Genotypic heterogeneity and correlation to intergenic haplotype within high HbF <i>β</i>‐thalassemia intermedia

Papachatzopoulou, Adamantia; Kourakli, Alexandra; Makropoulou, Panagiota; Kakagianne, Theodora; Sgourou, Argyro; Papadakis, Manousos; Athanassiadou, Aglaia

doi:10.1111/j.1600-0609.2005.00618.x

Cited by 31 publications

(19 citation statements)

References 43 publications

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“…The major genetic modifiers of β-thalassemia are genotypes of β- and α-globin and expression of γ-globin [6,7]. Some genotypic factors have been reported to affect synthesis of the γ-globin chain, such as the 3'HS1 (+179 C→T) polymorphism [8], the (AT)xNy(AT)z motif in the 5'HS2 site [9], and the (AT)x(T)y motif in the -540 region of the β-globin gene[10]. Variation of rs11886868 (T→C) in the BCL11A gene has also been shown to correlate with increased HbF in European TI patients [11].…”

Section: Introductionmentioning

confidence: 99%

The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity

et al. 2010

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BackgroundThe clinical syndrome of thalassemia intermedia (TI) results from the β-globin genotypes in combination with factors to produce fetal haemoglobin (HbF) and/or co-inheritance of α-thalassemia. However, very little is currently known of the molecular basis of Chinese TI patients.MethodsWe systematically analyzed and characterized β-globin genotypes, α-thalassemia determinants, and known primary genetic modifiers linked to the production of HbF and the aggravation of α/β imbalance in 117 Chinese TI patients. Genotype-phenotype correlations were analyzed based on retrospective clinical observations.ResultsA total of 117 TI patients were divided into two major groups, namely heterozygous β-thalassemia (n = 20) in which 14 were characterized as having a mild TI with the Hb levels of 68-95 g/L except for five co-inherited αααanti-3.7 triplication and one carried a dominant mutation; and β-thalassemia homozygotes or compound heterozygotes for β-thalassemia and other β-globin defects in which the β+-thalassemia mutation was the most common (49/97), hemoglobin E (HbE) variants was second (27/97), and deletional hereditary persistence of fetal hemoglobin (HPFH) or δβ-thalassemia was third (11/97). Two novel mutations, Term CD+32(A→C) and Cap+39(C→T), have been detected.ConclusionsChinese TI patients showed considerable heterogeneity, both phenotypically and genotypically. The clinical outcomes of our TI patients were mostly explained by the genotypes linked to the β- and α-globin gene cluster. However, for a group of 14 patients (13 β0/βN and 1 β+/βN) with known heterozygous mutations of β-thalassemia and three with homozygous β-thalassemia (β0/β0), the existence of other causative genetic determinants is remaining to be molecularly defined.

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Section: Introductionmentioning

confidence: 99%

The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity

et al. 2010

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“…Sequence analysis of the 5′ flanking region of the (Table 2), which have all been reported previously (16)(17)(18)(19)(20)(21). However, no variation, apart from the XmnI polymorphism, could be identified in the G g promoter region.…”

Section: Resultsmentioning

confidence: 95%

“…The increase of Hb F can neutralize the toxic effects of the unbound a-globin chains in b-thal and reduce the severity of the disease (22). Several nt variations such as G g −158 (C>T) and variations upstream of the A g-globin gene showing high level of Hb F have been studied in b-TI patients (7,17,18,20,(23)(24)(25). The focus of this study was to find the changes which might influence Hb F overexpression.…”

Section: Discussionmentioning

confidence: 98%

Molecular Analysis of γ-Globin Promoters, HS-111 and 3′HS1, in β-thalassemia Intermedia Patients Associated with High Levels of Hb F

