The genetic correlation and causal association between key factors that influence vascular calcification and cardiovascular disease incidence

BackgroundSerum calcium (Ca), vitamin D (VD), and vitamin K (VK) levels are key determinants of vascular calcification, which itself impacts cardiovascular disease (CVD) risk. The specific relationships between the levels of these different compounds and particular forms of CVD, however, remain to be fully defined. ObjectiveThis study was designed to explore the associations between these serum levels and CVDs with the goal of identifying natural interventions capable of controlling vascular calcification and thereby protecting against CVD pathogenesis, extending the healthy lifespan of at-risk individuals. MethodsLinkage disequilibrium score (LDSC) regression and a two-sample Mendelian randomization (MR) framework were leveraged to systematically examine the causal interplay between these serum levels and nine forms of CVD, as well as longevity through the use of large publically accessible Genome-Wide Association Studies (GWAS) datasets. The optimal concentrations of serum Ca and VD to lower CVD risk were examined through a restrictive cubic spline (RCS) approach. ResultsAfter Bonferroni correction, the positive genetic correlations were observed between serum Ca levels and myocardial infarction (MI) (p = 1.356E-04), as well as coronary artery disease (CAD) (p = 3.601E-04). Negative genetic correlations were detected between levels of VD and CAD (p = 0.035), while elevated VK1 concentrations were causally associated with heart failure (HF) [odds ratios (OR) per 1-standard deviation (SD) increase: 1.044], large artery stroke (LAS) (OR per 1-SD increase: 1.172), and all stroke (AS) (OR per 1-SD increase: 1.041). Higher serum Ca concentrations (OR per 1-SD increase: 0.865) and VD levels (OR per 1-SD increase: 0.777) were causally associated with reduced odds of longevity. These findings remained consistent in sensitivity analyses, and serum Ca and VD concentrations of 2.376 mmol/L and 46.8 nmol/L, respectively, were associated with a lower CVD risk (p < 0.001). ConclusionOur findings support a genetic correlation between serum Ca and VD and CVD risk, and a causal relationship between VK1 levels and CVD risk. The optimal serum Ca (2.376 mmol/L) and VD levels (46.8 nmol/L) can reduce cardiovascular risk.

Automated summary

This study investigates the associations between serum calcium, vitamin D, and vitamin K levels and cardiovascular diseases (CVDs), and identifies optimal concentrations of these serum levels for reducing CVD risk. Results show positive genetic correlations between serum calcium levels and myocardial infarction (MI) and coronary artery disease (CAD), while negative genetic correlations are observed between vitamin D levels and CAD. Elevated VK1 concentrations are causally associated with heart failure, large artery stroke, and all stroke. Higher serum calcium and vitamin D levels are causally associated with reduced odds of longevity. The optimal serum calcium and vitamin D levels for reducing cardiovascular risk are 2.376 mmol/L and 46.8 nmol/L, respectively.