Integrated Genetics and Micronutrient Data to Inform the Causal Association Between Serum Calcium Levels and Ischemic Stroke

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.

Altered serum calcium homeostasis independently predicts mortality in patients with acute coronary syndrome: a retrospective observational cohort study

“…The last but not the least, a relation of sCa with mortality caused by non-cardiovascular diseases cannot be excluded in the present study. Abnormalities of sCa have been reported to be associated with stroke, cancer and infection, which would also contribute to increased mortality 8 23 24…”

“…Abnormal serum calcium levels (sCa) have been previously reported to be an independent predictor of the incidence of cardiovascular diseases and associated with cardiovascular risk factors such as hypertension, dyslipidaemia and diabetes. [4][5][6][7][8][9][10][11][12] Since sCa can be easily measured through established assays, identifying the association between sCa and outcomes can be useful in clinical practice. A few published studies have shown that altered serum calcium homeostasis was an independent risk factor for short-term mortality in patients with cardiovascular diseases.…”

“…Abnormal serum calcium levels (sCa) have been previously reported to be an independent predictor of the incidence of cardiovascular diseases and associated with cardiovascular risk factors such as hypertension, dyslipidaemia and diabetes 4–12. Since sCa can be easily measured through established assays, identifying the association between sCa and outcomes can be useful in clinical practice.…”

An Updated Mendelian Randomization Analysis of the Association Between Serum Calcium Levels and the Risk of Alzheimer’s Disease

“…The 14 serum calcium SNPs were identified by a GWAS using 61,079 individuals of European descent ( O’seaghdha et al, 2013 ). These 14 serum calcium SNPs, especially the 8 SNPs at the genome-wide significance threshold, have been widely used as the potential instrumental variables to evaluate the association of serum calcium with other human complex diseases or phenotypes ( Larsson et al, 2017 , 2019 ; Xu et al, 2017 ; Meng et al, 2020 ; Wang Y. et al, 2020 ; Qu et al, 2021 ; Sun et al, 2021 ; Young et al, 2021 ; Yuan et al, 2021 ). Detailed information about these 14 SNPs is presented in Supplementary Table 1 .…”