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Integrated Genetics and Micronutrient Data to Inform the Causal Association Between Serum Calcium Levels and Ischemic
Qiang Meng1, Lu Huang2, Kai Tao2
1Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
Insights
This study investigated the link between serum calcium levels and ischemic stroke (IS) risk. Findings indicate that higher serum calcium levels causally increase the risk of ischemic stroke, supporting a potential therapeutic target.
Area of Science:
- Cardiovascular Epidemiology
- Genetic Epidemiology
- Nutritional Science
Background:
- Cardiovascular diseases (CVD), including coronary artery disease (CAD) and ischemic stroke (IS), are major health concerns.
- The relationship between dietary calcium intake and CVD risk is debated, with limited conclusive evidence.
- Previous Mendelian randomization (MR) studies yielded inconsistent results regarding serum calcium levels and IS risk.
Purpose of the Study:
- To conduct an updated Mendelian randomization (MR) study to clarify the causal association between serum calcium levels and ischemic stroke (IS) risk.
- To utilize large-scale genome-wide association study (GWAS) datasets for robust genetic analysis.
Main Methods:
- Employed a two-sample Mendelian randomization (MR) design.
- Selected 14 independent genetic variants associated with serum calcium levels as instrumental variables.
- Utilized summary statistics from large-scale GWAS datasets for serum calcium and ischemic stroke (IS) from the MEGASTROKE Consortium.
Main Results:
- A significant positive causal association was found between genetically predicted higher serum calcium levels and increased risk of ischemic stroke (IS).
- Robust inverse-variance weighted (IVW) methods yielded β = 0.243 (P = 0.002).
- Further support from MR-Egger regression (β = 0.256, P = 0.005) and other MR sensitivity analyses confirmed the findings.
Conclusions:
- Genetically determined higher serum calcium levels are causally associated with an increased risk of ischemic stroke (IS).
- These findings suggest that serum calcium levels may be a modifiable risk factor for ischemic stroke.
- Further research into calcium regulation and its impact on cerebrovascular health is warranted.
Abstract:
There has been an increased interest for observational studies or randomized controlled trials exploring the impact of calcium intake on cardiovascular diseases (CVD) including coronary artery disease (CAD) and ischemic stroke (IS). However, a direct relationship between total calcium intake and CVD has not been well established and remains controversial. Mendelian randomization (MR) studies have been performed to evaluate the causal association between serum calcium levels and CAD risk and found that increased serum calcium levels could increase the risk of CAD. However, MR analysis found no significant association between genetically higher serum calcium levels and IS as well as its subtypes. Hence, three MR studies reported inconsistent effects of serum calcium levels on CAD and IS. Here, we performed an updated MR study to investigate the association of serum calcium levels with the risk of IS using large-scale genome-wide association study (GWAS) datasets. We selected 14 independent genetic variants as the potential instrumental variables from a large-scale serum calcium GWAS dataset and extracted summary statistics corresponding to the 14 serum calcium genetic variants from the MEGASTROKE Consortium IS GWAS dataset. Interestingly, we found a significant association between serum calcium levels and IS risk using the robust inverse-variance weighted (IVW) and penalized robust IVW methods, with β = 0.243 and P = 0.002. Importantly, the MR results from the robust MR-Egger and penalized robust MR-Egger methods further supported the causal association between serum calcium levels and IS risk, with β = 0.256 and P = 0.005. Meanwhile, the estimates from other MR methods are also consistent with the above findings.
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