Genetic epidemiology and functional studies of β-thalassaemia in Kilifi, Kenya

Macharia, Alexander Waiganjo (2024). Genetic epidemiology and functional studies of β-thalassaemia in Kilifi, Kenya. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00096394

Abstract

It is generally believed that β-thalassaemia is rare in sub-Saharan Africa; however, in studies conducted in Kilifi, we recently observed HbA2 levels within the diagnostic range for β-thalassaemia (≥4%) in multiple children and identified two β-thalassaemia mutations. In this thesis, I have investigated this observation further by documenting the prevalence, genetic types, and origins of β-thalassaemia in this region. Additionally, I have explored the malaria protective mechanisms associated with these mutations and examined their health consequences. I found that in Kilifi, β-thalassaemia is defined by four different mutations, three β0 (rs33959855, rs33941849, rs193922563) and one a β⁺ mutation (rs35004220). I estimated the allele frequency for all mutations to be 0.3% and the birth prevalence of homozygosity to be approximately 1 in 100,000.

Based on evidence from a literature review and ethnolinguistic and haplotype analysis, I hypothesized that rs33959855 was introduced through admixture with the South Asian population during the Asian-Swahili trade in 1200CE. However, the origins of the other mutations remained inconclusive.

Through in vitro studies using β-thalassaemia RBCs and survival analysis, I observed a modest reduction in invasion by Plasmodium falciparum 3D7 parasites. However, β-thalassaemia was not associated either with under-5 mortality or protection against hospital admission with clinical malaria. These mutations were, however, associated with several negative outcomes. Specifically, co-inheritance of both β-thalassaemia and the HbS sickle mutation was the cause of 10% of all sickle cell disease cases in the region. Moreover, homozygosity for β-thalassaemia was associated with transfusion dependent β-thalassaemia major, as illustrated by a case report involving rs33941849 mutation. β-thalassaemia carriers were also at a higher risk of admission to hospital with severe anaemia, although the risk was mitigated by coinheritance of α-thalassaemia.

These findings underscore the importance of raising awareness and establishing guidelines for diagnosis and management of β-thalassaemia in Kilifi.

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