Abstract
Tissue fibrosis is a core pathologic process that contributes to mortality in ~45% of the population and is likely to be influenced by the host genetic architecture. Here we demonstrate, using liver disease as a model, that a single-nucleotide polymorphism (rs12979860) in the intronic region of interferon-λ4 (IFNL4) is a strong predictor of fibrosis in an aetiology-independent manner. In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C (CHC), 555 with chronic hepatitis B (CHB) and 488 with non-alcoholic fatty liver disease (NAFLD), those with rs12979860CC have greater hepatic inflammation and fibrosis. In CHC, those with rs12979860CC also have greater stage-constant and stage-specific fibrosis progression rates (P<0.0001 for all). The impact of rs12979860 genotypes on fibrosis is maximal in young females, especially those with HCV genotype 3. These findings establish rs12979860 genotype as a strong aetiology-independent predictor of tissue inflammation and fibrosis.
Highlights
Tissue fibrosis is a core pathologic process that contributes to mortality in B45% of the population and is likely to be influenced by the host genetic architecture
To examine whether the association of rs12979860 genotypes with the histological severity of non-alcoholic fatty liver disease (NAFLD) is independent of the well-known risk factors for liver damage in NAFLD, we considered in the analysis cardio-metabolic risk factors such as diabetes, hypertension, lipid profiles and homeostasis model assessment-estimated insulin resistance (HOMA-IR)
We provide strong evidence in large cohorts and using multiple complementary approaches that rs12979860 genotype is associated with hepatic inflammation and fibrosis, irrespective of disease aetiology
Summary
Tissue fibrosis is a core pathologic process that contributes to mortality in B45% of the population and is likely to be influenced by the host genetic architecture. Liver disease develops as a consequence of any number of insults, with chronic viral hepatitis B and C (CHB and CHC) and non-alcoholic fatty liver disease (NAFLD) among the most prevalent These three diseases offer an opportunity to understand the role of genetic factors in the evolution of liver fibrosis and to determine whether they are aetiology independent. A recent study added to this controversy by demonstrating that CHC patients with the rs12979860 CC responder genotype had greater hepatic necroinflammation and worse clinical outcomes, they had lower mean Ishak fibrosis scores, compared with those with rs12979860 CT/TT genotypes, and no association with fibrosis progression on paired biopsies[13] These findings are hard to reconcile, as fibrosis is a consequence of hepatic inflammation[1,22] and prospective paired biopsy cohorts clearly demonstrate that necroinflammatory grade on initial liver biopsy is the best predictor of fibrosis progression[23,24]. A recent meta-analysis failed to resolve this conundrum, as the authors demonstrated that rs12979860 CC and rs8099917 TT genotypes were not associated with severe inflammation in treatment–naive patients, rs12979860 CC was only weakly associated with fibrosis (P 1⁄4 0.04)[25], probably reflecting the inter-study variability in the outcomes
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