Background: Sickle cell anemia (SCA) is an inherited disorder characterized by chronic hemolysis and persistent hematological abnormalities. This study investigated the association of the hypoxia-inducible factor-1 alpha (HIF-1α) C1772T genetic variant, a key regulator of the hypoxic response, with hematological indices in SCA patients.

Methods: This case-control study included 100 adult SCA patients and 100 age- and gender-matched healthy controls in Taif. Hematological parameters were measured, and HIF-1α C1772T genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Statistical analyses were performed using Student's t-test or the Mann-Whitney U test, Chi-square (χ²) test, and odds ratio (OR) calculations with confidence intervals (CI).

Results: SCA patients exhibited markedly reduced hemoglobin (t = 27.59, p < 0.0001) and hematocrit levels (t = 41.54, p < 0.0001), and elevated white blood cell (t = 7.45, p < 0.0001) and platelet counts (t = 9.22, p < 0.0001). The CT genotype occurred more frequently in SCA patients (18%) than in controls (7%) (χ² = 5.5, p = 0.019; OR = 2.91, 95% CI: 1.16–7.33). Similarly, the T allele frequency was higher among SCA patients (9%) than controls (3.5%) (χ² = 5.2, p = 0.023; OR = 2.72, 95% CI: 1.11–6.68). Among SCA patients, carriers of the CT genotype had significantly higher hemoglobin (t = 2.83, p = 0.005), hematocrit (t = 3.05, p = 0.002), and fetal hemoglobin levels (p = 0.047), but lower serum ferritin levels (p = 0.026) than CC carriers.

Conclusions: The HIF-1α C1772T polymorphism is associated with SCA in this population. The presence of the T allele, particularly in the heterozygous CT genotype, may increase susceptibility to SCA. Additionally, CT carriers exhibited a more favourable hematological profile than those with the CC genotype. These findings suggest that this polymorphism may influence susceptibility to SCA, pathophysiology, and clinical severity of SCA.