Abstract
Sickle cell disease (SCD) is a monogenic disease characterized by multisystem morbidity and highly variable clinical course. Inter-individual variability in hemoglobin F (HbF) levels is one of the main modifiers that account for the clinical heterogeneity in SCD. HbF levels are affected by, among other factors, single nucleotide polymorphisms (SNPs) at the BCL11A gene and the HBS1L-MYB intergenic region and Xmn1 gene. Our aim was to investigate HbF-enhancer haplotypes at these loci to obtain a first overview of the genetic situation of SCD patients in Egypt and its impact on the severity of the disease. The study included 100 SCD patients and 100 matched controls. Genotyping of BCL11A (rs1886868 C/T), HBS1L-MYB (rs9389268 A/G) and Xmn1 γG158 (rs7842144 C/T) SNPs showed no statistically significant difference between SCD patients and controls except for the hetero-mutant genotypes of BCL11A which was significantly higher in SCD patients compared with controls. Baseline HbF levels were significantly higher in those with co-inheritance of polymorphic genotypes of BCL11A + HSB1L-MYB and BCL11A + Xmn1. Steady-state HbF levels, used as an indicator of disease severity, were significantly higher in SCD-Sβ patients having the polymorphic genotypes of HSB1L-MYB. Fold change of HbF in both patient groups did not differ between those harboring the wild and the polymorphic genotypes of the studied SNPs. In conclusion, BCL11A, HSB1L, and Xmn1 genetic polymorphisms had no positive impact on baseline HbF levels solely but had if coexisted. Discovery of the molecular mechanisms controlling HbF production could provide a more effective strategy for HbF induction.
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References
Smiley D, Dagogo-Jack S, Umpierrez G (2008) Therapy insight: metabolic and endocrine disorders in sickle cell disease. Nat Clin Pract Endocrinol Metab 4(2):102–109
Bae HT, Baldwin CT, Sebastiani P, Telen MJ, Ashley-Koch A, Garrett M, Hooper WC, Bean CJ, DeBaun MR, Arking DE, Bhatnagar P, Casella JF, Keefer JR, Barron-Casella E, Gordeuk V, Kato GJ, Minniti C, Taylor J, Campbell A, Luchtman-Jones L, Hoppe C, Gladwin MT, Zhang Y, Steinberg MH (2012) Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the major modifiers of HbF in African Americans. Blood 120:1961–1962
Rees DC, Williams TN, Gladwin MT (2010) Sickle-cell disease. Lancet 376:2018–2031
Lettre G (2012) The search for genetic modifiers of disease severity in the hemoglobinopathies, Cold Spring Harb. Perspect. Med 2 (10) (2012) 1–12
Bauer DE, Kamran SC, Orkin SH (2012) Reawakening fetal hemoglobin: prospects for new therapies for the beta-globin disorders. Blood 120(15):2945–2953
Thein SL, Craig JE (1998) Genetics of Hb F/F cell variance in adults and heterocellular hereditary persistence of fetal hemoglobin. Hemoglobin 22(5–6):401–414
Fong C, Menzel S, Lizarralde MA, Barreto G (2015) Genetic variants associated with fetal hemoglobin levels show the diverse ethnic origin in Colombian patients with sickle cell anemia. Biomedica 35(3):437–443
Lettre G, Sankaran VG, Bezerra MA, Araújo AS, Uda M, Sanna S et al (2008) DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci U S A 105(33):11869–11874
Fanis P, Kousiappa L, Phylactides M, Kleanthous M (2014) Genotyping of BCL11A and HBS1L-MYB SNPs associated with fetal haemoglobin levels: a SNaPshot minisequencing approach. BMC Genomics 15:108
Wyszynski DF, Baldwin CT, Cleves MA, Amirault Y, Nolan VG, Farrell JJ et al (2004) 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) 50:23–33
Stamatoyannopoulos G (2001) (2001) the molecular basis of blood diseases, 3rd edn. W.B. Saunders, Philadelphia
