Calcium, Its Regulatory Hormones, and Their Causal Role on Blood Pressure: A Two-Sample Mendelian Randomization Study

• Published in: The journal of clinical endocrinology and metabolism Vol. 107; no. 11; pp. 3080 - 3085
• Main Authors: Giontella, Alice, Lotta, Luca A, Baras, Aris, Minuz, Pietro, Gill, Dipender, Melander, Olle, Fava, Cristiano
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.11.2022
• Subjects: Alfacalcidol; Analysis; Basic Medicine; Blood levels; Blood pressure; Calcifediol; Calcium (blood); Calcium homeostasis; Cancer; Chromosomes; Fibroblast growth factor 23; Fibroblast growth factors; Genome-wide association studies; Genomics; Homeostasis; Hormones; Medical and Health Sciences; Medical Genetics and Genomics (including Gene Therapy); Medicin och hälsovetenskap; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; Oncology, Experimental; Parathyroid hormone; Sensitivity analysis; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Vitamin D; blood pressure; calcium homeostasis; Mendelian randomization
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgac501

Abstract Context Vitamin D (Vit-D), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) are the major calciotropic hormones involved in the regulation of blood calcium levels from the intestine, kidney, and bone through a tight endocrine feedback loop system. Altered levels of calcium itself or through the effect of its regulatory hormones could affect blood pressure (BP), but the exact mechanisms remain unclear. Objective To evaluate whether a causal relationship exists between serum calcium level and/or the regulatory hormones involved in its homeostasis with BP, we performed a two-sample Mendelian randomization (MR) study. Methods From 4 large genome-wide association studies (GWAS) we obtained independent (r2 < 0.001) single nucleotide polymorphisms (SNPs) associated with serum calcium (119 SNPs), Vit-D (78 SNPs), PTH (5 SNPs), and FGF23 (5 SNPs), to investigate through MR their association with systolic BP (SBP) and diastolic BP (DBP) in a Swedish urban-based study, the Malmö Diet and Cancer study (n = 29 298). Causality was evaluated by the inverse variance weighted method (IVW) and weighted median, while MR Egger and MR-PRESSO were used as sensitivity analyses. Results Genetically predicted serum calcium level was found to be associated with DBP (IVW: beta = 0.10, SE = 0.04, P = 0.007) and SBP (IVW: beta = 0.07, SE = 0.04, P = 0.04). Genetically predicted Vit-D and PTH showed no association with the traits, while FGF23 was inversely associated with SBP (IVW: beta = −0.11, SE = 0.04, P = 0.01), although this association lost statistical significance in sensitivity analysis. Conclusion Our study shows a direct association between genetically predicted calcium level and DBP, and a weaker association with SBP. No such clear association was found for genetically predicted calciotropic hormone levels. It is of interest to detect which target genes involved in calcium homeostasis mediate the effect of calcium on BP, particularly for improving personalized intervention strategies.