Abstract
Increase in fetal hemoglobin (Hb F) reduces globin chain imbalance in β-thalassemia, consequently improving symptoms. QTL mapping together with previous genome-wide association study involving approximately 110,000 gene-based SNPs in mild and severe β0-thalassemia/Hb E patients revealed SNPs in HBS1L significantly associated with severity and Hb F levels. Given its potential as binding site for transcription factor activator protein 4, HBS1L exon 1 C32T polymorphism was genotyped in 455 cases, providing for the first time evidence that C allele is associated with elevated Hb F level among β0-thalassemia/Hb E patients with XmnI-Gγ−/−and XmnI-Gγ+/−polymorphisms.
References
Thein SL. Pathophysiology of β thalassemia—a guide to molecular therapies. Hematology. 2005;2005:31–7.
Fucharoen S, Winichagoon P. Clinical and hematologic aspects of hemoglobin E beta-thalassemia. Curr Opin Hematol. 2000;7:106–12. doi:10.1097/00062752-200003000-00006.
Rees DC, Porter JB, Clegg JB, Weatherall DJ. Why are hemoglobin F levels increased in HbE/beta thalassemia? Blood. 1999;94:3199–204.
Garner C, Tatu T, Reittie JE, Littlewood T, Darley J, Cervino S, et al. Genetic influences on F cells and other hematologic variables: a twin heritability study. Blood. 2000;95:342–6.
Close J, Game L, Clark B, Bergounioux J, Gerovassili A, Thein SL. Genome annotation of a 1.5 Mb region of human chromosome 6q23 encompassing a quantitative trait locus for fetal hemoglobin expression in adults. BMC Genomics. 2004;5:33. doi:10.1186/1471-2164-5-33.
Garner C, Mitchell J, Hatzis T, Reittie J, Farrall M, Thein SL. Haplotype mapping of a major quantitative-trait locus for fetal hemoglobin production, on chromosome 6q23. Am J Hum Genet. 1998;62:1468–74. doi:10.1086/301859.
Craig JE, Rochette J, Fisher CA, Weatherall DJ, Marc S, Lathrop GM, et al. Dissecting the loci controlling fetal haemoglobin production on chromosomes 11p and 6q by the regressive approach. Nat Genet. 1996;12:58–64. doi:10.1038/ng0196-58.
Garner CP, Tatu T, Best S, Creary L, Thein SL. Evidence of genetic interaction between the beta-globin complex and chromosome 8q in the expression of fetal hemoglobin. Am J Hum Genet. 2002;70:793–9. doi:10.1086/339248.
Wyszynski DF, Baldwin CT, Cleves MA, Amirault Y, Nolan VG, Farrell JJ, et al. Polymorphisms near a chromosome 6q QTL area are associated with modulation of fetal hemoglobin levels in sickle cell anemia. Cell Mol Biol Noisy-le-grand. 2004;50:23–33.
Sripichai O, Whitacre J, Munkongdee T, Kumkhaek C, Makarasara W, Winichagoon P, et al. Genetic Analysis of Candidate Modifier Polymorphisms in Hb E-{beta}0-Thalassemia Patients. Ann N Y Acad Sci. 2005;1054:433–8. doi:10.1196/annals.1345.066.
Sripichai O, Makarasara W, Munkongdee T, Kumkhaek C, Nuchprayoon I, Chuansumrit A, et al. A scoring system for the classification of beta-thalassemia/Hb E disease severity. Am J Hematol. 2008;83:482–4. doi:10.1002/ajh.21130.
Tsunoda T, Takagi T. Estimating transcription factor bindability on DNA. Bioinformatics. 1999;15:622–30. doi:10.1093/bioinformatics/15.7.622.
Winichagoon P, Fucharoen S, Wilairat P, Chihara K, Fukumaki Y. Nondeletional type of hereditary persistence of fetal haemoglobin: molecular characterization of three unrelated Thai HPFH. Br J Haematol. 1994;87:797–804. doi:10.1111/j.1365-2141.1994.tb06740.x.
Cheng CK, Hoo RLC, Chow BKC, Leung PCK. Functional cooperation between multiple regulatory elements in the untranslated exon 1 stimulates the basal transcription of the human GnRH-II gene. Mol Endocrinol. 2003;17:1175–91. doi:10.1210/me.2002-0418.
Boulanger A, Liu S, Henningsgaard AA, Yu S, Redmond TM. The upstream region of the Rpe65 gene confers retinal pigment epithelium-specific expression in vivo and in vitro and contains critical octamer and e-box binding sites. J Biol Chem. 2000;275:31274–82. doi:10.1074/jbc.M003441200.
Hu YF, Luscher B, Admon A, Mermod N, Tjian R. Transcription factor AP-4 contains multiple dimerization domains that regulate dimer specificity. Genes Dev. 1990;4:1741–52. doi:10.1101/gad.4.10.1741.
Cui Y, Narayanan CS, Zhou J, Kumar A. Exon-I is involved in positive as well as negative regulation of human angiotensinogen gene expression. Gene. 1998;224:97–107. doi:10.1016/S0378-1119(98)00512-5.
Aranburu A, Carlsson R, Persson C, Leanderson T. Transcription factor AP-4 is a ligand for immunoglobulin-kappa promoter E-box elements. Biochem J. 2001;354:431–8. doi:10.1042/0264-6021:3540431.
Wallrapp C, Verrier SB, Zhouravleva G, Philippe H, Philippe M, Gress TM, et al. The product of the mammalian orthologue of the Saccharomyces cerevisiae HBS1 gene is phylogenetically related to eukaryotic release factor 3 (eRF3) but does not carry eRF3-like activity. FEBS Lett. 1998;440:387–92. doi:10.1016/S0014-5793(98)01492-6.
Doma MK, Parker R. Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation. Nature. 2006;440:561–4. doi:10.1038/nature04530.
Acknowledgments
This work was supported by National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand and the Thailand Research Fund. We are grateful to Dr. Prapon Wilairat for proof reading the manuscript.
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Pandit, R.A., Svasti, S., Sripichai, O. et al. Association of SNP in exon 1 of HBS1L with hemoglobin F level in β0-thalassemia/hemoglobin E. Int J Hematol 88, 357–361 (2008). https://doi.org/10.1007/s12185-008-0167-3
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DOI: https://doi.org/10.1007/s12185-008-0167-3