et al. 2009

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The nucleotide (nt) variations in the promoter region of the gamma-globin genes, HS-111 and 3'HS1 regions, were studied in Iranian patients with beta-thalassemia intermedia (beta-TI), beta-thalassemia major (beta-TM) and healthy individuals. Of the five nt variations at the 5' end of the (A)gamma-globin gene, -369 (C>G), -611 (-T) and -603/604 (GA>AG) were found in all samples, whereas -588 (A>G) and -AAGC at -222 to -225 were found at different frequencies in the studied groups. Therefore, the -369, -611 and -603/604 variations were considered common mutations in this population, and the difference with respect to the -AAGC deletion was not significant. However, the A allele of the -588 variation and [+] allele of the XmnI polymorphism were more frequent in beta-TI patients, especially those who had the IVS-II-1(G>A)/IVS-II-1(G>A) genotype. The + allele of XmnI also had complete correlation with the A allele of -588 variation. The HS-111 (-21 A) variation also showed association with beta-TI patients who had high levels of Hb F. Bearing in mind that the -588 variation lies within the postulated adult-specific silencer region and that the majority of beta-TI patients had allele A, then it can be envisaged that this allele could have a role in altering the repressor function at this region. Therefore, the A allele of -588, [+] allele of XmnI and HS-111 (-21 A) variation are useful genetic markers to differentiate between beta-TM and beta-TI patients. However, these nt changes alone may not be the only elements raising the level of Hb F, other regulatory and modifying factors also play a role in Hb F production.

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“…A number of studies have assessed the β-thal and sickle cell disease severity, correlated with Hb F levels, in relation with several SNPs residing within the human β-globin cluster, such as the G γ XmnI (HBG2:g.-158C>T) polymorphism (13,20), the intergenic A γ-δ haplotypes and region (16,21), the 3 0 HS1 (3 0 hypersensitive site 1) (þ179C>T) variant that generates a GATA-1 binding site (17), and the recently identified association of variants centromeric to the β-globin region, lying within the olfactory receptor cluster (22). In addition, modifier genes outside the β-globin gene cluster have been shown to play a role in Hb F expression; apart from the well-established associations of SNPs residing in the intergenic HBS1L-MYB region (10) and the BCL11A locus (4), polymorphic variants in other regions have been associated with Hb F expression in adults, including chromosomes 6q22-q23, 8q11-q12, and Xp22 (23)(24)(25) as well as with disease severity in β-thal (Tafrali et al, submitted).…”

Section: Discussionmentioning

confidence: 99%

“…Peripheral blood was collected from 95 adult β-TM and 11 adult β-TI patients (16,17), as well as 94 ethnically matched adult healthy (non thalassemic) donors of Western Greek origin. In addition, we recruited an 434 E. Giannopoulou et al independent sample comprising 35 Hb S [β6(A3)Glu!Val, GAG>GTG]/βthal compound heterozygous patients of Western Greek origin receiving HU as an Hb F-augmenting agent in their treatment regimen.…”

Section: Subjects and Patient Classificationmentioning

confidence: 99%

A Single Nucleotide Polymorphism in theHBBP1Gene in the Human β-Globin Locus is Associated with a Mild β-Thalassemia Disease Phenotype

et al. 2012

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The rs2071348 (g.5264146A>C) polymorphism on the HBB pseudogene, namely HBBP1, previously emerged as a variant significantly associated with a milder disease phenotype in Asian β(0)-thalassemia/hemoglobin (Hb) E (β(0)-thal/Hb E [β26(B8)Glu→Lys, GAG>AAG]) patients. In this study, we aimed to explore the possible association of rs2071348 with β-thalassemia (β-thal) disease severity in a group of β-thal major (β-TM) patients (severe phenotype) and β-thal intermedia (β-TI) patients (mild phenotype) of Hellenic origin and compare the results with normal (non thalassemic) individuals of the same origin. In addition, we explored whether this single nucleotide polymorphism (SNP) can be exploited as a pharmacogenomic marker to predict the outcome of Hb F-augmenting therapy in β-thal patients receiving hydroxyurea (HU). Our data suggest that the rs2071348 polymorphism is associated with higher Hb F levels and a milder β-thal disease phenotype. However, the rs2071348 polymorphism in the HBBP1 gene does not correlate with response to HU treatment.

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Genotypic heterogeneity and correlation to intergenic haplotype within high HbF β‐thalassemia intermedia

Abstract: The genetic determinant(s) of high HbF in the absence of HPFH is linked to intergenic haplotype T and does not disrupt intergenic transcription.

Cited by 31 publications

References 43 publications

The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity

The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity

Molecular Analysis of γ-Globin Promoters, HS-111 and 3′HS1, in β-thalassemia Intermedia Patients Associated with High Levels of Hb F

A Single Nucleotide Polymorphism in theHBBP1Gene in the Human β-Globin Locus is Associated with a Mild β-Thalassemia Disease Phenotype

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