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

Xiaolin Ni; Lei Liu; Yao Yao; Chi Zhang; Huabin Su; Yuan Lv; Rongqiao Li; Liang Sun; Qi Zhou; Xiaoquan Zhu; Ze Yang; Zuoguan Chen; Wei He; Huolan Zhu; Shenqi Zhang; Caiyou Hu; Huiping Yuan

doi:10.3389/fcvm.2023.1096662

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

Front Cardiovasc Med. 2023 Jan 26:10:1096662. doi: 10.3389/fcvm.2023.1096662. eCollection 2023.

Authors

Xiaolin Ni^{1

2

3}, Lei Liu⁴, Yao Yao⁵, Chi Zhang¹, Huabin Su⁶, Yuan Lv⁶, Rongqiao Li⁶, Liang Sun¹, Qi Zhou¹, Xiaoquan Zhu¹, Ze Yang¹, Zuoguan Chen⁷, Wei He⁸, Huolan Zhu⁹, Shenqi Zhang¹⁰, Caiyou Hu⁶, Huiping Yuan¹

Affiliations

¹ The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, National Center of Gerontology of National Health Commission, Beijing, China.
² State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
³ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
⁴ Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
⁵ China Center for Health Development Studies, Peking University, Beijing, China.
⁶ Jiangbin Hospital, Zhenjiang, China.
⁷ Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences Peking Union Medical College, Beijing, China.
⁸ Department of Cardiology, Beijing Hospital, National Center of Gerontology, Beijing, China.
⁹ Department of Geriatrics, Shaanxi Provincial Clinical Research Center for Geriatric Medicine, Shaanxi Provincial People's Hospital, Xi'an, China.
¹⁰ Department of Joint and Sports Medicine, Zaozhuang Municipal Hospital Affiliated to Jining Medical University, Zaozhuang, Shandong, China.

Abstract

Background: Serum 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.

Objective: This 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.

Methods: Linkage 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.

Results: After 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).

Conclusion: Our 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.

Keywords: cardiovascular disease; risk factor; serum calcium; vitamin D; vitamin K.

Grants and funding

The data collection and analysis were supported by grants from the Natural Science Foundation of China (82260289, 91849118, and 81870552) and National Key Research and Development Program of China (2018YFC2000400). The trial design and personnel service were supported by grants from the Guangxi Natural Science Foundation (2014GXNSFDA118028, 2018GXNSFAA138156, and guike0991198) and Self-funded Scientific Research Project of the Health and Family Planning Commission of Guangxi Zhuang Autonomous Region (Z20170162).