Potential Modifiable Risk Factors for Addressing Genetic Risk for Cardiovascular Diseases

A Mendelian randomization (MR) study, published in Nutrition, Metabolism & Cardiovascular Diseases, identified 11 modifiable factors which associated with genetic risk for cardiovascular disease (CVD).

A previous genome-wide association study using data from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics consortium’s 1000 Genomes-based genome-wide association meta-analysis identified 15 modifiable risk factors for CVD. In this analysis, the effects of the genetic variants associated with the metabolic risk factors and lifestyle behaviors were evaluated in a MR analysis for the effect sizes on genetic CVD risk.

Most of the 15 previously published risk factors had high effect sizes, ranging from 45 (smoking initiation) to 175 (triglycerides), suggesting no weak predictors (all P <.05), except for sedentary time (effect size, 33) and alcohol dependence (effect size, 41).

Overall, the MR analysis had power to detect small effect sizes.

The 9 predictors which had causal roles for coronary artery disease (CAD) included genetically predicted hypertension (odds ratio [OR], 5.19) low-density lipoprotein cholesterol (LDL-C) per 1-standard deviation (SD) increase (OR, 1.55), triglycerides per 1-SD increase (OR, 1.29), initiating smoking (OR, 1.26), BMI per 1-SD increase (OR, 1.25), type 2 diabetes (OR, 1.11), diastolic blood pressure (BP) per 1-mm Hg increase (OR, 1.05), alcohol dependence (OR, 1.04), and systolic BP per 1-mm Hg increase (OR, 1.03).

For ischemic stroke, the 5 predictors which had causal roles were genetically predicted hypertension (OR, 4.92), smoking initiation (OR, 1.24), type 2 diabetes (OR, 1.07), diastolic BP per 1-mm Hg increase (OR, 1.05), and systolic BP per 1-mm Hg increase (OR, 1.03).

There was also suggestive evidence of a harmful impact from genetically higher fasting glucose per 1-mmol/L increase for both CAD (OR, 1.26) and ischemic stroke (OR, 1.25) and smoking heaviness per 1-SD increase on CAD (OR, 1.17).

In a sensitivity analysis, direct pleiotropic associations were observed between type 2 diabetes, fasting glucose, high-density lipoprotein cholesterol (HDL-C), BMI, and smoking intensity for either CAD or ischemic stroke (all P <1.67´10^–3).

In the weighted median analysis, both CAD and ischemic stroke were significantly associated with hypertension, systolic BP, diastolic BP, smoking initiation, and educational level and CAD alone also associated with type 2 diabetes, LDL-C, HDL-C, triglycerides, and BMI. In the MR-Pleiotropy Residual Sum and Outlier model, both CAD and ischemic stroke were associated with hypertension, systolic BP, diastolic BP, type 2 diabetes, smoking initiation, and educational level and CAD alone associated with LDL-C, HDL-C, triglycerides, and BMI.

The major limitation of this study was the assumption in the MR model that there was a linear association between the risk factors and diseases.

“…this MR study provided novel insight into the causal risk factors for CVD from a genetic standpoint, suggesting that BP, glucose, lipids, BMI, smoking, alcohol intake, and education are promising targets for the prevention of CVD,” the study authors wrote. “Further studies are warranted to confirm these findings in other populations and to elucidate the underlying mechanisms.”

Reference

Jia Y, Wang R, Guo D, et al. Contribution of metabolic risk factors and lifestyle behaviors to cardiovascular disease: A mendelian randomization study. Nutr Metab Cardiovasc Dis. Published online May 2, 2022. Doi:10.1016/j.numecd.2022.04.019