Determinanti genetici dell’espressione dell’emoglobina HbF

Background: Increased levels of fetal hemoglobin (HbF, α2γ2) may reduce beta thalassemia severity. We have investigated the influence of three known major loci on the HbF trait (HBG2, rs7482144; BCL11A, rs1427407; HBS1L-MYB, rs9399137), prevalent Sardinian mutations in human Kruppel-like factor 1 (KLF1) recently reported to be responsible for persistence of high levels of fetal hemoglobin (HPFH) and two new predicted polymorphisms (HBE1 rs67385638; HBG2 rs2855122) involved in the increased HbF and HbA2 levels. Methods: We selected 4 cohorts of samples with different phenotypes: 87 HPFH, 41 subjects with normal HbF levels, 395 patients with beta thalassemia major and 59 beta thalassemia intermedia patients. Four single nucleotide polymorphisms (SNP) were genotyped by TaqMan procedure and one by restriction enzyme, KLF1 mutation was studied by Sanger sequencing. Fetal hemoglobin (HbF) from HPFH subjects was determined using the High Performance Liquid Chromatography (HPLC). Genotype frequencies were compared with frequencies reported in a global reference populations and in the Sardinian Population (PROGENIA). Results: We defined the genetic variants at five SNPs, reported to be associated with higher HbF levels. Although the distribution of the different SNP genotypes was significantly different in the all cohortes analysed, in the HPFH cohort as a whole, our data showed statistical significance only in the genetic association between BCL11A and HbF levels. However, splitting the HPFH samples in two categories based on the presence of the KLF1 mutation, the correlation of hemoglobin variations with some SNPs reached statistical significance in the KLF1 positive population with a trend toward the statistical significance in the KLF negative population exclusively for the rs67385638 SNP, suggesting that different pathways of globin regulation might be acting through the different SNPs.