Beta-Globin Gene Haplotypes Among Cameroonians and Review of the Global Distribution: Is There a Case for a Single Sickle Mutation Origin in Africa?

Abstract

Studies of hemoglobin S haplotypes in African subpopulations have potential implications for patient care and our understanding of genetic factors that have shaped the prevalence of sickle cell disease (SCD). We evaluated HBB gene cluster haplotypes in SCD patients from Cameroon, and reviewed the literature for a global distribution. We reviewed medical records to obtain pertinent socio-demographic and clinical features for 610 Cameroonian SCD patients, including hemoglobin electrophoresis and full blood counts. RFLP-PCR was used to determine the HBB gene haplotype on 1082 chromosomes. A systematic review of the current literature was undertaken to catalogue HBB haplotype frequencies in SCD populations around the world. Benin (74%; n = 799) and Cameroon (19%; n = 207) were the most prevalent haplotypes observed among Cameroonian patients. There was no significant association between HBB haplotypes and clinical life events, anthropometric measures, hematological parameters, or fetal hemoglobin (HbF) levels. The literature review of the global haplotype distributions was consistent with known historical migrations of the people of Africa. Previously reported data from Sudan showed a distinctly unusual pattern; all four classical haplotypes were reported, with an exceptionally high proportion of the Senegal, Cameroon, and atypical haplotypes. We did not observe any significant associations between HBB haplotype and SCD disease course in this cohort. Taken together, the data from Cameroon and from the wider literature suggest that a careful reassessment of African HBB haplotypes may shed further light on the evolutionary dynamics of the sickle allele, which could suggest a single origin of the sickle mutation.

Sickle Cell Disease

“…24 Later, the genetic identification of several haplotypes of the HbS gene (Bantu, Benin, Cameroon, Senegal, and ArabIndian), suggesting different origins of the HbS mutation across areas of high prevalence, led to speculation that the HbS gene haplotype could explain phenotypic differences. 25 A pilot study, looking at nine identical twin pairs, tried to disentangle the roles of genetic and nongenetic factors, with interesting but limited results because of the small sample. 26 The following sections summarize current knowledge of the role of genetic and nongenetic modifiers (Fig.…”

Burden, genotype and phenotype profiles of adult patients with sickle cell disease in Cape Town, South Africa

“…[19] Most variants were not associated with haematological indices except the CC genotype at rs6466533 and Bantu/Bantu haplotype combination with platelet counts, probably because of the modest sample size. The differences in MAF of the recently identified HbF-promoting loci in a Sardinian population [30] among African populations from the Human 1000 Genome Project (1000G) ( Table 3) emphasises the necessity of large-scale genomic analyses on various populations across the continent, as there are vast variations between any two African populations.…”

“…[28] Published primers and methods [29] genotyping five restriction fragment length polymorphic regions in the β-globin gene cluster were used to analyse XmnI (5ʹGγ), HindIII (Gγ), HindIII (Aγ), HincII (3˙ʹΨβ) and HinfI (5ʹβ) to determine the β-globin haplotype background. [19] Single-nucleotide polymorphisms (SNPs)…”

“…[14] The co-inheritance of α-thalassaemia has also been associated with improved clinical manifestations of SCD. [15][16][17][18] Although the multiple independent origins of the HbS mutation have been questioned recently, [19] the SCD mutation is classically associated with five region-defined β-globin gene haplotypes, Benin, Bantu or Central African (CAR), Cameroon, Senegal and Indian-Arab, [20][21][22][23] four of which are from Africa and associated with malaria incidence. [24] Because of the low incidence of malaria, the incidence of SCD in South Africa (SA) is equally extremely low; the HbS allele can be found in some indigenous SA ethnic groups (Venda and Shangaan) at an approximated frequency of 0.2%.…”

“…[28] Published primers and methods [29] genotyping five restriction fragment length polymorphic regions in the β-globin gene cluster were used to analyse XmnI (5ʹGγ), HindIII (Gγ), HindIII (Aγ), HincII (3˙ʹΨβ) and HinfI (5ʹβ) to determine the β-globin haplotype background. [19] Single-nucleotide polymorphisms (SNPs)Using a reported method, [9] SNaPshot genotyping, capillary electrophoresis and direct cycle sequencing were used to assay five selected HbF-associated variants: rs8176703, rs372091, rs2334880, rs1427407 and rs7606173. In addition, 18 other variants were analysed using the iPLEX Gold Sequenom Mass Genotyping Array (Inqaba Biotec, SA): X12_123681790, X16_391593, rs10468869, rs10756993, rs113267280, rs11754265, rs141494605, rs148706947, rs183437571, rs192197462, rs570013781, rs59329875, rs62573842, rs6466533, rs6590706, rs67104793, rs7163278 and rs76901220.…”