| dc.description.abstract | This thesis comprises studies of the relationship between host genetic factors and incidence of uncomplicated malaria in a vaccine trial site in Iganga district. The studies focused on selected host gene markers that are believed to influence malaria susceptibility. The gene markers are sickle cell trait, glucose-6-phosphate dehydrogenase (G6PD) deficiency, inducible nitric oxide synthase 2 (NOS2), RANTES and haptoglobin genes. Three reports (Paper I-III) were generated from these studies and all have been published in peer –reviewed journals. In these studies, 423 children were recruited and had a mean age of 3.9 years (SD: ±2.3). Slightly over half of the study participants (52.7%) were males. At recruitment, mean haemoglobin was 12 g/dL (SD: ±1.5) and mean weight was 15.5 kg (SD: ± 5.2). The predominant blood groups were O+ (39.4%) and B+ (30.4%). In paper I, we evaluated the impact of polymorphisms in glucose-6-phosphate dehydrogenase (G6PD A-), sickle haemoglobin and nitric oxide synthase genes (NOS2-954G>C) on incidence of uncomplicated malaria among children in Iganga, Uganda. The prevalences of sickle cell hemoglobin trait, G6PD A- and NOS2 -954G>C mutations were 26.6%, 22.7% and 17.3%, respectively. About 4% of the study children had co-existence of sickle cell Hb trait and G6PD deficiency. Sickle cell Hb heterozygotes (Hb AS) aged less than 1 year experienced significantly more malaria episodes annually than children with normal hemoglobin (Hb AA) {Adjusted incident rates ratio (aIRR) = 1.98; 95%CI [1.240-3.175]; P-value=0.004}. Beyond one year of age till nine years, the number of malaria episodes experienced was not significantly affected by the sickle cell Hb genotype. Inducible nitric oxide synthase 2 (NOS2 -954G>C) heterozygosity was associated with lower incidence of malaria (aIRR=0.59; 95%CI [0.386-0.887] ;P=0.012) in all age groups. Given the high frequency of sickle Hb, G6PD and NOS2 gene mutations (26.6%, 22.7% and 17.3%, respectively), screening of sickle Hb and G6PD deficiency in regional endemic areas is recommended. This will ensure proper management of patients with acute hemolytic anaemia. Additionally, association between host gene polymorphisms and malaria incidence could influence the outcome endpoints of malaria drug or vaccine trials. Thus, the design, planning and interpretation of results for malaria intervention clinical trials needs to consider selected host genetic factors of the study population. In paper II, the frequency of RANTES gene polymorphisms and their association with the incidence of uncomplicated malaria among children in Iganga, Uganda were determined. The frequencies of the RANTES −403A and In1.1C allele were 53.7% and 19.2 %, respectively. No mutations were found at the −28 locus. After adjustment of incidence rates for age, blood group, insecticide-treated bed net (ITN) use, malaria history and the sickle cell trait, there was no clear association with malaria incidence. Other studies evaluating additional markers that could potentially modulate RANTES gene transcription are recommended so as to provide further explanations to the study findings. Paper III reports about the genetic diversity of haptoglobin among children living in the malaria endemic district. Haptoglobin genotypes Hp1-1, Hp2-1 and Hp2-2 were found in 41%, 36.2% and 22.9% of the cohort children respectively, with an overall allele frequency of 59% for the Hp1 allele and 41% for the Hp2 allele. Although no association of these markers with incidence of uncomplicated malaria was observed, the existence of these mutant genotypes at high allelic frequencies could suggest that these mutant alleles may have been maintained by protection from other infections. Other studies in different settings are needed to confirm these associations. In conclusion, the thesis reports high frequencies of mutations in sickle Hb, G6PD, RANTES and haptoglobin gene markers in the children’s cohort at Iganga. However, the most significant ageindependent effect on malaria susceptibility was the heterozygous NOS2 −954 G>C mutation, which showed reduction in incidence of acute malaria infections. No remarkable associations with malaria incidence were observed with the other gene markers. Considering that the present study was limited to selected gene markers, a genome wide association approach is recommended to provide a clearer understanding of the thesis finding. | en_US |
