title: Molecular studies of beta-thalassemia heterozygotes with raised Hb F levels.
abstract: Hb F levels in beta-thalassemia heterozygotes are usually less than 2%, but amongst 1,059 patients studied, 73 (7%) had Hb F levels above 2.5% (2.6-14.0%). To investigate factors that may influence the increase of Hb F levels in these heterozygotes, we characterized the beta-thalassemia mutations and their chromosomal background, gamma-globin gene promoter variations, and alpha-globin genotypes. All 73 beta-thalassemia heterozygotes carried beta-thalassemia point mutations previously observed in the Greek population; gene mapping excluded b gene cluster deletions; only two cases had an additional gamma-globin gene (gammagammagamma/gammagamma). Five alpha-globin genes (alphaalphaalpha/alphaalpha) were detected in 17/73 cases (23%) as compared to a carrier rate of 1.76% in the general population. Molecular, hematological, and biosynthetic findings in these compound heterozygotes indicated that the raised Hb F levels were caused by cell selection due to ineffective erythropoiesis. In the remaining 56 simple beta-thalassemia heterozygotes, 11 beta-thalassemia mutations were observed, each on the expected haplotype(s), and analysis of the gamma gene promoters revealed three known polymorphisms (in linkage disequilibrium), with minimal influence on gamma-globin levels. However, the overall distribution of beta-thalassemia mutations in the 56 simple beta-thalassemia heterozygotes was significantly different (P<0.0002) compared to that in 986 simple beta-thalassemia heterozygotes with <2.5% Hb F, implicating an association between beta-thalassemia mutations and moderately increased Hb F levels, most notably codon 39 (C-->T), IVS-II-1 (G-->A), codon 6 (-A), and codon 8 (-AA), which accounted for 41/56 (73%) cases with >2.5% Hb F. In the remaining 15/56 (27%) cases, no common underlying globin genotypes could explain the raised Hb F levels. Overall, this study indicates that the control of Hb F levels in beta-thalassemia heterozygotes is heterogeneous and multi-factorial.
authors.affiliation: First Department of Pediatrics, University of Athens, Aghia Sophia Children's Hospital, Greece.
authors.forename: C
authors.initials: C
authors.lastname: Vrettou
authors.forename: E
authors.initials: E
authors.lastname: Kanavakis
authors.forename: J
authors.initials: J
authors.lastname: Traeger-Synodinos
authors.forename: A
authors.initials: A
authors.lastname: Metaxotou-Mavrommati
authors.forename: I
authors.initials: I
authors.lastname: Basiakos
authors.forename: E
authors.initials: E
authors.lastname: Maragoudaki
authors.forename: A
authors.initials: A
authors.lastname: Stamoulakatou
authors.forename: I
authors.initials: I
authors.lastname: Papassotiriou
authors.forename: C
authors.initials: C
authors.lastname: Kattamis
mesh_terms: D002874:Chromosome Mapping; D005260:Female; D005319:Fetal Hemoglobin / Q000378:metabolism*; D015321:Gene Rearrangement; D005838:Genotype; D005914:Globins / Q000235:genetics; D006115:Greece / Q000453:epidemiology; D006403:Hematologic Tests; D006579:Heterozygote; D006801:Humans; D008297:Male; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017086:beta-Thalassemia / Q000235:genetics / Q000378:metabolism*
chemical_list: D005914:Globins; D005319:Fetal Hemoglobin