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.

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Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibrosis progression. At functional level, rs641738 associated with MBOAT7 transcript and protein levels in liver and blood, and with serum inflammatory, oxidative stress and macrophage activation markers. MBOAT7 was expressed in immune cell subsets, implying a role in hepatic inflammation. We conclude that the MBOAT7 rs641738 polymorphism is a novel risk variant for liver inflammation in hepatitis C, and thereby for liver fibrosis.

Clinical and virological outcomes are variable following acute infection with hepatitis C virus (HCV): there is successful viral clearance in some individuals, while persistent infection is established in the majority of cases (35). Chronic infection is characterized by attenuated and narrowly focused CD4 ϩ and CD8 ϩ T-cell responses (reviewed in reference 14) in conjunction with reduced proliferative, cytokine, and cytolytic capacity of HCV-specific T cells (10, 20, 40) and loss of antigen recognition (3). Conversely, CD4ϩ and CD8 ϩ T-cell responses are maintained in individuals who clear the virus (6,17,21,32,34,42). Therefore, effective T-cell-dependent immune responses to HCV-specific viral epitopes, restricted by the presence of host human leukocyte antigens (HLA) class I (CD8 ϩ cytotoxic T cells [CTL]) and class II (CD4 ϩ helper T cells), appear to make an important contribution to adaptive immunity and disease outcome. The high rate of HCV replication and mutation renders its genome susceptible to changes within and flanking HLA-restricted epitopes, thereby providing mutated HCV sequences with a means of "escaping" HLA-restricted immune responses. The relevance of HCV immune escape mutations in chronic infection (reviewed in reference 2) was first demonstrated in chimpanzees (7,9,41) and then subsequently demonstrated in humans (4, 33). Evidence for CTL escape and reversion has been recently demonstrated in acute infection (36) and 18 to 22 years after a common-source outbreak (24). As in human immunodeficiency virus (HIV) (1), flanking epitope escape mutations affecting proteasomal epitope processing provide an effective mechanism of immune escape in HCV (26). However, direct evidence for viral escape in humans is limited, as the sequence of the transmitted virus is rarely known and most previous studies have focused on a limited number of HLA alleles (38; www.hcv.lanl.gov).We have chosen a population-based approach to assess in * Corresponding author. Mailing address: Centre for Clinical Immu-