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

Abstract

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 T_h2 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 T_h2 cytokines in candidate gene studies, we found that four of the five QTL regions contain T_h17 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 T_h17 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.

Keywords: QTL; Th17; fibrosis; intensity of infection; linkage; schistosomiasis.

Figure 1

Genes and quantitative trait loci associated with schistosomiasis plotted on a human karyotype. Blue lines indicate QTL, with reported −log p-value for association shown on the y axis. Genes containing SNP associated with schistosomiasis infection (Table 3) are shown in blue, genes associated with pathology (Table 4) are shown in red and genes associated with both pathology and infection are shown in black. Genes are arranged vertically on the plot for clarity and their position on the y axis is arbitrary.

Figure 2

Schistosomiasis QTL and numbers of publications mentioning each gene in each QTL regions. (A) SM1 region 5q31-q33; (B) 6p21-q21; (C) SM2 6q23-q24; (D) 1p21-q23. Negative log p-values for associations between markers and schistosomiasis are shown on the left-hand axis. Counts of publications which mention both schistosomiasis and genes in the QTL are shown by the blue columns and on a log scale on the right-hand y axis. Markers used in mapping are shown in red on the top axis (including genes used as markers). Genes for which there was only one publication are omitted for clarity and positions of genes and markers have been adjusted by up to 1Mb for clarity. Note the cluster of T_h2 cytokine genes (IL3, IL4, IL5, IL9, IL13) in SM1 with large numbers of publications between 131 and 135 Mb but low LOD scores. However, in a reanalysis of the same data using weighted pairwise correlations the peak of the QTL shifted toward this cytokine cluster (69).