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Genetic Modifiers of Fetal Haemoglobin in Sickle Cell Disease

Molecular Diagnosis & Therapy volume 23, pages 235–244 (2019)Cite this article

Abstract

Fetal haemoglobin (HbF) levels have a clinically beneficial effect on sickle cell disease (SCD). Patients with SCD demonstrate extreme variability in HbF levels (1–30%), a large part of which is likely genetically determined. The main genetic modifier loci for HbF persistence, HBS1L-MYB, BCL11A and the β-globin gene cluster in adults also act in SCD patients. Their effects are, however, modified significantly by a disease pathology that includes a drastically shortened erythrocyte lifespan with an enhanced survival of those red blood cells that carry HbF (F cells). We propose a model of how HbF modifier genes and disease pathology interact to shape HbF levels measured in patients. We review current knowledge on the action of these loci in SCD, their genetic architecture, and their putative functional components. At each locus, one strong candidate for a causative, functional DNA change has been proposed: Xmn1-HBG2 at the β-globin cluster, rs1427407 at BCL11A and the 3 bp deletion rs66650371 at HBS1L-MYB. These, however, explain only part of the impact of these loci and additional variants are yet to be identified. Further progress in understanding the genetic control of HbF levels requires that confounding factors inherent in SCD, such as ethnic complexity, the role of F cells and the influence of drugs, are suitably addressed. This will depend on international collaboration and on large, well-characterised patient cohorts with genome-wide single-nucleotide polymorphism or sequence data.

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References

  1. Lettre G, Sankaran VG, Bezerra MA, Araujo AS, Uda M, Sanna S, et al. 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 USA. 2008;105(33):11869–74.

    Article  PubMed  Google Scholar 

  2. Thein SL, Wood WG. The molecular basis of beta thalassemia, deltabeta thalassemia and hereditary persistence of fetal hemoglobin. In: Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, editors. Disorders of hemoglobin: genetics, pathophysiology, and clinical management. 2nd ed. New York: Cambridge University Press; 2009. p. 323–56.

    Chapter  Google Scholar 

  3. Forget BG. Molecular basis of hereditary persistence of fetal hemoglobin. Ann N Y Acad Sci. 1998;850:38–44.

    Article  CAS  PubMed  Google Scholar 

  4. Collins FS, Cole JL, Lockwood WK, Iannuzzi MC. The deletion in both common types of hereditary persistence of fetal hemoglobin is approximately 105 kilobases. Blood. 1987;70(6):1797–803.

    CAS  PubMed  Google Scholar 

  5. Serjeant GR, Serjeant BE, Hambleton IR, Oakley M, Thein SL, Clark B. A plea for the newborn diagnosis of Hb S-hereditary persistence of fetal hemoglobin. Hemoglobin. 2017;41(3):216–7. https://doi.org/10.1080/03630269.2017.1360336.

    Article  CAS  PubMed  Google Scholar 

  6. Craig JE, Barnetson RA, Prior J, Raven JL, Thein SL. Rapid detection of deletions causing delta beta thalassemia and hereditary persistence of fetal hemoglobin by enzymatic amplification. Blood. 1994;83(6):1673–82.

    CAS  PubMed  Google Scholar 

  7. Labie D, Pagnier J, Lapoumeroulie C, Rouabhi F, Dunda-Belkhodja O, Chardin P, et al. Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients. Proc Natl Acad Sci USA. 1985;82(7):2111–4.

    Article  CAS  PubMed  Google Scholar 

  8. Kulozik AE, Kar BC, Satapathy RK, Serjeant BE, Serjeant GR, Weatherall DJ. Fetal hemoglobin levels and beta (s) globin haplotypes in an Indian populations with sickle cell disease. Blood. 1987;69(6):1742–6.

    CAS  PubMed  Google Scholar 

  9. Antonarakis SE, Boehm CD, Serjeant GR, Theisen CE, Dover GJ, Kazazian HH Jr. Origin of the beta S-globin gene in blacks: the contribution of recurrent mutation or gene conversion or both. Proc Natl Acad Sci USA. 1984;81(3):853–6.

    Article  CAS  PubMed  Google Scholar 

  10. Shriner D, Rotimi CN. Whole-genome-sequence-based haplotypes reveal single origin of the sickle allele during the holocene wet phase. Am J Hum Genet. 2018;102(4):547–56. https://doi.org/10.1016/j.ajhg.2018.02.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Labie D, Dunda-Belkhodja O, Rouabhi F, Pagnier J, Ragusa A, Nagel RL. The − 158 site 5′ to the G gamma gene and G gamma expression. Blood. 1985;66(6):1463–5.

