The Genetic and Clinical Significance of Fetal Hemoglobin Expression in Sickle Cell Disease

Adekunle Adekile 1

Affiliations

01 January 2021

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doi: 10.1159/000511342

Abstract

Sickle cell disease (SCD) is phenotypically heterogeneous. One major genetic modifying factor is the patient's fetal hemoglobin (HbF) level. The latter is determined by the patient's β-globin gene cluster haplotype and cis- and trans-acting single nucleotide polymorphisms (SNPs) at other distant quantitative trait loci (QTL). The Arab/India haplotype is associated with persistently high HbF levels and also a relatively mild phenotype. This haplotype carries the Xmn1 (C/T) SNP, rs7482144, in the HBG2 locus. The major identified trans-acting QTL contain SNPs residing in the BCL11A on chromosome 2 and the HMIP locus on chromosome 6. These collectively account for 15-30% of HbF expression in different world populations and in patients with SCD or β-thalassemia. Patients with SCD in Kuwait and Eastern Saudi Arabia uniformly carry the Arab/India haplotype, but despite this, the HbF and clinical phenotypes show considerable heterogeneity. Pain episodes and avascular necrosis of the femoral head are particularly common, but severe bacterial infections, stroke, priapism, and leg ulcers are uncommon. Moreover, the HbF modifiers appear to be different; the reported BCL11A and HMIP SNPs appear to play insignificant roles. There are probably novel modifiers to be discovered in this population. This review examines the common clinical phenotypes in Kuwaiti patients with elevated HbF and the available information on HbF modifiers. The response of the patients to hydroxyurea is discussed. The presentation of patients with other sickle compound heterozygotes (Sβthal and HbSD), vis-à-vis their HbF levels, is also addressed critically.

Keywords: Fetal hemoglobin; Sickle cell disease.

Conflict of interest statement

The author declares no conflicts of interest.

Figures

Fig. 1 Structure and arrangement of alpha and beta globin genes on chromosomes 11 and 16, showing the regulatory regions.

Fig. 1 Structure and arrangement of alpha and beta globin genes on chromosomes 11 and 16, showing the regulatory regions.

Fig. 2 Hemoglobin switching from embryonic to adult life. From: Wood WG. Haemoglobin synthesis during human fetal development. Br Med Bull. 1976;32:282 [11].

Fig. 2 Hemoglobin switching from embryonic to adult life. From: Wood WG. Haemoglobin synthesis during human fetal development. Br Med Bull. 1976;32:282 [11].

Fig. 3 The 2 major subphenotypes of sickle cell disease. From: Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev. 2007;21(1):37–47 [12].

Fig. 3 The 2 major subphenotypes of sickle cell disease. From: Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev. 2007;21(1):37–47 [12].

Fig. 4 Age distribution of fetal hemoglobin (HbF) in Kuwaiti patients with sickle cell disease. From: Adekile, AD. Limitations of Hb F as a phenotypic modifier in sickle cell disease: study of Kuwaiti Arab patients. Hemoglobin. 2011;5:607 [47].

Fig. 4 Age distribution of fetal hemoglobin (HbF) in Kuwaiti patients with sickle cell disease. From: Adekile, AD. Limitations of Hb F as a phenotypic modifier in sickle cell disease: study of Kuwaiti Arab patients. Hemoglobin. 2011;5:607 [47].

Fig. 5 Distribution of fetal hemoglobin (HbF) among 268 Kuwaiti patients (adult and pediatric) with sickle cell disease. Adekile AD, 2019 (Unpublished).

Fig. 5 Distribution of fetal hemoglobin (HbF) among 268 Kuwaiti patients (adult and pediatric) with sickle cell disease. Adekile AD, 2019 (Unpublished).

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