THE CAUSAL ROLE OF SERUM CALCIUM, PTH AND FGF23 ON BLOOD PRESSURE: A TWO-SAMPLE MENDELIAN RANDOMIZATION

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Objective: Parathyroid hormone (PTH) and Fibroblast Growth Factor 23 (FGF23) are among the calciotropic hormones involved in the regulation of blood calcium levels among the intestine, kidney, and bone through a tight endocrine feedback loop system. Altered levels of each of them could affect blood pressure either independently or not by the calcium, but the exact mechanisms remain unclear. To evaluate whether a causal relationship exists between serum calcium level and its homeostasis’ regulatory hormones with blood pressure traits, we performed a Two-Sample Mendelian Randomization. Design and method: From three large genome-wide association studies (GWAS) we obtained independent (r2 < 0.001) and GWAS-significant (p < 5X10-8) single nucleotide polymorphisms (SNPs) associated with serum calcium level (120 SNPs), PTH (5 SNPs), and FGF23 (5 SNPs), to investigate through MR their association with Systolic (SBP) and Diastolic (DBP) blood pressure in a Swedish large-scale cohort study, the Malmö Diet and Cancer (n = 29,298). Causality was evaluated with the Inverse Variance Weighted Method (IVW), and sensitivity analyses through MR-Egger. Results: Serum calcium level was found to be associated with DBP (IWV: beta = 11.9, SE = 4.2, p = 0.004). Surprisingly PTH didn’t show any association with the traits, while FGF23 was inversely associated with the SBP (IWV: beta = -5.0, SE = 2.0, P = 0.01) even if the association lost its significance at sensitivity analysis with MR-Egger. Conclusions: Our study shows a strong direct association between serum calcium level, described by its genetic component, with diastolic blood pressure. These results underline the importance of understanding the target genes that could alter calcium homeostasis and that could bring harmful implications later in life, moreover, it will be relevant for improving personalized intervention strategies. Despite not showing a strong association as the one shown by serum calcium level, the genetically predicted FGF23 level confirms its involvement in the regulation of blood pressure. Further an alyses deserve to be performed to clarify involved gene pathways.