Five to ten percent of people infected with schistosome worms rapidly develop severe liver fibrosis. Here, Dessein and colleagues uncover single nucleotide variations in a growth factor gene that correlate with this life-threatening condition.
Most schistosome eggs pass into the intestines of their human hosts, but some become lodged in the liver. The body responds by producing inflammatory cytokines and repairing the subsequently damaged liver tissue with extracellular matrix proteins. However, in some people, the repair response leads to hepatic fibrosis as matrix proteins build up, plugging vessels and obstructing blood flow. Clinicians have noted that these fibrotic tendencies often run in families.
Here, Dessein et al. survey populations at risk for schistosome infection, including Chinese fishermen and farmers, Sudanese farmers, and Brazilian villagers living near schistosome-infested waters. In each population, they identified single nucleotide polymorphisms (SNPs) near the gene encoding connective tissue growth factor (CTGF) that were associated with severe liver fibrosis. One SNP in particular was common to all populations. This group and others had previously found that schistosome-related hepatic fibrosis was under the control of a major locus at chromosome 6q23. This region contains two candidate susceptibility genes, CTGF and IFNGR1, and the authors had previously found that IFNGR1, which encodes part of the interferon-γ receptor, was also linked to fibrosis.
The fibrosis-associated SNPs resulted in CTGF proteins that bound more readily to nuclear factors, suggesting that these variants likely affect how CTGF, a known mediator of pro-fibrotic activities, regulates the transcription of downstream genes. Previous studies in rats revealed that inhibiting CTGF reduces fibrosis. And many patients with fibrosis express excess CTGF.
Ten to thirty percent of the people in this study harbored deleterious CTGF SNPs. To understand why these variants have been maintained across populations over time, the group is now studying whether these alterations provide protection from other infectious diseases.
