Candidate gene family-based and case-control studies of susceptibility to high Schistosoma mansoni worm burden in African children: a protocol.

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.

The gut microbiome in konzo.

Konzo, a distinct upper motor neuron disease associated with a cyanogenic diet and chronic malnutrition, predominately affects children and women of childbearing age in sub-Saharan Africa. While the exact biological mechanisms that cause this disease have largely remained elusive, host-genetics and environmental components such as the gut microbiome have been implicated. Using a large study population of 180 individuals from the Democratic Republic of the Congo, where konzo is most frequent, we investigate how the structure of the gut microbiome varied across geographical contexts, as well as provide the first insight into the gut flora of children affected with this debilitating disease using shotgun metagenomic sequencing. Our findings indicate that the gut microbiome structure is highly variable depending on region of sampling, but most interestingly, we identify unique enrichments of bacterial species and functional pathways that potentially modulate the susceptibility of konzo in prone regions of the Congo.