Blood Cells, Molecules and Diseases 52 (2014) 175
Contents lists available at ScienceDirect
Blood Cells, Molecules and Diseases journal homepage: www.elsevier.com/locate/bcmd
Letter to the Editor Fetal hemoglobin in sickle cell anemia
To the Editor, As higher HbF levels in patients with β thalassemia or sickle cell anemia are associated with milder phenotypes, several groups are exploring the factors that regulate the switch from fetal to adult hemoglobin and its therapeutic potential. The contributions of cis-acting elements to HbF production are critical to understand the variable clinical phenotypes of β-thalassemia and sickle cell anemia. Recently, there has been considerable progress made in defining the loci or genomic regions that may often be involved in the regulation of the switch from fetal to adult hemoglobin [1,2]. In an article by Ngo et al. in 2013 to better understand regulation of HbF in sickle homozygotes with the Arab Indian (AI) haplotype, they compared polymorphisms in selected regions that define the AI haplotype [ATx Ty motifs, Xmn1 polymorphism] and also examined trans acting elements associated with HbF expression [SNPs in BCl11A, HBS1L-MYB, KLF1, and DLX4] [3]. The BCl11A and HBS1L-MYB SNPs that were associated with elevated HbF in other populations explained only 8.8% of the variation in HbF. More than 90% of the HbF variance in sickle cell patients with the AI haplotype remained unexplained. Hence, they suggested that other genetic elements possibly modulate the effect of the cis and trans acting regulators. These regulatory elements, which remain to be discovered, might be specific for the AI haplotype. In our study on “Effect of a group of genetic markers around the 5′ regulatory regions of the β globin gene cluster linked to high HbF” [4], we had tried to look at the potential regulatory effect of the Pre G γ globin haplotype and the Aγ–δ intergenic region haplotype on elevated HbF levels in 11 sickle cell anemia and 14 sickle-β thalassemia individuals along with homozygous thalassemia patients. All the sickle cell patients' chromosomes had shown the presence of the Arab Indian haplotype. Homozygosity for the Pre G γ globin TAG haplotype, which is linked to raised HbF levels [5] was seen in all our sickle cell anemia cases. A similar observation was also reported by Pissard et al. [6]. Only 3 sickle chromosomes in our sickle-thalassemia group showed the absence of the TAG haplotype. Additionally, all the sickle chromosomes were homozygous for the T haplotype in the Aγ–δ intergenic region, which has also shown to be linked to raised HbF [7]. Thus, our findings
1079-9796/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bcmd.2013.11.007
showed linkage of the TAG haplotype of the Pre G γ globin region and the T haplotype of the Aγ–δ intergenic region to the Arab Indian haplotype like Xmn1 polymorphism. Therefore, it will be interesting to look at the Pre G γ globin haplotype, and the Aγ–δ intergenic region haplotype in the Saudi sickle cell anemia patients in the study of Ngo et al. in 2013 to confirm its linkage disequilibrium with the Arab Indian haplotype.
References [1] D.E. Bauer, S.H. Orkin, Updates on fetal hemoglobin gene regulation in hemoglobinopathies, Curr. Opin. Pediatr. 23 (1) (Feb 2011) 1–8. [2] V.G. Sankaran, D.G. Nathan, Reversing the hemoglobin switch, N. Engl. J. Med. 363 (23) (Dec 2 2010) 2258–2260. [3] D. Ngo, H. Bae, M.H. Steinberg, P. Sebastiani, N. Solovieff, C.T. Baldwin, E. Melista, S. Safaya, L.A. Farrer, A.M. Al-Suliman, W.H. Albuali, M.H. Al Bagshi, Z. Naserullah, I. Akinsheye, P. Gallagher, H.Y. Luo, D.H. Chui, J.J. Farrell, A.K. Al-Ali, A. Alsultan, Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype, Blood Cells Mol. Dis. 51 (1) (2013) 22–26. [4] P. Dabke, R. Colah, K. Ghosh, A. Nadkarni, Effect of a group of genetic markers around the 5′ regulatory regions of the β globin gene cluster linked to high HbF on the clinical severity of β thalassemia, Blood Cells Mol. Dis. 50 (3) (2013) 156–160. [5] S.F. Ofori-Acquah, M.R. Lalloz, D.M. Layton, Localisation of cis regulatory elements at the beta-globin locus: analysis of hybrid haplotype chromosomes, Biochem. Biophys. Res. Commun. 254 (1999) 181–187. [6] S. Pissard, Y. Beuzard, Potential regulatory region for the expression of fetal haemoglobin in sickle cell disease, Blood 84 (1994) 331–338. [7] A. Papachatzopoulou, A. Kourakli, P. Makropoulou, T. Kakagianne, A. Sagourou, M. Papadakis, A. Athanassiadou, Genotypic heterogeneity and correlation to intergenic haplotype within high HbF β thalassemia intermedia, Eur. J. Haematol. 763 (2006) 22–330.