Solovieff N, Milton JN, Hartley SW, Sherva R, Sebastiani P, Dworkis DA, Klings ES, Farrer LA, Garrett ME, Ashley-Koch A, Telen MJ, Fucharoen S, Ha SY, Li CK, Chui DHK, Baldwin CT, Steinberg MH (2010) Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5′ olfactory receptor gene cluster. Blood 115:1815–1822
Labie D, Pagnier J, Lapoumeroulie C, Rouabhi F, Dunda-Belkhodja O, Chardin P, Beldjord C, Wajcman H, Fabry ME, Nagel RL (1985) Common haplotype dependency of high Gg-globin gene expression and high HbF levels in b-thalassemia and sickle cell anemia patients. Proc Natl Acad Sci U S A 82:2111–2114
Galarneau G, Palmer CD, Sankaran VG, Orkin SH, Hirschhorn JN, Letter G (2010) Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nat Genet 42:1049–1051
Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, Shao Z, Canver MC, Smith EC, Pinello L, Sabo PJ, Vierstra J, Voit RA, Yuan GC, Porteus MH, Stamatoyannopoulos JA, Lettre G, Orkin SH (2013) An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 342:253–257
Galanello R, Sanna S, Perseu L, Sollaino MC, Satta S, Lai ME, Barella S, Uda M, Usala G, Abecasis GR, Cao A (2009) Amelioration of Sardinian 0 thalassemia by genetic modifiers. Blood 114:3935–3937
Liu L, Pertsemlidis A, Ding LH, Story MD, Steinberg MH, Sebastiani P, Hoppe C, Ballas SK, Pace BS (2016) A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease. Exp Biol Med (Maywood) 241(7):706–718
Steinberg MH, Forget BG, Higgs DR, Weatherall DJ (eds) (2009) Disorders of hemoglobin: genetics, pathophysiology, and clinical management, 2nd edn. Cambridge University Press, Cambridge
Galanello R, Origa R (2010) Beta-thalassemia. Orphanet J Rare Dis 5:11
Gaston M, Smith J, Gallagher D, Flournoy-Gill Z, West S, Bellevue R et al (1987) Recruitment in the cooperative study of sickle cell disease (CSSCD). Control Clin Trial 8:131S–140S
Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR (1991) Pain in sickle cell disease. Rates and risk factors. N Engl J Med 325:11–16
Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP (1994) Mortality in sickle cell disease. Life expectancy and risk factors for early death. The New England Journal of Medicine 330:1639–1644
Stamatoyannopoulos G and Grosveld F. Hemoglobin switching. In: Stamatoyannopoulos G, Majerus PW, Perlmutter RM, Varmus H (eds) (2001) The molecular basis of blood diseases, 3rd Philadelphia: Saunders
Stadhouders R, Thongjuea S, Andrieu-Soler C, Palstra R-J, Bryne JC, van den Heuvel A et al (2011) Dynamic long-range chromatin interactions control Myb proto-oncogene transcription during erythroid development. EMBO J 31:986–999
Xu J, Sankaran VG, Ni M, Menne TF, Puran RV, Kim N et al (2010) Transcriptional silencing of gamma-globin by BCL11A involves long range interactions and cooperation with SOX6. Genes Dev 24(8):783–798
Jawaid K, Wahlberg K, Thein SL, Best S (2010) Binding patterns of BCL11A in the globin and GATA1 loci and characterization of the BCL11A fetal hemoglobin locus. Blood Cells Mol Dis 45:140–146
Vegiopoulos A, Garcia P, Emambokus N, Frampton J (2006) Coordination of erythropoiesis by the transcription factor c-Myb. Blood 107:4703–4710
Sankaran VG, Menne TF, Šćepanović D, Vergilio JA, Ji P, Kim J et al (2011) MicroRNA-15a and −16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13. Proc Natl Acad Sci U S A 108(4):1519–1524
Menzel S, Garner C, Gut I, Matsuda F, Yamaguchi M, Heath S et al (2007) A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15, Nat. Genet. 39(10):1197–1199
