Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China.
Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Mol Neurobiol. 2023 Jun;60(6):3004-3009. doi: 10.1007/s12035-023-03254-6. Epub 2023 Feb 10.
Elevated serum calcium (S-Ca), 25-hydroxyvitamin D (S-25OHD), and parathyroid hormone (S-PTH) levels have been associated with risk of aneurysmal subarachnoid hemorrhage (SAH) in observational studies. However, whether these associations are causal is unclear. The objective of the present study was to determine whether genetically predicted S-Ca, S-25OHD, and S-PTH levels are causally associated with aneurysmal SAH using a Mendelian randomization design. Analyses were performed using summary-level data for genetic variants associated with S-Ca, S-25OHD, and S-PTH concentrations. Summary data for aneurysmal SAH were adopted from a genome-wide association study (GWAS) on intracranial aneurysm (n = 79,429 individuals, 69% of the cases had aneurysmal SAH). The inverse variance-weighted approach was adopted as the primary analyses. For sensitivity analyses, the weighted median and MR-Egger approaches were adopted. Genetically predicted S-Ca and S-PTH levels were associated with aneurysmal SAH in the primary analyses. The odds ratios (ORs) of aneurysmal SAH were 1.96 (95% CI: 1.003-3.812; P = 0.049) and 1.495 (95% CI: 1.058-2.114; P = 0.023) for one SD increase of genetically predicted S-Ca and S-PTH levels, respectively. Genetically predicted S-25OHD concentration was not associated with aneurysmal SAH (per 1 SD increase in S-25OHD: OR = 0.92; 95% CI, 0.78-1.09; P = 0.332). Sensitivity analysis yielded similar results, and no evidence of pleiotropy was observed. Our results indicated that higher genetically predicted S-Ca and S-PTH levels may increase the risk of aneurysmal SAH.
血清钙（S-Ca）、25-羟维生素 D（S-25OHD）和甲状旁腺激素（S-PTH）水平升高与观察性研究中的蛛网膜下腔出血（SAH）风险相关。然而，这些关联是否具有因果关系尚不清楚。本研究旨在通过孟德尔随机化设计确定遗传预测的 S-Ca、S-25OHD 和 S-PTH 水平是否与动脉瘤性 SAH 有因果关系。分析使用与 S-Ca、S-25OHD 和 S-PTH 浓度相关的遗传变异的汇总水平数据进行。动脉瘤性 SAH 的汇总数据取自颅内动脉瘤的全基因组关联研究（GWAS）（n=79429 人，69%的病例为动脉瘤性 SAH）。采用逆方差加权法作为主要分析方法。对于敏感性分析，采用加权中位数和 MR-Egger 法。主要分析中，遗传预测的 S-Ca 和 S-PTH 水平与动脉瘤性 SAH 相关。遗传预测的 S-Ca 和 S-PTH 水平每增加一个标准差，动脉瘤性 SAH 的比值比（OR）分别为 1.96（95%CI：1.003-3.812；P=0.049）和 1.495（95%CI：1.058-2.114；P=0.023）。遗传预测的 S-25OHD 浓度与动脉瘤性 SAH 无关（S-25OHD 每增加一个标准差：OR=0.92；95%CI，0.78-1.09；P=0.332）。敏感性分析得出了类似的结果，且未观察到明显的混杂偏倚。我们的结果表明，较高的遗传预测 S-Ca 和 S-PTH 水平可能会增加动脉瘤性 SAH 的风险。