Anita Nadkarni⁎ Pooja Dabke Roshan B. Colah K. Ghosh National Institute of Immunohematology (ICMR), 13th Floor, New Multistoried Building, K.E.M. Hospital Campus, Parel, Mumbai 400012, India ⁎ Corresponding author at: National Institute of Immunohematology, 13th Floor, New Multistoried Building, K.E.M. Hospital Campus, Parel, Mumbai 400012, India. Fax: +91 22 24138521. E-mail address: [email protected] (A. Nadkarni). 1 October 2013
Contents lists available at ScienceDirect
Blood Cells, Molecules and Diseases journal homepage: www.elsevier.com/locate/bcmd
Letter to the Editor Fetal hemoglobin in sickle cell anemia
To the Editor, As higher HbF levels in patients with β thalassemia or sickle cell anemia are associated with milder phenotypes, several groups are exploring the factors that regulate the switch from fetal to adult hemoglobin and its therapeutic potential. The contributions of cis-acting elements to HbF production are critical to understand the variable clinical phenotypes of β-thalassemia and sickle cell anemia. Recently, there has been considerable progress made in defining the loci or genomic regions that may often be involved in the regulation of the switch from fetal to adult hemoglobin [1,2]. In an article by Ngo et al. in 2013 to better understand regulation of HbF in sickle homozygotes with the Arab Indian (AI) haplotype, they compared polymorphisms in selected regions that define the AI haplotype [ATx Ty motifs, Xmn1 polymorphism] and also examined trans acting elements associated with HbF expression [SNPs in BCl11A, HBS1L-MYB, KLF1, and DLX4] [3]. The BCl11A and HBS1L-MYB SNPs that were associated with elevated HbF in other populations explained only 8.8% of the variation in HbF. More than 90% of the HbF variance in sickle cell patients with the AI haplotype remained unexplained. Hence, they suggested that other genetic elements possibly modulate the effect of the cis and trans acting regulators. These regulatory elements, which remain to be discovered, might be specific for the AI haplotype. In our study on “Effect of a group of genetic markers around the 5′ regulatory regions of the β globin gene cluster linked to high HbF” [4], we had tried to look at the potential regulatory effect of the Pre G γ globin haplotype and the Aγ–δ intergenic region haplotype on elevated HbF levels in 11 sickle cell anemia and 14 sickle-β thalassemia individuals along with homozygous thalassemia patients. All the sickle cell patients' chromosomes had shown the presence of the Arab Indian haplotype. Homozygosity for the Pre G γ globin TAG haplotype, which is linked to raised HbF levels [5] was seen in all our sickle cell anemia cases. A similar observation was also reported by Pissard et al. [6]. Only 3 sickle chromosomes in our sickle-thalassemia group showed the absence of the TAG haplotype. Additionally, all the sickle chromosomes were homozygous for the T haplotype in the Aγ–δ intergenic region, which has also shown to be linked to raised HbF [7]. Thus, our findings
1079-9796/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bcmd.2013.11.007
showed linkage of the TAG haplotype of the Pre G γ globin region and the T haplotype of the Aγ–δ intergenic region to the Arab Indian haplotype like Xmn1 polymorphism. Therefore, it will be interesting to look at the Pre G γ globin haplotype, and the Aγ–δ intergenic region haplotype in the Saudi sickle cell anemia patients in the study of Ngo et al. in 2013 to confirm its linkage disequilibrium with the Arab Indian haplotype.
References [1] D.E. Bauer, S.H. Orkin, Updates on fetal hemoglobin gene regulation in hemoglobinopathies, Curr. Opin. Pediatr. 23 (1) (Feb 2011) 1–8. [2] V.G. Sankaran, D.G. Nathan, Reversing the hemoglobin switch, N. Engl. J. Med. 363 (23) (Dec 2 2010) 2258–2260. [3] D. Ngo, H. Bae, M.H. Steinberg, P. Sebastiani, N. Solovieff, C.T. Baldwin, E. Melista, S. Safaya, L.A. Farrer, A.M. Al-Suliman, W.H. Albuali, M.H. Al Bagshi, Z. Naserullah, I. Akinsheye, P. Gallagher, H.Y. Luo, D.H. Chui, J.J. Farrell, A.K. Al-Ali, A. Alsultan, Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype, Blood Cells Mol. Dis. 51 (1) (2013) 22–26. [4] P. Dabke, R. Colah, K. Ghosh, A. Nadkarni, Effect of a group of genetic markers around the 5′ regulatory regions of the β globin gene cluster linked to high HbF on the clinical severity of β thalassemia, Blood Cells Mol. Dis. 50 (3) (2013) 156–160. [5] S.F. Ofori-Acquah, M.R. Lalloz, D.M. Layton, Localisation of cis regulatory elements at the beta-globin locus: analysis of hybrid haplotype chromosomes, Biochem. Biophys. Res. Commun. 254 (1999) 181–187. [6] S. Pissard, Y. Beuzard, Potential regulatory region for the expression of fetal haemoglobin in sickle cell disease, Blood 84 (1994) 331–338. [7] A. Papachatzopoulou, A. Kourakli, P. Makropoulou, T. Kakagianne, A. Sagourou, M. Papadakis, A. Athanassiadou, Genotypic heterogeneity and correlation to intergenic haplotype within high HbF β thalassemia intermedia, Eur. J. Haematol. 763 (2006) 22–330.
Anita Nadkarni⁎ Pooja Dabke Roshan B. Colah K. Ghosh National Institute of Immunohematology (ICMR), 13th Floor, New Multistoried Building, K.E.M. Hospital Campus, Parel, Mumbai 400012, India ⁎ Corresponding author at: National Institute of Immunohematology, 13th Floor, New Multistoried Building, K.E.M. Hospital Campus, Parel, Mumbai 400012, India. Fax: +91 22 24138521. E-mail address: [email protected] (A. Nadkarni). 1 October 2013
