ASSOCIATION OF VITAMIN D RECEPTOR (VDR) VARIANTS, HYDROXYUREA THERAPY, AND CEREBROVASCULAR DISEASE STATUS ON 25-HYDROXYVITAMIN D (25(OH)D) LEVELS IN PATIENTS WITH SICKLE CELL ANEMIA

Abstract

Vitamin D, through binding to its specific receptor, vitamin D receptor (VDR), executes actions beyond calcium metabolism and impacts sickle cell anemia (SCA) pathophysiology, such as regulating inflammation, vascular tone, and thrombogenesis. Genetic polymorphisms that can potentially disturb VDR function or its levels may modify the vitamin D mechanism and have already been associated with several conditions, including stroke. Therefore, we evaluated the association of 25-hydroxyvitamin D (25(OH)D) levels with VDR gene polymorphisms, hydroxyurea (HU) therapy, and cerebrovascular disease (CVD) in an SCA cohort. 25(OH)D levels were determined using the automated microparticle chemiluminescence method in 45 non-related SCA patients (55.5% males). Genotyping for functional FokI (rs2228570) and Cdx-2 (rs11568820) VDR polymorphisms was performed with TaqMan fluorogenic probes. Nonparametric Mann-Whitney and Kruskal-Wallis tests, followed by Dunn's multiple comparisons post-test, were used to analyze continuous variables. The median 25(OH)D levels were 20.9 ng/mL (range, 10 – 37.2 ng/mL). 18 patients (40%) had vitamin D deficiency (25(OH)D < 20ng/mL), 22 (49%) had insufficient levels (25(OH)D 20 - 30 ng/mL) and 05 (11 %) had sufficient levels (25(OH)D > 30 ng/mL). No difference was observed in 25(OH)D levels according to FokI and Cdx-2 genotypes (p > 0.05). However, 25(OH)D levels were decreased in patients with CVD (p = 0.026) and patients under hydroxyurea (HU) therapy (p = 0.005). Considering patients under HU therapy, individuals with variant TT- FokI genotype had lower levels of 25(OH)D (median: 13.9 ng/mL) when compared to those with CC/CT genotypes (median: 20.2 ng/mL; p = 0.03). In the group of individuals without HU therapy, this finding was not observed (p > 0.05). Although not statistically significant, patients with CVD and TT- FokI genotype had lower levels of 25(OH)D (median: 12.3 ng/mL) when compared to individuals with CC/CT genotypes (median: 20,8 ng/mL; p = 0.075). Despite the influence of HU in 25(OH)D levels has already been addressed with conflicting results, the mechanism that might explain these associations is not yet known. Moreover, previous findings indicate that the effect of functional VDR variants can be influenced by vitamin D status. Therefore, under the influence of factors that affect vitamin D levels, the defective VDR isoform, resulting from the FokI polymorphism, possibly accentuates the 25(OH)D deficiency, contributing to an adverse outcome. In summary, 25(OH)D levels are reduced in SCA patients with CVD and those under HU therapy. Further studies are required to determine the mechanism underlying HU and 25(OH)D levels associations and the effect of vitamin D supplementations in patients with CVD in SCA, especially those under HU therapy.