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

Variants of IL6, IL10, FCN2, RNASE3, IL12B and IL17B loci are associated with Schistosoma mansoni worm burden in the Albert Nile region of Uganda

Background: Individuals genetically susceptible to high schistosomiasis worm burden may contribute disproportionately to transmission and could be prioritized for control. Identifying genes involved may guide development of therapy. // Methodology/Principal findings: A cohort of 606 children aged 10–15 years were recruited in the Albert Nile region of Uganda and assessed for Schistosoma mansoni worm burden using the Up-Converting Particle Lateral Flow (UCP-LF) test detecting circulating anodic antigen (CAA), point-of-care Circulating Cathodic Antigen (POC-CCA) and Kato-Katz tests. Whole genome genotyping was conducted on 326 children comprising the top and bottom 25% of worm burden. Linear models were fitted to identify variants associated with worm burden in preselected candidate genes. Expression quantitative trait locus (eQTL) analysis was conducted for candidate genes with UCP-LF worm burden included as a covariate. Single Nucleotide Polymorphism loci associated with UCP-LF CAA included IL6 rs2066992 (OR = 0.43, p = 0.0006) and rs7793163 (OR = 2.0, p = 0.0007); IL21 SNP kgp513476 (OR 1.79, p = 0.0025) and IL17B SNP kgp708159 (OR = 0.35, p = 0.0028). A haplotype in the IL10 locus was associated with lower worm burden (OR = 0.53, p = 0.015) and overlapped SNPs rs1800896, rs1800871 and rs1800872. Significant haplotypes (p<0.05, overlapping significant SNP) associated with worm burden were observed in IL6 and the Th17 pathway IL12B and IL17B genes. There were significant eQTL in the IL6, IL5, IL21, IL25 and IFNG regions. // Conclusions: Variants associated with S. mansoni worm burden were in IL6, FCN2, RNASE3, IL10, IL12B and IL17B gene loci. However only eQTL associations remained significant after Bonferroni correction. In summary, immune balance, pathogen recognition and Th17 pathways may play a role in modulating Schistosoma worm burden. Individuals carrying risk variants may be targeted first in allocation of control efforts to reduce the burden of schistosomiasis in the community

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 Th2 and Th17 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

Impact of environmental factors on Biomphalaria pfeifferi vector capacity leading to human infection by Schistosoma mansoni in two regions of western Côte d'Ivoire.

ABSTRACT: BACKGROUND: Intestinal schistosomiasis remains a worrying health problem, particularly in western Côte d'Ivoire, despite control efforts. It is therefore necessary to understand all the factors involved in the development of the disease, including biotic and abiotic factors. The aim of this study was to examine the factors that could support the maintenance of the intermediate host and its vectorial capacity in western Côte d'Ivoire.MethodsData on river physicochemical, microbiological, and climatic parameters, the presence or absence of snails with Schistosoma mansoni, and human infections were collected between January 2020 and February 2021. Spearman rank correlation tests, Mann-Whitney, analysis of variance (ANOVA), and an appropriate model selection procedure were used to analyze the data.ResultsThe overall prevalence of infected snails was 56.05%, with infection reaching 100% in some collection sites and localities. Of 26 sites examined, 25 contained thermophilic coliforms and 22 contained Escherichia coli. Biomphalaria pfeifferi was observed in environments with lower land surface temperature (LST) and higher relative air humidity (RAH), and B. pfeifferi infection predominated in more acidic environments. Thermal coliforms and E. coli preferred higher pH levels. Lower maximum LST (LST_Max) and higher RAH and minimum LST (LST_Min) were favorable to E. coli, and lower LST_Max favored coliforms. The presence of B. pfeifferi was positively influenced by water temperature (T °C), LST_Min, RAH, and precipitation (Pp) (P 2 = 0.879, P = 0.04959).ConclusionsThe results obtained reflect the environmental conditions that are conducive to the maintenance of S. mansoni infection in this part of the country. To combat this infection as effectively as possible, it will be necessary not only to redouble efforts but also to prioritize control according to the level of endemicity at the village level

Transcriptome analysis of peripheral blood of Schistosoma mansoni infected children from the Albert Nile region in Uganda reveals genes implicated in fibrosis pathology.

Over 290 million people are infected by schistosomes worldwide. Schistosomiasis control efforts focus on mass drug treatment with praziquantel (PZQ), a drug that kills the adult worm of all Schistosoma species. Nonetheless, re-infections have continued to be detected in endemic areas with individuals living in the same area presenting with varying infection intensities. Our objective was to characterize the transcriptome profiles in peripheral blood of children between 10-15 years with varying intensities of Schistosoma mansoni infection living along the Albert Nile in Uganda. RNA extracted from peripheral blood collected from 44 S. mansoni infected (34 high and 10 low by circulating anodic antigen [CAA] level) and 20 uninfected children was sequenced using Illumina NovaSeq S4 and the reads aligned to the GRCh38 human genome. Differential gene expression analysis was done using DESeq2. Principal component analysis revealed clustering of gene expression by gender when S. mansoni infected children were compared with uninfected children. In addition, we identified 14 DEGs between S. mansoni infected and uninfected individuals, 56 DEGs between children with high infection intensity and uninfected individuals, 33 DEGs between those with high infection intensity and low infection intensity and no DEGs between those with low infection and uninfected individuals. We also observed upregulation and downregulation of some DEGs that are associated with fibrosis and its regulation. These data suggest expression of fibrosis associated genes as well as genes that regulate fibrosis in S. mansoni infection. The relatively few significant DEGS observed in children with schistosomiasis suggests that chronic S. mansoni infection is a stealth infection that does not stimulate a strong immune response

High-depth African genomes inform human migration and health

The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity among African individuals has been surveyed1. Here we performed whole-genome sequencing analyses of 426 individuals—comprising 50 ethnolinguistic groups, including previously unsampled populations—to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon—but in other genes, variants denoted as ‘likely pathogenic’ in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health

High-depth African genomes inform human migration and health.

The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity among African individuals has been surveyed1. Here we performed whole-genome sequencing analyses of 426 individuals-comprising 50 ethnolinguistic groups, including previously unsampled populations-to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon-but in other genes, variants denoted as 'likely pathogenic' in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health

High-depth African genomes inform human migration and health

The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity among African individuals has been surveyed1. Here we performed whole-genome sequencing analyses of 426 individuals—comprising 50 ethnolinguistic groups, including previously unsampled populations—to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon—but in other genes, variants denoted as ‘likely pathogenic’ in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health

Gene expression changes in mammalian hosts during schistosomiasis: a review

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.</ns3:p

The Genetics of Human Schistosomiasis Infection Intensity and Liver Disease: A Review.

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