Genetic Modifiers of Fetal Haemoglobin in Sickle Cell Disease
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REVIEW ARTICLE
Genetic Modifiers of Fetal Haemoglobin in Sickle Cell Disease Stephan Menzel1 · Swee Lay Thein2 Published online: 26 November 2018 © Springer Nature Switzerland AG 2018
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. Key Points Raised fetal haemoglobin (HbF) levels have been shown to lead to milder sickle cell disease (SCD). The main genetic loci for HbF persistence in adults, HBS1L-MYB, BCL11A and the β-globin gene cluster, contribute significantly to the variability of HbF levels in SCD patients. The functional molecular changes leading to raised HbF levels and their interaction with SCD pathological mechanisms are not fully understood.
* Stephan Menzel [email protected] * Swee Lay Thein [email protected] 1
School of Cancer and Pharmaceutical Sciences, King’s College London, The Rayne Institute, 123 Coldharbour Lane, London SE5 9NU, UK
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
2
Ethnic complexity, the unresolved role of F cells and the increasing use of hydroxyurea treatment are factors complicating further research. Large, well-characterised patient cohorts and international collaboration will be required to make further progress.
1 Fetal Haemoglobin (HbF) Modifier Variants in Sickle Cell Disease (SCD) In sickle cell disease (SCD), the levels of fetal haemoglobin (HbF) result from the interaction of inherited genetic factors and pathological disease mechanisms, a situation Vol.:(0123456789)
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that pose
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