title: Polymorphic variations influencing fetal hemoglobin levels: association study in beta-thalassemia carriers and in normal individuals of Portuguese origin.
abstract: 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.
authors.affiliation: Research Centre for Anthropology and Health (CIAS), Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: Clara
authors.initials: C
authors.lastname: Pereira
authors.affiliation: Department of Hematology, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Relvas
authors.affiliation: Department of Hematology, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal.
authors.forename: Celeste
authors.initials: C
authors.lastname: Bento
authors.affiliation: Research Centre for Anthropology and Health (CIAS), Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: Augusto
authors.initials: A
authors.lastname: Abade
authors.affiliation: Department of Hematology, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal.
authors.forename: M Letícia
authors.initials: ML
authors.lastname: Ribeiro
authors.affiliation: Research Centre for Anthropology and Health (CIAS), Department of Life Sciences, University of Coimbra, Coimbra, Portugal; Department of Hematology, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal. Electronic address: lmanco@antrop.uc.pt.
authors.forename: Licínio
authors.initials: L
authors.lastname: Manco
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics; D056426:Genetic Loci; D015894:Genome, Human; D055106:Genome-Wide Association Study; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010445:Peptide Elongation Factors / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011174:Portugal; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics; D012097:Repressor Proteins; D017086:beta-Thalassemia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D055545:gamma-Globins / Q000235:genetics*
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D010445:Peptide Elongation Factors; D020598:Proto-Oncogene Proteins c-myb; D012097:Repressor Proteins; C080774:erythroid Kruppel-like factor; D055545:gamma-Globins; D005319:Fetal Hemoglobin; D019204:GTP-Binding Proteins; C000628258:HBS1L protein, human
keywords: BCL11A; Beta-thalassemia carriers; HBG2; HMIP; HPFH; HbF; KLF1 loci