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SAMJ: South African Medical Journal

On-line version ISSN 2078-5135
Print version ISSN 0256-9574

SAMJ, S. Afr. med. j. vol.107 n.5 Pretoria May. 2017


The description of the HbS allele frequency, β-globin haplotype background and α-globin gene deletion for the patients is given in Table 1. Genotyping for the HbS mutation revealed that 85.2% (n=23) of the patients were homozygous for the mutation (haemoglobin SS), with the rest being heterozygous (haemoglobin AS) with a possibility of β0-thalassaemia (HbS/β0) (n=4), all of whom were South African with mixed and Indian ancestry. Fig. 4 shows the distribution of the SCD β-globin gene haplotypes: the Bantu and Atypical haplotypes accounted for 65.4% and 26.9%, respectively, whereas the Senegal and Benin haplotypes accounted for 3.8% each, with no observation of the Cameroon and Indian-Arab haplotypes. In combination, the Bantu/Bantu haplotype represented 50.0% of the patients (Table 1). The heterozygous 3.7 kb α-globin gene deletion was observed in 42.3% of the patients.

Frequency of genetic variants associated with HbF levels

Table 2 shows the observed alleles and minor allele frequency (MAF) of genetic variants previously associated with HbF, some recently in a Sardinian population. [30] All variants were in HWE (p>0.05) with the exception of four loci (X12_123681790, rs141494605, rs183437571 and rs192197462) that presented monomorphic alleles in all patients. Tests of association between the variants and all haematological indices including Hb levels were conducted; however, no significant associations were observed except for rs6466533 and the SCD haplotype combinations. The CC genotype (rs6466533) was associated with higher platelet counts than the heterozygous TC genotype (p<0.05).



Similarly, the Bantu/Bantu haplotype combination was associated with higher platelet counts than the Atypical/Atypical genotype (p<0.05). Table 3 shows the MAF of the above variants in African populations: Esan (Nigeria), Luhya (Kenya), Mandinka (Gambia) and Mende (Sierra Leone); American (including African-American), European and both East and South Asian populations.



To the best of our knowledge, this is the first study describing the clinical and genetic backgrounds of SCD patients at GSH and reporting on adult patients with SCD in SA. The results of this study indicate a similar trend of a rapid increase in the number of cases of SCD that was previously reported at RCWMCH in Cape Town.[27] This was also the result of migration from SSA countries where SCD is most prevalent. Related to this was a specific administrative difficulty in taking care of some patients who lack the up-to-date and correct paperwork for immigrants and asylum seekers. This was an indirect indication that most patients arrived as adults in SA, contrary to the observation in the second part of the last decade at RCWMCH, where most patients were SA born. It is therefore expected that the adult SCD population at GSH will continue to grow from the compounded effects of future referrals from neighbouring paediatric hospitals and the arrival of new adult patients from migrant populations, as migration, particularly into SSA, continues to be the reality for many people seeking political asylum, economic opportunities and better healthcare. Concomitant with this migration, the improved clinical management and healthcare of paediatric SCD patients is expected to increase the pool of adult patients living with SCD. This will increase the number of patients who will survive well beyond reproductive age, which is likely to increase the frequency of the HbS allele in the population.

Newborn screening and comprehensive clinical care programmes, which are also possible in SA, have reduced SCD-related premature childhood deaths by 70% in high-income nations such as the USA,[31,32] and most patients can survive into adulthood. [33] A similar increasing trend of SCD in countries previously not affected by the disease has been observed in Ireland,[34] Italy,[35] Germany,[36] England[37] and France.[38] Therefore, the evidence that the SCD burden is comparable to that of communicable diseases and other major global diseases such as hypertension and diabetes[2] will have increasing resonance. The marked increase in patients between 2001 and 2005 could also be associated with the ending of a civil war, a transitional government and political instability in DRC, the effects of which had spread into neighbouring states. The more recent increase (2011 - 2016) is more likely to be due to economic and health-motivated migration. The increase of SCD in both paediatric and adult settings will impose a new burden on the healthcare system in SA concomitant with a new need for training at all levels of medical education, as well as the need for policies from health authorities for the prevention, management and care of haemoglobinopathies.

The number of annual vaso-occlusive crises was similar to that reported in Cameroon, as was the mean number of vaso-occlusive crises per year.[9] Major challenges faced by healthcare professionals at GSH were patient compliance with HU treatment, compliance with supportive medication such as folic acid and patient clinic attendance. There were several barriers to HU treatment, including the financial implications of taking time off work to attend the clinic and receive it (maximum one month's supply), and misconceptions about the treatment and its possible carcinogenic effects, as well as potential impotence in male patients.[39] Most patients who fail to comply with clinic appointments do so simply because they feel better and therefore see no need to go to the hospital.

The novel aspect of this article is the report on the genetic background of four key modifiers of HbF: variants at the BCL11A erythroid-specific enhancer, β-globin haplotypes, α-thalassaemia 3.7 kb gene deletion and several other known HbF-promoting polymorphisms. It is imperative to gain a better understanding of genetic variants affecting the predisposition to specific complications such as stroke and acute chest syndrome, and polymorphisms affecting susceptibility to pain, as well as the pharmacogenomics of commonly prescribed treatments such as HU, malaria prophylaxis and pain medication. The dominance of the Bantu haplotype in this cohort is in accordance with the Congolese origin of most patients. Indeed, the Bantu haplotype is most prevalent below the equatorial malaria belt across southern African countries.[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.

It should be made clear that the intention of this article is not to stigmatise SCD nor immigrant patients, but to inform and prepare medical care providers and healthcare officials of the increasing need for management of haemoglobinopathies in SA. This trend is not restricted to SA, with countries such as Italy[40] the Republic of Ireland,[34] England[41] and Germany[36] affected by the reality of population movement and new burden of disease, developing neonatal screening programmes and establishing SCD centres in response to similar increases in SCD prevalence.

Study limitations

The final sample size of patients included in the present study was limited because of poor patient compliance with clinic attendance, self-transfers to other hospitals and the shortened period of recruitment. The sample size did not allow for robust statistical analyses to reveal potent markers of specific phenotypes or clinical measures. HbF levels were measured for a handful of patients performed using high performance liquid chromatography before initiation of HU treatment. This haematological measure would have been ideal to check for association with genetic variants as baseline HbF.


Over the past 10 years, the number of adult patients living with SCD has increased considerably, imposing the creation of a weekly outpatient service at GSH. The genetic profile is similar to that of many other SCD patients from the other SSA countries from where most patients originate. The trend has a number of implications, particularly for medical education at academic and training institutions, policy action on prevention and care at the National Department of Health, and research in haemoglobinopathies in SA.

Acknowledgments. We would like to thank the nursing staff of the Haematology Service at GSH for their support and the patients for their participation.

Contribution to authorship. GP and AW conceived and designed the experiments. GP, KM and MJ recruited and sampled the patients. GP and KM performed the experiments. GP, KM and AW analysed the data. AW, MJ, SM and NN contributed reagents/materials/analysis tools. GP and AW wrote the article. GP, KM, MJ, SM, NN and AW revised and approved the manuscript.

Funding statement. The molecular experiments of the study were funded by the National Health Laboratory Services, SA and the National Institutes of Health, USA, grant no. 1U01HG007459-01. The students' bursaries were supported by the Oppenheimer Memorial Trust, the National Research Foundation, and FirstRand Laurie Dippenaar Scholarship, SA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.



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A Wonkam

Accepted 10 June 2016

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