    CAS  PubMed  Google Scholar 

  12. 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(1):342–6.

    CAS  PubMed  Google Scholar 

  13. Galarneau G, Palmer CD, Sankaran VG, Orkin SH, Hirschhorn JN, Lettre G. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nat Genet. 2010;42(12):1049–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shaikho EM, Farrell JJ, Alsultan A, Qutub H, Al-Ali AK, Figueiredo MS, et al. A phased SNP-based classification of sickle cell anemia HBB haplotypes. BMC Genom. 2017;18(1):608. https://doi.org/10.1186/s12864-017-4013-y.

    Article  CAS  Google Scholar 

  15. Shaikho EM, Farrell JJ, Alsultan A, Sebastiani P, Steinberg MH. Genetic determinants of HbF in Saudi Arabian and African Benin haplotype sickle cell anemia. Am J Hematol. 2017;92(9):E555–7. https://doi.org/10.1002/ajh.24822.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Liu L, Muralidhar S, Singh M, Sylvan C, Kalra IS, Quinn CT, et al. High-density SNP genotyping to define beta-globin locus haplotypes. Blood Cells Mol Dis. 2009;42(1):16–24.

    Article  CAS  PubMed  Google Scholar 

  17. Liu L, Pertsemlidis A, Ding LH, Story MD, Steinberg MH, Sebastiani P, et al. Original research: a case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease. Exp Biol Med (Maywood). 2016;241(7):706–18. https://doi.org/10.1177/1535370216642047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wonkam A, Ngo Bitoungui VJ, Vorster AA, Ramesar R, Cooper RS, Tayo B, et al. Association of variants at BCL11A and HBS1L-MYB with hemoglobin F and hospitalization rates among sickle cell patients in Cameroon. PLoS One. 2014;9(3):e92506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Adeyemo TA, Ojewunmi OO, Oyetunji IA, Rooks H, Rees DC, Akinsulie AO, et al. A survey of genetic fetal-haemoglobin modifiers in Nigerian patients with sickle cell anaemia. PLoS One. 2018;13(6):e0197927. https://doi.org/10.1371/journal.pone.0197927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Menzel S, Garner C, Gut I, Matsuda F, Yamaguchi M, Heath S, et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet. 2007;39(10):1197–9.

    Article  CAS  PubMed  Google Scholar 

  21. Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci USA. 2008;105(5):1620–5.

    Article  PubMed  Google Scholar 

  22. Sedgewick AE, Timofeev N, Sebastiani P, So JC, Ma ES, Chan LC, et al. BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies. Blood Cells Mol Dis. 2008;41:255–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science. 2013;342(6155):253–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Canver MC, Smith EC, Sher F, Pinello L, Sanjana NE, Shalem O, et al. BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature. 2015;527(7577):192–7. https://doi.org/10.1038/nature15521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061–73.

    Article  CAS  PubMed  Google Scholar 

  26. Bhatnagar P, Purvis S, Barron-Casella E, DeBaun MR, Casella JF, Arking DE, et al. Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients. J Hum Genet. 2011;56(4):316–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mtatiro SN, Singh T, Rooks H, Mgaya J, Mariki H, Soka D, et al. Genome wide association study of fetal hemoglobin in sickle cell anemia in Tanzania. PLoS One. 2014;9(11):e111464. https://doi.org/10.1371/journal.pone.0111464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gardner K, Fulford T, Silver N, Rooks H, Angelis N, Allman M, et al. g(HbF): a genetic model of fetal hemoglobin in sickle cell disease. Blood Adv. 2018;2(3):235–9. https://doi.org/10.1182/bloodadvances.2017009811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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(1):58–64.

    Article  CAS  PubMed  Google Scholar 

  30. Thein SL, Menzel S, Peng X, Best S, Jiang J, Close J, et al. 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 USA. 2007;104(27):11346–51.

    Article  CAS  PubMed  Google Scholar 

  31. Menzel S, Rooks H, Zelenika D, Mtatiro SN, Gnanakulasekaran A, Drasar E, et al. Global genetic architecture of an erythroid quantitative trait locus, HMIP-2. Ann Hum Genet. 2014;78(6):434–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Stadhouders R, Aktuna S, Thongjuea S, Aghajanirefah A, Pourfarzad F, van Ijcken W, et al. HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers. J Clin Investig. 2014;124(4):1699–710.

