Jing-Yi Sun1, Haihua Zhang2, Yan Zhang3, Longcai Wang4, Bao-Liang Sun5, Feng Gao6, Guiyou Liu7. 1. Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250021, China. 2. Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, China. 3. Department of Pathology, The Affiliated Hospital of Weifang Medical University, Weifang, 261053, China. 4. Department of Anesthesiology, The Affiliated Hospital of Weifang Medical University, Weifang, 261053, China. 5. Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Department of Neurology, Second Affiliated Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, Shandong, China. 6. Department of Trauma and Emergency Surgeon, The Second Affiliated Hospital, Harbin Medical University, Harbin, China. Electronic address: gaofeng19761222@163.com. 7. Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, China; Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Department of Neurology, Second Affiliated Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, Shandong, China; National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China; Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China. Electronic address: liuguiyou1981@163.com.
Abstract
BACKGROUND & AIMS: Mendelian randomization (MR) studies have reported the causal association between serum calcium levels and bone mineral density (BMD). The results showed that genetically increased serum calcium levels in individuals with normal calcium levels did not increase BMD and could even reduce BMD. However, whether there are differences in the association between serum calcium and BMD in different age strata remains unclear. METHODS: We selected eight serum calcium genetic variants with genome-wide significance (P < 5.00E-08) as the potential instrumental variables. We conducted an MR analysis to evaluate the impact of serum calcium levels on total body BMD in five age strata, 0-15, 15-30, 30-45, 45-60, and ≥60 years, using large-scale serum calcium (61,079 individuals) and total body BMD genome-wide association study (66,628 individuals) datasets. For pleiotropy analysis, we used a manual method and four common statistical methods, namely the MR-Egger intercept, MR-PRESSO, heterogeneity, and Steiger filtering tests. For MR analysis, we selected four MR methods, namely inverse-variance weighted, weighted median, MR-Egger, and MR-PRESSO. In addition to the univariable MR analysis, we conducted a multivariate MR analysis taking into account the effect of serum parathyroid hormone levels. RESULTS: Univariable MR analysis using the inverse-variance weighted method indicated that per 0.5-mg/dL increase (about 1 standard deviation) in serum calcium levels was statistically significantly associated with reduced total body BMD only in the ≥60 years stratum (effect estimate (beta) = -0.545, 95% confidence interval (CI): -0.892 to -0.198, P = 0.002). The weighted median regression (beta = -0.446, 95% CI: -0.821 to -0.094, P = 1.40E-02) and MR-PRESSO (beta = -0.545, 95% CI: -0.892 to -0.198, P = 0.022) MR methods further supported this suggestive association. The multivariable MR analysis also found a significant association between increased serum calcium levels and reduced total body BMD in the ≥60 years stratum (beta = -0.547, 95% CI: -0.934 to -0.16, P = 0.006). CONCLUSIONS: Our results provide genetic evidence that increased serum calcium levels did not improve BMD in the general population and that the elevated serum calcium levels in generally healthy populations, especially in adults older than 60 years, may even reduce the BMD. Our results are comparable with those of recent MR findings.
BACKGROUND & AIMS: Mendelian randomization (MR) studies have reported the causal association between serum calcium levels and bone mineral density (BMD). The results showed that genetically increased serum calcium levels in individuals with normal calcium levels did not increase BMD and could even reduce BMD. However, whether there are differences in the association between serum calcium and BMD in different age strata remains unclear. METHODS: We selected eight serum calcium genetic variants with genome-wide significance (P < 5.00E-08) as the potential instrumental variables. We conducted an MR analysis to evaluate the impact of serum calcium levels on total body BMD in five age strata, 0-15, 15-30, 30-45, 45-60, and ≥60 years, using large-scale serum calcium (61,079 individuals) and total body BMD genome-wide association study (66,628 individuals) datasets. For pleiotropy analysis, we used a manual method and four common statistical methods, namely the MR-Egger intercept, MR-PRESSO, heterogeneity, and Steiger filtering tests. For MR analysis, we selected four MR methods, namely inverse-variance weighted, weighted median, MR-Egger, and MR-PRESSO. In addition to the univariable MR analysis, we conducted a multivariate MR analysis taking into account the effect of serum parathyroid hormone levels. RESULTS: Univariable MR analysis using the inverse-variance weighted method indicated that per 0.5-mg/dL increase (about 1 standard deviation) in serum calcium levels was statistically significantly associated with reduced total body BMD only in the ≥60 years stratum (effect estimate (beta) = -0.545, 95% confidence interval (CI): -0.892 to -0.198, P = 0.002). The weighted median regression (beta = -0.446, 95% CI: -0.821 to -0.094, P = 1.40E-02) and MR-PRESSO (beta = -0.545, 95% CI: -0.892 to -0.198, P = 0.022) MR methods further supported this suggestive association. The multivariable MR analysis also found a significant association between increased serum calcium levels and reduced total body BMD in the ≥60 years stratum (beta = -0.547, 95% CI: -0.934 to -0.16, P = 0.006). CONCLUSIONS: Our results provide genetic evidence that increased serum calcium levels did not improve BMD in the general population and that the elevated serum calcium levels in generally healthy populations, especially in adults older than 60 years, may even reduce the BMD. Our results are comparable with those of recent MR findings.
Authors: Luyan Gao; Kun Wang; Qing-Bin Ni; Hongguang Fan; Lan Zhao; Lei Huang; Mingfeng Yang; Huanming Li Journal: Front Genet Date: 2022-02-11 Impact factor: 4.599