article · The Journal of Experimental Medicine
Hepatic fibrosis is a major cause of death in individuals suffering from chronic liver inflammation, including infections caused by schistosomes and hepatitis C virus. The rate at which liver fibrosis develops varies between patients and is influenced by genetic factors on chromosome 6q23, where the connective tissue growth factor gene is situated. Specific single nucleotide polymorphisms near this gene are linked to severe fibrosis across diverse human populations. The genetic variant rs9402373 is significantly associated with severe hepatic fibrosis in Chinese, Sudanese, and Brazilian individuals infected with either Schistosoma japonicum or Schistosoma mansoni. An additional variant, rs12526196, shows an independent association in Chinese and Sudanese populations. Both variants influence nuclear factor binding and may modify gene transcription or transcript stability, indicating a biological pathway that could be targeted therapeutically.
Liver fibrosis is the leading cause of death in people with chronic schistosome infections. Pinpointing specific genetic variations shared across geographically diverse populations in Africa, Asia, and South America helps explain why some individuals experience more rapid and severe liver damage than others. This knowledge improves understanding of disease mechanisms and highlights potential molecular targets for developing medical interventions to prevent fatal complications.
The research identifies genetic variants that could serve as diagnostic biomarkers to predict severe fibrosis progression and suggests connective tissue growth factor pathways as targets for future chemotherapy. Potential end users include clinical diagnostic developers and pharmaceutical companies formulating anti-fibrotic drugs. This work represents early-stage genetic association research, meaning significant clinical validation and drug discovery efforts would be required before real-world diagnostic or therapeutic products emerge.
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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 x 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 x 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.
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DOI: 10.1084/jem.20090383
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