    Article  CAS  PubMed  Google Scholar 

  33. Farrell JJ, Sherva RM, Chen ZY, Luo HY, Chu BF, Ha SY, et al. A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression. Blood. 2011;117(18):4935–45. https://doi.org/10.1182/blood-2010-11-317081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mtatiro SN, Mgaya J, Singh T, Mariki H, Rooks H, Soka D, et al. Genetic association of fetal-hemoglobin levels in individuals with sickle cell disease in Tanzania maps to conserved regulatory elements within the MYB core enhancer. BMC Med Genet. 2015;16:4. https://doi.org/10.1186/s12881-015-0148-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Opoka RO, Ndugwa CM, Latham TS, Lane A, Hume HA, Kasirye P, et al. Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia. Blood. 2017;130(24):2585–93. https://doi.org/10.1182/blood-2017-06-788935.

    Article  CAS  PubMed  Google Scholar 

  36. Green NS, Barral S. Genetic modifiers of HbF and response to hydroxyurea in sickle cell disease. Pediatr Blood Cancer. 2011;56(2):177–81.

    Article  PubMed  Google Scholar 

  37. Green NS, Ender KL, Pashankar F, Driscoll C, Giardina PJ, Mullen CA, et al. Candidate sequence variants and fetal hemoglobin in children with sickle cell disease treated with hydroxyurea. PLoS One. 2013;8(2):e55709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Adekile A, Menzel S, Gupta R, Al-Sharida S, Farag A, Haider M, et al. Response to hydroxyurea among Kuwaiti patients with sickle cell disease and elevated baseline HbF levels. Am J Hematol. 2015;90(7):E138–9. https://doi.org/10.1002/ajh.24027.

    Article  PubMed  Google Scholar 

  39. Friedrisch JR, Sheehan V, Flanagan JM, Baldan A, Summarell CC, Bittar CM, et al. The role of BCL11A and HMIP-2 polymorphisms on endogenous and hydroxyurea induced levels of fetal hemoglobin in sickle cell anemia patients from southern Brazil. Blood Cells Mol Dis. 2016;62:32–7. https://doi.org/10.1016/j.bcmd.2016.11.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Menzel S, Jiang J, Silver N, Gallagher J, Cunningham J, Surdulescu G, et al. The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans. Blood. 2007;110(10):3624–6.

    Article  CAS  PubMed  Google Scholar 

  41. Soranzo N, Spector TD, Mangino M, Kuhnel B, Rendon A, Teumer A, et al. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet. 2009;41(11):1182–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mtatiro SN, Makani J, Mmbando B, Thein SL, Menzel S, Cox SE. Genetic variants at HbF-modifier loci moderate anemia and leukocytosis in sickle cell disease in Tanzania. Am J Hematol. 2015;90(1):E1–4. https://doi.org/10.1002/ajh.23859.

    Article  CAS  PubMed  Google Scholar 

  43. Leonardo FC, Brugnerotto AF, Domingos IF, Fertrin KY, de Albuquerque DM, Bezerra MA, et al. Reduced rate of sickle-related complications in Brazilian patients carrying HbF-promoting alleles at the BCL11A and HMIP-2 loci. Br J Haematol. 2016;173(3):456–60. https://doi.org/10.1111/bjh.13961.

    Article  CAS  PubMed  Google Scholar 

  44. Milton JN, Gordeuk VR, Taylor JGT, Gladwin MT, Steinberg MH, Sebastiani P. Prediction of fetal hemoglobin in sickle cell anemia using an ensemble of genetic risk prediction models. Circ Cardiovasc Genet. 2014;7(2):110–5. https://doi.org/10.1161/CIRCGENETICS.113.000387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chang KH, Smith SE, Sullivan T, Chen K, Zhou Q, West JA, et al. Long-term engraftment and fetal globin induction upon BCL11A gene editing in bone-marrow-derived CD34+ hematopoietic stem and progenitor cells. Mol Ther Methods Clin Dev. 2017;4:137–48. https://doi.org/10.1016/j.omtm.2016.12.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Deng W, Rupon JW, Krivega I, Breda L, Motta I, Jahn KS, et al. Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell. 2014;158(4):849–60. https://doi.org/10.1016/j.cell.2014.05.050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Vierstra J, Reik A, Chang KH, Stehling-Sun S, Zhou Y, Hinkley SJ, et al. Functional footprinting of regulatory DNA. Nat Methods. 2015;12(10):927–30. https://doi.org/10.1038/nmeth.3554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ye L, Wang J, Tan Y, Beyer AI, Xie F, Muench MO, et al. Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: an approach for treating sickle cell disease and beta-thalassemia. Proc Natl Acad Sci USA. 2016;113(38):10661–5. https://doi.org/10.1073/pnas.1612075113.

