Polymorphic variations influencing fetal hemoglobin levels: Association study in beta-thalassemia carriers and in normal individuals of Portuguese origin

Three major loci have been associated with HbF levels, including − 158C/T (XmnI) at HBG2 promoter region, and several polymorphisms at BCL11A intron-2 and HBS1L-MYB (HMIP) intergenic region. Mutations in the KLF1 gene were recently associated with increased HbF levels.This study aims to evaluate whether genetic variability at these loci influences HbF levels in β-thalassemia carriers and in normal individuals of Portuguese origin.Sixty five β-thalassemia carriers, HbF levels ranging from 0.2% to 9.5%, and 60 individuals with normal hematological parameters, HbF levels ranging from 0.2% to 7.4%, were selected for this study.In β-thal carriers linear regression models revealed a strong statistical significant association for HBG2 (XmnI) rs7482144 (β = 0.455; P = 5.858 × 10− 7), and nominal significance for BCL11A rs766432 (β = 0.215; P = 0.029) and HMIP rs9399137 (β = 0.209; P = 0.011). In normal individuals, a case (HbF > 2%; n = 15) vs. control (HbF < 1.7%; n = 45) model, showed nominal significant associations for BCL11A SNPs rs11886868 (OR = 4; P = 0.001), rs766432 (OR = 3.7; P = 0.002) and rs7606173 (OR = 0.36; P = 0.032). KLF1 rs3817621 was not found associated with HbF levels.Our results suggest that in Portuguese β-thal carriers the HBG2 XmnI polymorphism is strongly associated with HbF levels. In normal individuals, BCL11A polymorphisms, but not HMIP or HBG2 (XmnI) loci, are nominally associated with HbF expression.