Abstract
Hemoglobinopathies though a monogenic disorder, show phenotypic variability. Hence, understanding the genetics underlying the heritable sub-phenotypes of hemoglobinopathies, specific to each population, would be prognostically useful and could inform personalized therapeutics. This study aimed to evaluate the role of genetic modifiers leading to higher HbF production with cumulative impact of the modifiers on disease severity. 200 patients (100 β-thalassemia homozygotes, 100 Sickle Cell Anemia), and 50 healthy controls were recruited. Primary screening followed with molecular analysis for confirming the β-hemoglobinopathy was performed. Co-existing α-thalassemia and the polymorphisms located in 3 genetic loci linked to HbF regulation were screened. The most remarkable result was the association of SNPs with clinically relevant phenotypic groups. The γ-globin gene promoter polymorphisms [− 158 C → T, + 25 G → A],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. 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.
Highlights
Hemoglobinopathies though a monogenic disorder, show phenotypic variability
On the basis of clinical history, the β-thalassemia patients were classified into a severe group (50 Thalassemia major: thalassemia homozygous group (TM)) and milder group (50 Thalassemia Intermedia: TI)
The results revealed a cumulative effect of the mutant alleles of the 3 SNPs − 158(C → T), rs11886868 (C → T), and rs1427407 (G → T) significantly higher in β-thalassemia intermedia patients, and as the best SNP model with testing balance accuracy of 74.9% and crossvalidation consistency of 9/10
Summary
Hemoglobinopathies though a monogenic disorder, show phenotypic variability. understanding the genetics underlying the heritable sub-phenotypes of hemoglobinopathies, specific to each population, would be prognostically useful and could inform personalized therapeutics. 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]. Both the diseases are caused by mutations in the β-globin gene and are inherited as an autosomal recessive single gene disorder. In this study, we have screened for the presence of primary and secondary modifiers in hemoglobinopathy patients and have analysed the cumulative effect of these modifiers on the phenotypic variability in the patient group
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