Browsing by Author "Nyangiri, Oscar A."

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Candidate gene family-based and case-control studies of susceptibility to high Schistosoma mansoni worm burden in African children
    (AAS open research, 2021) Nyangiri, Oscar A.; Sokouri, A. Edwige; Koffi, Mathurin; Mewamba, Estelle; Simo, Gustave; Namulondo, Joyce; Mulindwa, Julius; Nassuuna, Jacent; Alison, Elliott; Karume, Kévin; Mumba, Dieudonne; M. Casacuberta-Partal; Dam, G. J. van; Bruno, Bucheton; Harry, Noyes; Matovu, Enock
    Background: Approximately 25% of the risk of Schistosoma mansoni is associated with host genetic variation. We will test 24 candidate genes, mainly in the T h2 and T h17 pathways, for association with S. mansoni infection intensity in four African countries, using family based and case-control approaches. Methods: Children aged 5-15 years will be recruited in S. mansoni endemic areas of Ivory Coast, Cameroon, Uganda and the Democratic Republic of Congo (DRC). We will use family based (study 1) and case-control (study 2) designs. Study 1 will take place in Ivory Coast, Cameroon, Uganda and the DRC. We aim to recruit 100 high worm burden families from each country except Uganda, where a previous study recruited at least 40 families. For phenotyping, cases will be defined as the 20% of children in each community with heaviest worm burdens as measured by the circulating cathodic antigen (CCA) assay. Study 2 will take place in Uganda. We will recruit 500 children in a highly endemic community. For phenotyping, cases will be defined as the 20% of children with heaviest worm burdens as measured by the CAA assay, while controls will be the 20% of infected children with the lightest worm burdens. Deoxyribonucleic acid (DNA) will be genotyped on the Illumina H3Africa SNP (single nucleotide polymorphisms) chip and genotypes will be converted to sets of haplotypes that span the gene region for analysis. We have selected 24 genes for genotyping that are mainly in the Th2 and Th17 pathways and that have variants that have been demonstrated to be or could be associated with Schistosoma infection intensity. Analysis: In the family-based design, we will identify SNP haplotypes disproportionately transmitted to children with high worm burden. Case-control analysis will detect overrepresentation of haplotypes in extreme phenotypes with correction for relatedness by using whole genome principal components.
  • Thumbnail Image
    Item
    Gene Expression Changes in Mammalian Hosts during Schistosomiasis
    (Open Research Africa, 2021) Namulondo, Joyce; Mulindwa, Julius; Nyangiri, Oscar A.; Egesa, Moses; Noyes, Harry; Matovu, Enock
    Schistosomiasis affects over 250 million people worldwide with an estimated mortality of more than 200,000 deaths per year in sub-Saharan Africa. Efforts to control schistosomiasis in the affected areas have mainly relied on mass administration of praziquantel, which kills adult but not immature worms of all Schistosoma species. Mammalian hosts respond differently to Schistosoma infection with some being more susceptible than others, which is associated with risk factors such as sociodemographic, epidemiological, immunological and/or genetic. Host genetic factors play a major role in influencing molecular processes in response to schistosomiasis as shown in gene expression studies. These studies highlight gene profiles expressed at different time points of infection using model animals. Immune function related genes; cytokines (Th1 and Th17) are upregulated earlier in infection and Th2 upregulated later indicating a mixed Th1/Th2 response. However, Th1 response has been shown to be sustained in S. japonicum infection. Immune mediators such as matrix metalloproteinases (Mmps) and tissue inhibitors of matrix metalloproteinases (Timps) are expressed later in the infection and these are linked to wound healing and fibrosis. Downregulation of metabolic associated genes is recorded in later stages of infection. Most mammalian host gene expression studies have been done using rodent models, with fewer in larger hosts such as bovines and humans. The majority of these studies have focused on S. japonicum infections and less on S. haematobium and S. mansoni infections (the two species that cause most global infections). The few human schistosomiasis gene expression studies so far have focused on S. japonicum and S. haematobium infections and none on S. mansoni, as far as we are aware. This highlights a paucity of gene expression data in humans, specifically with S. mansoni infection. This data is important to understand the disease pathology, identify biomarkers, diagnostics and possible drug targets.
  • Thumbnail Image
    Item
    The Genetics of Human Schistosomiasis Infection Intensity and Liver Disease: A Review
    (Frontiers in Immunology, 2021) Mewamba, Estelle M.; Nyangiri, Oscar A.; Egesa, Moses; Matovu, Enock; Simo, Gustave
    Schistosomiasis remains the fourth most prevalent parasitic disease affecting over 200 million people worldwide. Control efforts have focussed on the disruption of the life cycle targeting the parasite, vector and human host. Parasite burdens are highly skewed, and the majority of eggs are shed into the environment by a minority of the infected population. Most morbidity results from hepatic fibrosis leading to portal hypertension and is not well-correlated with worm burden. Genetics as well as environmental factors may play a role in these skewed distributions and understanding the genetic risk factors for intensity of infection and morbidity may help improve control measures. In this review, we focus on how genetic factors may influence parasite load, hepatic fibrosis and portal hypertension. We found 28 studies on the genetics of human infection and 20 studies on the genetics of pathology in humans. S. mansoni and S. haematobium infection intensity have been showed to be controlled by a major quantitative trait locus SM1, on chromosome 5q31-q33 containing several genes involved in the Th2 immune response, and three other loci of smaller effect on chromosomes 1, 6, and 7. The most common pathology associated with schistosomiasis is hepatic and portal vein fibroses and the SM2 quantitative trait locus on chromosome six has been linked to intensity of fibrosis. Although there has been an emphasis on Th2 cytokines in candidate gene studies, we found that four of the five QTL regions contain Th17 pathway genes that have been included in schistosomiasis studies: IL17B and IL12B in SM1, IL17A and IL17F in 6p21-q2, IL6R in 1p21-q23 and IL22RA2 in SM2. The Th17 pathway is known to be involved in response to schistosome infection and hepatic fibrosis but variants in this pathway have not been tested for any effect on the regulation of these phenotypes. These should be priorities for future studies.