Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
EBioMedicine. 2022 Feb;76:103865. doi: 10.1016/j.ebiom.2022.103865. Epub 2022 Feb 6.
Calcium plays a role in a wide range of biological functions. Here we conducted a phenome-wide Mendelian randomisation (MR-PheWAS) analysis and a systematic review for MR studies to comprehensively investigate the health effects of serum calcium.
One-hundred and thirty genetic variants strongly associated with serum calcium levels were used as instrumental variables. A phenome-wide association analysis (PheWAS) was conducted to examine the associations of genetically predicted serum calcium with 1473 distinct phenotypes in the UK Biobank including 339,197 individuals. Observed associations in PheWAS were further tested for replication in two-sample MR replication analysis. A systematic review for MR studies on serum calcium was performed to synthesize the published evidence and compare with the current MR-PheWAS findings.
Higher genetically predicted calcium levels were associated with decreased risk of 5 diseases in dermatologic and musculoskeletal systems and increased risk of 17 diseases in circulatory, digestive, endocrine, genitourinary and immune systems. Eight associations were replicated in two-sample MR analysis. These included decreased risk of osteoarthritis and increased risk of coronary artery disease, myocardial infarction, coronary atherosclerosis, hyperparathyroidism, disorder of parathyroid gland, gout, and calculus of kidney and ureter with increased serum calcium. Systematic review of 25 MR studies provided supporting evidence on five out of the eight disease outcomes, while the increased risk of gout, hyperparathyroidism and disorder of parathyroid gland were novel findings.
This study found wide-ranged health effects of high serum calcium, which suggests that the benefits and adversities of strategies promoting calcium intake should be assessed.
ET is supported by a CRUK Career Development Fellowship (C31250/A22804). XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province. SCL acknowledges research funding from the Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council (Vetenskapsrådet, 2019-00977), and the Swedish Cancer Society (Cancerfonden).
钙在广泛的生物学功能中发挥作用。在这里，我们进行了一项全基因组 Mendelian 随机化（MR-PheWAS）分析和一项系统评价，以全面研究血清钙的健康影响。
使用 130 种与血清钙水平密切相关的遗传变异作为工具变量。进行了一项全基因组关联分析（PheWAS），以检查遗传预测的血清钙与 UK Biobank 中 1473 种不同表型之间的关联，该研究纳入了 339197 人。在两样本 MR 复制分析中进一步测试了 PheWAS 中观察到的关联的复制。对血清钙的 MR 研究进行了系统评价，以综合已发表的证据，并与当前的 MR-PheWAS 结果进行比较。
较高的遗传预测钙水平与皮肤和肌肉骨骼系统 5 种疾病的风险降低有关，与循环、消化、内分泌、泌尿生殖和免疫系统 17 种疾病的风险增加有关。在两样本 MR 分析中，有 8 种关联得到了复制。其中包括骨关节炎风险降低和冠状动脉疾病、心肌梗死、冠状动脉粥样硬化、甲状旁腺功能亢进、甲状旁腺功能障碍、痛风、肾结石和输尿管结石风险增加与血清钙升高有关。对 25 项 MR 研究的系统评价提供了支持证据，证明了其中 5 种疾病结果，而痛风、甲状旁腺功能亢进和甲状旁腺功能障碍的风险增加则是新发现。
这项研究发现了高血清钙的广泛健康影响，这表明应该评估促进钙摄入的策略的益处和弊端。
ET 得到了英国癌症研究中心职业发展奖学金（C31250/A22804）的支持。XL 得到了浙江省杰出青年自然科学基金的支持。SCL 感谢瑞典心脏肺基金会（Hjärt-Lungfonden，20210351）、瑞典研究理事会（Vetenskapsrådet，2019-00977）和瑞典癌症协会（Cancerfonden）的研究资金。
