Abstract
Abnormal fibrosis occurs during chronic hepatic inflammations and is the principal cause of death in hepatitis C virus and schistosome infections. Hepatic fibrosis (HF) may develop either slowly or rapidly in schistosome-infected subjects. This depends, in part, on a major genetic control exerted by genes of chromosome 6q23. A gene (connective tissue growth factor [CTGF]) is located in that region that encodes a strongly fibrogenic molecule. We show that the single nucleotide polymorphism (SNP) rs9402373 that lies close to CTGF is associated with severe HF (P = 2 × 10−6; odds ratio [OR] = 2.01; confidence interval of OR [CI] = 1.51–2.7) in two Chinese samples, in Sudanese, and in Brazilians infected with either Schistosoma japonicum or S. mansoni. Furthermore, SNP rs12526196, also located close to CTGF, is independently associated with severe fibrosis (P = 6 × 10−4; OR = 1.94; CI = 1.32–2.82) in the Chinese and Sudanese subjects. Both variants affect nuclear factor binding and may alter gene transcription or transcript stability. The identified variants may be valuable markers for the prediction of disease progression, and identify a critical step in the development of HF that could be a target for chemotherapy.Hepatointestinal schistosomiasis is caused by two species of helminths: Schistosoma japonicum, which is prevalent in Asia, and S. mansoni, which is prevalent in Africa and South America. Both worms develop in their host mesenteric system and lay eggs triggering inflammation in the hepatic periportal space in which they are trapped. Worms live for years, and thus, chronic liver inflammation and significant tissue destruction are common in infected subjects. Tissue repair begins with the deposit of extracellular matrix proteins (ECMPs) in the damaged tissues, which are later replaced by normal hepatocytes. In some subjects, ECMPs accumulate in the periportal space, forming fibrosis deposits that reduce blood flow, causing varicose veins. Subjects die from the subsequent effects of hepatic fibrosis (HF). 5–10% of the 350 million infected subjects may develop severe HF. There are no good markers for predicting HF progression in schistosome-infected subjects. HF development is strongly influenced by a major locus located at chromosome 6q23 (Dessein et al., 1999). This region contains two major candidate genes: IFNGR1 encodes a chain of the IFN-γ receptor (IFN-γ being an antifibrogenic cytokine that protects against HF; Henri et al., 2002; Chevillard et al., 2003); and connective tissue growth factor (CTGF), which encodes a profibrogenic molecule produced by hepatocytes (Kobayashi et al., 2005; Gressner et al., 2007), hepatic stellate cells, myofibroblasts, and endothelial cells (Gressner and Gressner, 2008). CTGF transcripts are overexpressed in livers affected by fibrosis of various etiologies (Rachfal and Brigstock, 2003). In this report, functional single nucleotide polymorphisms (SNPs) implicate CTGF as a major actor in severe HF in schistosome-infected Chinese, Sudanese, and Brazilian subjects.