Genetic bases and modifiers of β-thalassemia in Argentina

Introduction β-syndromes are still a challenge for health professionals and many efforts are performed to achieve adequate diagnosis and develop novel treatments. The molecular bases of these syndromes are sequence variants in the HBB gene, which prevent the expression of β-globin chains. There are also modifiers that can alter the α:β-globin chain unbalance responsible for the pathophysiology of these syndromes, and modify the clinical course of these syndromes, preventing a correlation between the genotype of the patients and the exhibited phenotypes. Methods In this work, the β-globin sequence variants and secondary modifiers (KLF1, rs7482144, rs11886868, rs4895441, rs2071348, rs4296276, rs3191333 and rs77685897) were individually analyzed by several techniques in a cohort of 63 Argentinean patients with severe β-thalassemia. Results In 41 samples a genotype-exhibited phenotype correlation was corroborated. KLF1 analysis in this cohort revealed only one functional variant: rs79334031. SNVs associated with modifier loci (HBG2, HBBP1, HBS1L-MYB, BCL11A, KLF10 and AHSP) were analyzed in patients with transfusion-dependent and non-transfusion dependent thalassemia. Only for rs11886868 in BCL11A, the protective allele showed a statistically different distribution in the groups. A variant that maps in a potential target for hsa-miR-144-3p, rs77685897, in the 3’ UTR region of NFE2L2 was detected in heterozygous state in three patients. Conclusion The evaluation of the α and β-globin clusters by itself could not explain the genotype-phenotype correlation in 22 patients. The analysis of previously validated modifiers in our population highlighted the role of rs11886868 and revealed the need to further characterize genetic loci that could alter the clinical course of these syndromes.