The epidemiology of childhood sickle cell anaemia and the disease modifying effects of the -α^3.7 deletional form of α-thalassaemia and the glucose-6-phosphate dehydrogenase G202T allele in Uganda

Kiyaga, Charles (2024). The epidemiology of childhood sickle cell anaemia and the disease modifying effects of the -α^3.7 deletional form of α-thalassaemia and the glucose-6-phosphate dehydrogenase G202T allele in Uganda. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00098436

Abstract

Haemoglobin S (HbS), α-thalassaemia, and glucose-6-phosphate deficiency (G6PD) deficiency are three distinct erythrocyte genetic mutations that share a global distribution that reflects the geographical distribution of malaria. Consequently, it is believed that carriers of these conditions benefit from some degree of resistance against malaria. Since Uganda is a country in which malaria transmission has been historically high, it is assumed the prevalence of these mutations will also be high. However, the prevalence of all three of these conditions has not been documented previously at a national scale. Also not known is the potential disease-modifying effects of concurrent α-thalassaemia and G6PD deficiency on the survival of children with sickle cell anaemia (HbSS).

Through this thesis I have three broad aims: (1) to document the national geospatial distribution of HbS, the -α^3.7 deletional form of α-thalassaemia and the G202T form of G6PD deficiency (the dominant forms of each that are found in Africa) within Uganda; (2) to investigate the degree to which the geographical distributions of these mutations correlate with one another; and (3) to investigate the effects of α-thalassaemia and the G202T allele on the survival of children born with HbSS.

To address the first two aims, I collected blood samples from 100 consecutive HIV exposed infants 0-6 months of age, from each of the 122 districts in Uganda. I tested for HbS by isoelectric focusing (IEF) and for -α^3.7 α-thalassaemia and the G6PD G202T allele using DNA-based methods. I then mapped the prevalence of each of these conditions using Global Positioning System software and compared their distributions using geospatial methods. To address the third aim, I collected blood samples from subjects aged 0-18 years who were attending SCD clinics from across the country, and confirmed their diagnosis using iso-electric focusing. I then investigated the age-specific prevalence of α-thalassaemia and the G202T G6PD allele in this population, testing for changes in prevalence with increasing age, an indirect measure of their effects on survival.

HbS, α-thalassaemia and the G202T were found to have a high prevalence in Uganda overall, with allele frequencies of 0.061, 0.269 and 0.114 respectively. When mapped, their distributions appeared to be correlated at both district and regional scales. I found no evidence for a change in prevalence of α-thalassaemia with age among children with HbSS, which does not support its effects on survival. However, I did find a reducing prevalence of the G6PD G202T with age among males, suggesting a possible negative effect on survival. I conclude that these three distinct genetic mutations that arose historically from malaria pressure are common in Uganda, have correlated geographical distribution mainly in malaria endemic regions, and that G6PD G202T may affect the survival of males born with HbSS. Further research is needed to verify these novel observations.

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