Hematologically and Genetically Distinct Forms of Sickle Cell Anemia in Africa

Abstract

Patients with sickle cell anemia vary in the hematologic and clinical features of their disease, in part because of variability in the presence of linked and unlinked genes that modify the expression of the disease. The hemoglobin S gene is strongly linked to three different haplotypes of polymorphic endonuclease-restriction sites of the beta-like gene cluster (genes in the vicinity of the beta-globin gene)--one prevalent in Atlantic West Africa, another in central West Africa, and yet another in Bantu-speaking Africa (equatorial, East, and southern Africa). We have studied the differences in the hematologic characteristics of patients with sickle cell anemia from the first two geographical areas. We find that the Senegalese (Atlantic West Africa) patients have higher levels of hemoglobin F, a preponderance of G gamma chains in hemoglobin F, a lower proportion of very dense red cells, and a lower percentage of irreversibly sickled cells than those from Benin (central West Africa). We interpret these data to mean that the gamma-chain composition and the hemoglobin F level are haplotype linked and that the decrease in the percentage of dense cells and irreversibly sickled cells is secondary to the elevation in the hemoglobin F level. Patients with sickle cell anemia in the New World probably correspond to various combinations of these types, in addition to the still hematologically undefined haplotype associated with sickle cell anemia in the Bantu-speaking areas of Africa.

Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease

“…The absence of a strong effect for a-thalassemia in SCD pulmonary hypertension was unexpected in contrast to the findings with Hb SC, despite the increased statistical power from the presence of the a 3.7 allele at nearly three times the frequency of Hb C. Still, the magnitude of a 3.7 's effect may be sufficiently small to be below the threshold for detection for the statistical power in this study. Likewise, haplotypes of the b-globin locus have been used in the past to study both the variation in SCD severity and the evolutionary history of the b S mutation [47][48][49][50]27]. In particular, some of the variability in Hb F expression is attributable to functional alleles in the fetal hemoglobin genes inherited on specific b S -globin haplotypes [48,[51][52][53].…”

“…Likewise, haplotypes of the b-globin locus have been used in the past to study both the variation in SCD severity and the evolutionary history of the b S mutation [47][48][49][50]27]. In particular, some of the variability in Hb F expression is attributable to functional alleles in the fetal hemoglobin genes inherited on specific b S -globin haplotypes [48,[51][52][53]. Fetal hemoglobin expression may be relevant to pulmonary hypertension, as this and other studies have observed significantly lower levels of Hb F in SCD pulmonary hypertension cases (Table IV) [9,10].…”

Hematopoietic SCT for the Black African and non-Black African variants of sickle cell anemia

“…The non-Black African SCA variant manifests with a less severe phenotype than the Black African variant. [6][7][8] Children with Black African variant SCA were prone to invasive infections caused by Streptococcus pneumonia, Haemophilus influenzae and Plasmodium falciparum (in malaria areas). Malaria is more endemic in Black African areas and therefore malaria is more common in black SCA patients.…”

“…Patients with the Black African SCA variant manifest a more severe form of SCA than patients with the non-Black African variant. [6][7][8] For patients with the Black African variant, painful crises, chest syndrome and stroke are more frequent and appear earlier in life, while patients with the nonblack African variant are more likely to become dependent on RBC transfusions.…”

The Natural History of Sickle Cell Disease

“…Characterization of the DNA structure flanking the b-globin locus of HbS suggests that the mutation has arisen on at least three independent occasions in the African continent, referred to as b-globin haplotypes and named after the areas where they were first described: Benin, Senegal, and Central African Republic or Bantu (Pagnier et al 1984;Nagel et al 1985;Chebloune et al 1988). The HbC trait is believed to be a relatively recent mutation limited to West Africa where it occurs at high frequencies (.20%) in central Ghana and Burkina Faso, in only 2% in Nigeria, and does not occur, except in peoples of West African origin, in East and Central Africa.…”