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 <i>VDR</i> 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 <i>FokI</i> (rs2228570) and <i>Cdx-2</i> (rs11568820) <i>VDR</i> 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 <i>FokI VDR</i> polymorphism was associated with a higher frequency (OR: 2.82; 95% CI: 1.38-5.76, <i>p</i> = 0.006) and higher cumulative incidence (34% vs 16%, <i>p</i> = 0.001) of CVD compared to the other genotypes. Among patients under hydroxyurea (HU) therapy, individuals with the TT-<i>FokI</i> genotype (median: 13.9 ng/mL) had lower 25(OH)D levels compared to those with CC/CT genotypes (median: 20.2 ng/mL; <i>p</i> = 0.033). Similarly, patients with CVD and the TT-<i>FokI</i> genotype (median: 12.3 ng/mL) had reduced 25(OH)D levels compared to CC/CT carriers (median: 20.8 ng/mL; <i>p</i> = 0.034). These findings suggest that the <i>FokI VDR</i> polymorphism may serve as a potential genetic modulator of cerebrovascular complications in individuals with SCA.