Among the clinical complications of Sickle Cell Anemia (SCA), stroke is the most serious. Transcranial Doppler (TCD) is a screening tool that predicts the risk of stroke in pediatric patients, leading to the initiation of prophylactic therapy. However, due to the TCD's intrinsic limitations, the identification of new predictors of stroke risk are necessary. The CAV1 is an interesting gene for assessing this risk and is responsible for encoding the caveolin-1 protein. This protein regulates signaling pathways and processes that are involved in the pathophysiology of stroke in SCA, mainly by negatively regulating the bioavailability of Nitric Oxide (NO), an important vasodilator. Therefore, we evaluated the association of CAV1 gene polymorphisms with Cerebrovascular Disease (CVD) in an SCA cohort.

We evaluated 339 individuals with SCA under 20-years of age followed by the Hematology and Hemotherapy Foundation of Pernambuco (HEMOPE). Three polymorphisms were selected: rs3807989 (G>A), rs7804372 (T>A) and rs1997623(A>C). Genotyping for polymorphisms was performed by real-time PCR with allelic discrimination using TaqMan fluorogenic probes. Categorical variables were analyzed using Fisher's exact test. Nonparametric Mann-Whitney and Kruskal-Wallis tests were used to analyze continuous variables.

Polymorphisms rs3807989 and rs7804372 were not statistically associated with the analyzed variables. The rs1997623 showed a statistically significant association with stroke (p = 0.003) and CVD (p = 0.011). Furthermore, the wild-type “A” allele was related to higher stroke (p = 0.0032; OR = 2.568; 95% CI 1.374–4.655) and CVD frequency (p = 0.0092; OR = 1.950; 95% CI 1.205–3.160) when compared to the variant allele “C”.

Previous findings indicate that the “C”allele was related to lower levels of CAV1 expression. Thus, the protective action of the rs1997623-C allele regarding sickle-cerebrovascular outcomes is possibly due to decreased expression of the CAV1 gene, leading to increased bioavailability of NO, and ultimately low endothelial dysfunction and vasculopathy.

Studies related to the elucidation of the influence of genetic variants on the incidence of cerebrovascular disease are useful to provide an alternative prognostic test. Thus, it would be possible to identify early children at high risk of developing this clinical complication, reducing the occurrence of primary strokes in patients with SCA through the necessary preventive treatments. In summary, these findings rs1997623 might be related to the multifactorial landscape of CVD in SCA, though further investigations are needed to confirm these results.