Effect of sex and underlying disease on the genetic association of QT interval and sudden cardiac death

Background Sudden cardiac death (SCD) accounts for ≈300 000 deaths annually in the United States. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease, while women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the genetics of QT interval duration. Using sex‐ and coronary artery disease–stratified analyses, we assess differences in genetic association between longer QT interval and SCD risk. Methods and Results We examined 2282 SCD subjects and 3561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic versus nonischemic) and by sex. We used logistic regression to test for association between the top QT interval–associated single‐nucleotide polymorphism, rs12143842 (in the NOS1AP locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups. No statistically significant differences were observed between the sexes for associations with rs12143842, despite the odds ratio being higher in females across all subgroup analyses. Consistent with our hypothesis, female non‐ischemics had the highest odds ratio point estimate for association between rs12143842 and SCD risk and male ischemics the lowest odds ratio point estimate (P=0.036 for difference). Similar trends were observed for the Mendelian randomization analysis. Conclusions While individual subgroup comparisons did not achieve traditional criteria for statistical significance, this study is consistent with the hypothesis that the causal association of longer QT interval on SCD risk is stronger in women and nonischemic individuals

Metabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty

Global ageing poses a substantial economic burden on health and social care costs. Enabling a greater proportion of older people to stay healthy for longer is key to the future sustainability of health, social and economic policy. Frailty and associated decrease in resilience plays a central role in poor health in later life. In this study, we present a population level assessment of the metabolic phenotype associated with frailty. Analysis of serum from 1191 older individuals (aged between 56 and 84 years old) and subsequent longitudinal validation (on 786 subjects) was carried out using liquid and gas chromatography-mass spectrometry metabolomics and stratified across a frailty index designed to quantitatively summarize vulnerability. Through multivariate regression and network modelling and mROC modeling we identified 12 significant metabolites (including three tocotrienols and six carnitines) that differentiate frail and non-frail phenotypes. Our study provides evidence that the dysregulation of carnitine shuttle and vitamin E pathways play a role in the risk of frailty

A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Aims Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA. Methods and results We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk. Conclusions Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community

Lifestyle and behavioral factors and mitochondrial DNA copy number in a diverse cohort of mid-life and older adults

Mitochondrial DNA copy number (mtDNAcn) is a putative biomarker of oxidative stress and biological aging. Modifiable factors, including physical activity (PA), avoidance of heavy alcohol use and smoking, and maintaining good mental health, may reduce oxidative stress and promote healthy aging. Yet, limited data exist regarding how these factors are associated with mtDNAcn or whether age, sex or race/ethnicity moderate associations. In this cross-sectional study, we selected 391 adults (183 non-Hispanic White, 110 Black and 98 Hispanic; mean = 67 years) from the VITAL-DEP (VITamin D and OmegA-3 TriaL-Depression Endpoint Prevention) ancillary to the VITAL trial. We estimated associations between lifestyle and behavioral factors (PA, alcohol consumption, cigarette smoking and depression) and log-transformed mtDNAcn using multivariable linear regression models. MtDNAcn was not correlated with chronological age; women had ~17% higher mtDNAcn compared to men. There were no significant associations between PA measures (frequency, amount or intensity) or alcohol consumption with mtDNAcn. Cigarette smoking (per 5 pack-years) was significantly associated with mtDNAcn (percent difference = -2.9% (95% confidence interval (CI) = -5.4%, -0.4%)); a large contrast was observed among heavy vs. non-smokers (≥30 vs. 0 pack-years): percent difference = -28.5% (95% CI = -44.2%, -8.3%). The estimate of mtDNAcn was suggestively different for past vs. no depression history (percent difference = -15.1% 95% CI = -30.8%, 4.1%), but this difference was not statistically significant. The association between smoking and log-mtDNAcn varied by sex and race/ethnicity; it was stronger in men and Black participants. While chance findings cannot be excluded, results from this study support associations of smoking, but not chronological age, with mtDNAcn and suggest nuanced considerations of mtDNAcn as indicative of varying oxidative stress states vs. biological aging itself