    Article  CAS  PubMed  Google Scholar 

  49. Traxler EA, Yao Y, Wang YD, Woodard KJ, Kurita R, Nakamura Y, et al. A genome-editing strategy to treat beta-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat Med. 2016;22(9):987–90. https://doi.org/10.1038/nm.4170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Xu J, Peng C, Sankaran VG, Shao Z, Esrick EB, Chong BG, et al. Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Science. 2011;334(6058):993–6. https://doi.org/10.1126/science.1211053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Antoniani C, Meneghini V, Lattanzi A, Felix T, Romano O, Magrin E, et al. Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human β-globin locus. Blood. 2018;131(17):1960–73. https://doi.org/10.1182/blood-2017-10-811505.

    Article  CAS  PubMed  Google Scholar 

  52. Liu N, Hargreaves VV, Zhu Q, Kurland JV, Hong J, Kim W, et al. Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch. Cell. 2018;173(2):430-42.e17. https://doi.org/10.1016/j.cell.2018.03.016.

    CAS  Article  Google Scholar 

  53. Martyn GE, Wienert B, Yang L, Shah M, Norton LJ, Burdach J, et al. Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding. Nat Genet. 2018;50(4):498–503. https://doi.org/10.1038/s41588-018-0085-0.

    Article  CAS  PubMed  Google Scholar 

  54. Wang X, Thein SL. Switching from fetal to adult hemoglobin. Nat Genet. 2018;50(4):478–80. https://doi.org/10.1038/s41588-018-0094-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bhagat S, Patra PK, Thakur AS. Fetal haemoglobin and beta-globin gene cluster haplotypes among sickle cell patients in Chhattisgarh. J Clin Diagn Res. 2013;7(2):269–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Joly P, Lacan P, Garcia C, Delasaux A, Francina A. Rapid and reliable beta-globin gene cluster haplotyping of sickle cell disease patients by FRET Light Cycler and HRM assays. Clin Chim Acta. 2011;412(13–14):1257–61.

    Article  CAS  PubMed  Google Scholar 

  57. Hanchard N, Elzein A, Trafford C, Rockett K, Pinder M, Jallow M, et al. Classical sickle beta-globin haplotypes exhibit a high degree of long-range haplotype similarity in African and Afro-Caribbean populations. BMC Genet. 2007;8:52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nagel RL, Steinberg MH. Genetics of the beta-S gene: origins, genetic epidemiology, and epistasis in sickle cell anemia. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, editors. Disorders of hemoglobin: genetics, pathophysiology, and clinical management. 1st ed. Cambridge: Cambridge University Press; 2001. p. 711–55.

    Google Scholar 

  59. Lapoumeroulie C, Dunda O, Ducrocq R, Trabuchet G, Mony-Lobe M, Bodo JM, et al. A novel sickle cell mutation of yet another origin in Africa: the Cameroon type. Hum Genet. 1992;89(3):333–7.

    CAS  PubMed  Google Scholar 

  60. Gene transfer for sickle cell disease [ClinicalTrials.gov identifier NCT03282656]. US National Institutes of Health, ClinicalTrials.gov. https://clinicaltrials.gov/show/NCT03282656. Accessed 11 Sept 2018.

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Acknowledgements

We thank Dr Siana Nkya, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania, for contributing to Fig. 4. The following public data resources were used for this article: University of South Carolina Santa Cruz (UCSC) genome browser (https://genome-euro.ucsc.edu), the Leiden Open Variation Database (http://lovd.nl/2.0/index_list.php), 1000 Genomes Project (http://phase3browser.1000genomes.org), ithanet (http://www.ithanet.eu) and the Database of human Hemoglobin Variants and Thalassemia Mutations (HbVar) (http://globin.cse.psu.edu/globin/hbvar/).

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  1. School of Cancer and Pharmaceutical Sciences, King’s College London, The Rayne Institute, 123 Coldharbour Lane, London, SE5 9NU, UK

    Stephan Menzel

  2. Sickle Cell Branch, National Heart, Lung and Blood Institute, The National Institutes of Health, Building 10, Room 5-5142, 10 Center Drive, Bethesda, MD, 20814, USA

    Swee Lay Thein

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Correspondence to Stephan Menzel or Swee Lay Thein.

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Stephan Menzel and Swee Lay Thein declare no conflicts of interest that are directly relevant to the content of this review.

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This study was partially supported by the following funds to Stephan Menzel and Swee Lay Thein: EU FP7 THALAMOSS Project (THALAssaemia MOdular Stratification System for personalized therapy of β-thalassemia; grant number [306201]-FP7-Health-2012-INNOVATION-1) and Shire UK plc (Collaborative Grant).

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Menzel, S., Thein, S.L. Genetic Modifiers of Fetal Haemoglobin in Sickle Cell Disease. Mol Diagn Ther 23, 235–244 (2019). https://doi.org/10.1007/s40291-018-0370-8

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