Vitamin D receptor gene polymorphisms and 25-hydroxyvitamin D levels: association with cerebrovascular disease in sickle cell anemia

Sickle cell anemia (SCA) is associated with a high prevalence of cerebrovascular complications, such as ischemic stroke, particularly at young ages. Among various molecules, vitamin D has been implicated in stroke occurrence. By binding to the vitamin D receptor (VDR), vitamin D regulates several mechanisms, potentially influencing pathways involved in the pathophysiology of cerebral vasculopathy. Here, we evaluated the association between VDR gene polymorphisms and 25-hydroxyvitamin D (25(OH)D) levels with CVD in a cohort of patients with SCA. The frequency of CVD and laboratory data were retrospectively obtained from the medical records. Genotyping for the functional FokI (rs2228570) and Cdx-2 (rs11568820) VDR polymorphisms was performed in 459 unrelated SCA patients. 25(OH)D levels were measured in a subset of 45 patients. The TT genotype of the FokI VDR polymorphism was associated with a higher frequency (OR: 2.82; 95% CI: 1.38–5.76, p = 0.006) and higher cumulative incidence (34% vs 16%, p = 0.001) of CVD compared to the other genotypes. Among patients under hydroxyurea (HU) therapy, individuals with the TT-FokI genotype (median: 13.9 ng/mL) had lower 25(OH)D levels compared to those with CC/CT genotypes (median: 20.2 ng/mL; p = 0.033). Similarly, patients with CVD and the TT-FokI genotype (median: 12.3 ng/mL) had reduced 25(OH)D levels compared to CC/CT carriers (median: 20.8 ng/mL; p = 0.034). These findings suggest that the FokI VDR polymorphism may serve as a potential genetic modulator of cerebrovascular complications in individuals with SCA.