The Effect of Human Genetic Factors on Childhood Malaria in Asembo, Western Kenya

Human genetic factors confer protection or susceptibility to malaria. Classical examples include sickle cell trait, which confers up to 90% protection from severe Plasmodium falciparum malaria and Duffy antigen negativity, which offers almost complete resistance to Plasmodium vivax infection. Unfortunately, such genetic factors are insufficiently understood to design interventions. I conducted the current study in Asembo, western Kenya by recruiting a paediatric cohort, characterizing malaria epidemiology, genotyping for single nucleotide polymorphisms (SNPs) to identify genetic factors affecting malaria incidence and investigating their possible relationships with naturally acquired immunity. In addition, I investigated the effect of co-inheritance of genetic factors on malaria incidence. Children under 12 years were followed up over a 6 year period (2008-2013) to calculate malaria incidence. Odds ratios for malaria were also calculated for categorical risk factors identified during a nested cross sectional survey. The parasite density threshold associated with a malaria fever was investigated through a logistic regression approach. Interactions between the gene variants, and between the gene variants and age were investigated using the likelihood ratio test (LRT). Evidence for differences in age-specific rates of malaria was also investigated by LRT. Through these studies, risk factors of malaria were identified. I established differences in age and genotype specific incidence, suggesting that malaria candidate genes affect naturally acquired immunity to malaria. In addition, this study identified pairs of genes that may interact to affect malaria incidence. Gene frequencies of various malaria candidate genes as typed in this study may be an important consideration in interpreting results of intervention trials in this population. The high frequency of the G6PD deficiency genotypes determined in this study is clinically relevant as it determines the use of primaquine, a key drug which causes haemolysis in deficient individuals, but which is useful in malaria elimination due to its gametocytocidal activity