Genotype–Phenotype Spectrum, Socio-Demographic Drivers, and the Protective Impact of Fetal Hemoglobin in Sickle Cell Disease: A Cross-Sectional Analysis from West Bengal, India

Sickle cell disease (SCD) in India is often linked to the Arab–Indian haplotype, characterized by elevated fetal hemoglobin (HbF) levels and a relatively mild phenotype. However, data on genetic heterogeneity and genotype–phenotype correlations in Eastern India remain limited. This hospital-based cross-sectional study at Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, included 204 participants: 94 with SCD, 80 with sickle cell trait, and 30 healthy controls. Clinical, hematological, and socio-demographic data were analyzed. Among SCD patients (57 males, 37 females; mean age 24.2 years), 85.1% had a monthly household income ≤ ₹10,000, and 55.3% reported consanguinity. Geospatial mapping revealed clustering in North 24 Parganas, South 24 Parganas, and Kolkata. The predominant genotype was HbS-β thalassemia (62.8%). The median values for hemoglobin, HbF, platelet count, and leukocyte count were 8.7 g/dL, 17.4%, 214 × 109/L, and 8.8 × 109/L, respectively. HbF expression showed marked inter-individual variability, ranging from 7.7% to 49.6%. HbF levels showed a significant inverse correlation with leukocyte count (ρ=-0.733, p < 0.001), annual transfusion frequency (r=-0.387, 95% CI [−0.546, −0.200], p < 0.001), and vaso-occlusive crisis (VOC) frequency (r=-0.364, 95% CI [−0.528, −0.175], p < 0.001). In conclusion, SCD in West Bengal shows marked genetic and clinical heterogeneity, with HbS-β thalassemia as the predominant genotype. Higher HbF levels were associated with lower leukocyte counts, fewer transfusions, and fewer VOCs, supporting its role as a disease modifier. However, persistent variability suggests additional genetic and environmental influences, highlighting the need for region-specific screening and individualized management.