Makani J, Menzel S, Nkya S, Cox SE, Drasar E, Soka D, Komba AN, Mgaya J, Rooks H, Vasavda N, Fegan G, Newton CR, Farrall M, Lay Thein S (2011) Genetics of fetal hemoglobin in Tanzanian and British patients with sickle cell anemia. Blood 117(4):1390–1392
Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W et al. (2008) Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Nat Acad Sci USA.105:1620-5
Sedgewick AE, Timofeev N, Sebastiani P, So JCC, Ma ESK, Chan LC, Fucharoen G, Fucharoen S, Barbosa CG, Vardarajan BN, Farrer LA, Baldwin CT, Steinberg MH, Chui DHK (2008) BCL11A is a major HbF quantitative trait locus in three different populations with β-hemoglobinopathies. Blood Cells Mol Dis 41:255–258
Borg J, Papadopoulos P, Georgitsi M, Gutiérrez L, Grech G, Fanis P et al. (2010) Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet.42:801-5
Thein SL, Menzel S, Lathrop M, Garner C (2009) Control of fetal hemoglobin: new insights emerging from genomics and clinical implications. Hum Mol Genet 18:216–223. https://doi.org/10.1093/hmg/ddp401
Thein SL, Menzel S, Peng X, Best S, Jiang J, Close J, Silver N, Gerovasilli A, Ping C, Yamaguchi M, Wahlberg K, Ulug P, Spector TD, Garner C, Matsuda F, Farrall M, Lathrop M (2007) Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Proc Natl Acad Sci U S A 104:11346–11351
Creary LE, Ulug P, Menzel S, McKenzie CA, Hanchard NA, Taylor V et al (2009) Genetic variation on chromosome 6 influences F cell levels in healthy individuals of African descent and HbF levels in sickle cell patients. PLoS One 4(1):e4218
Nagel RL (1994) Origins and dispersion of the sickle gene. In: Embury SH, Hebbel RP, Mohandas N, Steinberg MH (eds) Sickle cell disease: basic principles and clinical practice. Raven Press, New York, pp 353–380
Lapoumeroulie C, Dunda O, Ducrocq R, Trabuchet G, Mony-Lobé M, Bodo JM et al (1992) A novel sickle cell mutation of yet another origin in Africa: the Cameroon type. Hum Genet 89(3):333–337
Adekile AD (1997) Historical and anthropological correlates of βS haplotypes and α- and β-thalassemia alleles in the Arabian peninsula. Hemoglobin. 21(3):281–296
Green NS, Fabry ME, Kaptue-Noche L, Nagel RL (1993) Senegal haplotype is associated with higher HbF than Benin and Cameroon haplotypes in African children with sickle cell anemia. Am J Hematol 44(2):145–146
Nagel RL, Rao SK, Dunda-Belkhodja O, Connolly MM, Fabry ME, Georges A, Krishnamoorthy R, Labie D (1987) The hematologic characteristics of sickle cell anemia bearing the Bantu haplotype: the relationship between G gamma and HbF level. Blood 69(4):1026–1030
Akinsheye I, Alsultan A, Solovieff N, Ngo D, Baldwin CT, Sebastiani P, Chui DHK, Steinberg MH (2011) Fetal hemoglobin in sickle cell anemia. Blood 118(1):19–27
Sheehan VA, Luo Z, Flanagan JM, Howard TA, Thompson BW, Wang WC, Kutlar A, Ware RE, BABY HUG Investigators (2013) Genetic modifiers of sickle cell anemia in the BABY HUG cohort: influence on laboratory and clinical phenotypes. Am J Hematol 88:571–576
Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354:1264–1272
Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt NP, Roos C, Hirschhorn JN, Berglund G, Hedblad B, Groop L, Altshuler DM, Newton-Cheh C, Orho-Melander M (2008) Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med 358:1240–1249
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El-Ghamrawy, M., Yassa, M.E., Tousson, A.M.S. et al. Association between BCL11A, HSB1L-MYB, and XmnI γG-158 (C/T) gene polymorphism and hemoglobin F level in Egyptian sickle cell disease patients. Ann Hematol 99, 2279–2288 (2020). https://doi.org/10.1007/s00277-020-04187-z
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DOI: https://doi.org/10.1007/s00277-020-04187-z