The possibility that the severity of hemoglobinopathies could be reduced by induction of HbF was realized as the symptoms of hemoglobinopathies are observed after 6 months of age after the birth when there is a gradual reduction in the HbF levels. An interacting combination of α-thalassemia with hemoglobinopathy has been shown to alleviate the severity by reducing the intracellular precipitation of free alpha-globin chains in β-thalassemia and by reducing HbS concentration in SCA patients 3, 4. The most common secondary modifier is the co-inheritance of α-thalassemia and the elevated levels of fetal hemoglobin (HbF), both of which directly reduce the globin chain imbalance. Several modifier genes have been identified which influence the severity of hemoglobinopathies. Thus, the clinical variability observed among the patients prompted the search for the additional genetic modulators of these diseases. It has been observed that patients inheriting the same β-globin gene mutations, display phenotypic heterogeneity. However, milder β ++ mutations, present in the conserved 5′ β-globin promoter region and 3′ untranslated region, may alter the mRNA expression, leading to the moderate synthesis of the β-globin chain 2. Severe β-thalassemia mutation (β 0/β +) may completely down-regulate β-globin chain synthesis. In β-thalassemics, the primary determinant of disease severity is the type of β-globin gene mutation that the patient inherits. However, despite this apparent genetic simplicity, both the disorders display a remarkable spectrum of phenotypic severity. Both the diseases are caused by mutations in the β-globin gene and are inherited as an autosomal recessive single gene disorder. Β-Thalassemia and sickle cell anemia (SCA) form a major health burden in India as they cause a high degree of morbidity, moderate to severe hemolytic anemia with the carrier frequency varying from 3 to 17% among different population groups of India 1. Our study emphasizes the complex genetic interactions underlying the disease phenotype that may be a prognostic marker for predicting the clinical severity and assist in disease management. The γ-globin gene promoter polymorphisms ,BCL11A rs1427407 G → T, − 3 bp HBS1L-MYB rs66650371 and rs9399137 T → C polymorphisms were correlated with higher HbF, in group that has lower disease severity score (P < 0.00001), milder clinical presentation, and a significant delay in the age of the first transfusion. The most remarkable result was the association of SNPs with clinically relevant phenotypic groups. Co-existing α-thalassemia and the polymorphisms located in 3 genetic loci linked to HbF regulation were screened. Primary screening followed with molecular analysis for confirming the β-hemoglobinopathy was performed. 200 patients (100 β-thalassemia homozygotes, 100 Sickle Cell Anemia), and 50 healthy controls were recruited. This study aimed to evaluate the role of genetic modifiers leading to higher HbF production with cumulative impact of the modifiers on disease severity. Hence, understanding the genetics underlying the heritable sub-phenotypes of hemoglobinopathies, specific to each population, would be prognostically useful and could inform personalized therapeutics. Hemoglobinopathies though a monogenic disorder, show phenotypic variability.
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