Foetal haemoglobin in normal healthy adults: relationship with polymorphic sequences cis to the β globin gene

Zertal-Zidani, Samia; Ducrocq, Rolande; Sahbatou, Mourad; Satta, Dalila; Krishnamoorthy, Rajagopal

doi:10.1038/sj.ejhg.5200809

Cited by 21 publications

(24 citation statements)

References 31 publications

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“…Since the T allele is underrepresented in highlanders, it seems not to be advantageous at high altitude. The −158 C→T polymorphism is a modulating factor for the γ-globin gene expression (Tasiopoulou et al, 2007), and the T allele is associated with an increased expression of G γ chains, resulting in an increased HbF level in adults (Sampietro et al, 1992;Leonova et al, 1996;Zertal-Zidani et al, 2002;Tasiopoulou et al, 2007). The T allele did not significantly affect the expression of γ-genes in healthy people, but increases the HbF production under conditions of erythropoietic stress (Thein, 2005).…”

Section: Discussionmentioning

confidence: 99%

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Native highland and lowland populations differ in .GAMMA.-globin gene promoter polymorphisms related to altered fetal hemoglobin levels and delayed fetal to adult globin switch after birth

Rottgardt

Rothhammer

Dittmar

2010

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Lowered partial oxygen pressure at high altitude exerts a strong selection pressure. Since hypoxia is most serious for the fetus, fetal hemoglobin genes (HBG1, HBG2) are candidates for genetic adaptation to high altitude. The aim of this study was to compare promoter polymorphisms of these genes for differences between highland and lowland populations. In 50 native highlanders of the Chilean Andes and 50 lowlanders of European ancestry, the promoters of HBG1 and HBG2 genes were sequenced. In the HBG1 promoter, the 4-basepair AGCA deletion was less frequently present in highlanders than in lowlanders (10% vs. 24%, P = 0.014). In the HBG2 promoter, the frequency of the T allele of the common −158 C > T polymorphism was decreased in highlanders, compared with lowlanders (8% vs. 34%, P = 0.000009). A combined analysis of both markers showed that none of the highlanders with the AGCA deletion carried the HBG2 T allele, in contrast to 43% of lowlanders (P = 0.030). Since the AGCA deletion is associated with diminished expression of fetal γ globin chains, it might affect fetal oxygen supply at high altitude. Both the AGCA deletion and the HBG2 −158 T allele are associated with a delayed fetal to adult globin switch after birth, resulting in a delayed production of adult hemoglobin, thereby possibly affecting the oxygen supply of infants at high altitude.

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Section: Discussionmentioning

confidence: 99%

“…This polymorphism has been found in Mediterranean populations. Elevated HbF levels, due to increased G γ globin expression, have been associated with a C→T substitution at position −158 (Gilman and Huisman, 1985) and an A→G substitution at position −309 of the HBG2 promoter in adults (Zertal-Zidani et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Native highland and lowland populations differ in .GAMMA.-globin gene promoter polymorphisms related to altered fetal hemoglobin levels and delayed fetal to adult globin switch after birth

Rottgardt

Rothhammer

Dittmar

2010

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“…This condition had been regarded as a multifactorial quantitative trait linked to polymorphic variations in regulatory sequences of the -and β-globin genes, especially the -158 C>T polymorphism [11][12][13], or in introns of -genes, but also with other loci mapping elsewhere in the genome (Xp 22.2-22.3 region, 6q23 and 8q) [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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

Pereira

Relvas

Bento

et al. 2015

Blood Cells, Molecules, and Diseases

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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 influence 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 haematological parameters, HbF levels ranging from 0.2% to 7.4%, were selected for this study. In β-thal carriers linear regression models revealed strong statistical significant association for HBG2 (XmnI) rs7482144 (β=0.45; P=5.85x10 -7 ), and nominal significance for BCL11A rs766432 (β=0.21; P=0.02) and HMIP rs9399137 (β=0.20; P=0.01). 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=0.03). 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.3

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“…It is estimated that eighty-nine percent of adult Hb F and F cell variance is due to heritable factors [30] and the XmnI polymorphism (C→T) at position −158 of the HBG2 promoter accounts for the greatest single share of this genetic variability [28,94]. High F cell and Hb F levels in normal populations can be due to, at least in part, to the XmnI polymorphism [29,57,84,89,103,108]. Additionally, with hematological stress (e.g.…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

Perry

Gearhart

Wiener

et al. 2008

Neurobiology of Aging

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From a normal human brain phage display library screen we identified the gamma (A)-globin chain of fetal hemoglobin (Hb F) as a protein that bound strongly to Aβ1-42. We showed the oxidized form 1 These authors are co-corresponding authors for all stages of refereeing and publication and contributed equally to this work. Rodney T. Perry; Rm. 210H, 1665 University Blvd.; University of Alabama at Birmingham, Birmingham, USA; Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosure Statement:I so state for myself and on behalf of the other authors on the manuscript, Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease, that we have no conflicts and sources of funding that influence the results of this paper, the data is not published or submitted elsewhere, and that appropriate approval and procedures were used concerning human subjects. I also verify that all authors on this manuscript have reviewed the contents of the manuscript, approve of its contents, and validate the accuracy of the data. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of adult Hb (metHb A) binds with greater affinity to Aβ1-42 than metHb F. MetHb is more toxic than oxyhemoglobin because it loses its heme group more readily. Free Hb and heme readily damage vascular endothelial cells similar to Alzheimer's disease (AD) vascular pathology. The XmnI polymorphism (C→T) at −158 of the gamma (G)-globin promoter region can contribute to increased Hb F expression. Using family-based association testing, we found a significant protective association of this polymorphism in the NIMH sibling dataset (n=489) in families, with at least two affected and one unaffected sibling (p=0.006), with an age of onset >50 years (p=0.010) and >65 years (p=0.013), and families not homozygous for the APOE4 allele (p=0.041). We hypothesize that Hb F may be less toxic than adult Hb in its interaction with Aβ and may protect against the development of AD.

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Foetal haemoglobin in normal healthy adults: relationship with polymorphic sequences cis to the β globin gene

Cited by 21 publications

References 31 publications

Native highland and lowland populations differ in .GAMMA.-globin gene promoter polymorphisms related to altered fetal hemoglobin levels and delayed fetal to adult globin switch after birth

Native highland and lowland populations differ in .GAMMA.-globin gene promoter polymorphisms related to altered fetal hemoglobin levels and delayed fetal to adult globin switch after birth

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

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

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