1.04–1.30; P = 0.0061). Genetically predicted maternal diabetes could increase the risk of myocardial infarction (OR = 1.18; 95% CI: 1.09–1.29; P = 0.0001). Genetically predicted siblings’ diabetes was causally associated with higher risks of myocardial infarction (OR = 1.17; 95% CI: 1.08–1.27; P = 0.0001) and hypertension (OR = 1.19; 95% CI: 1.06–1.34; P = 0.0036). No significant differences were observed in other outcomes.ConclusionThis study supports causal effects of not only individual but also familial diabetes on the development of cardiovascular diseases, which will help realize the potential effect of family history in the prevention of cardiovascular diseases.