Role of novel genetic variations on tissue fibrosis

Tissue fibrosis is a highly heritable complex phenotype that has both core and disease-specific pathways and is responsible for nearly half of all deaths worldwide. There are no approved therapies for tissue fibrosis. Non-alcoholic fatty liver disease (NAFLD) is a primary cause of liver disease that affects around a quarter of the global population. Adverse outcomes in NAFLD and in many other chronic liver diseases are in large part secondary to the consequences of liver fibrosis. However, our understanding of the genetic basis of tissue fibrosis and of fibrosis in NAFLD is limited, with known variants explaining only a small proportion of the heritability. This suggests that there is a substantial burden of yet to be identified “missing heritability”. Furthermore, most existing studies have focused on single nucleotide polymorphisms that account for genetic variation between individuals, with less information on other types of genetic variation, such as copy number variation (CNV). In the latter, genes exist in abnormal numbers of copies, mostly due to duplication or deletion. The studies in this thesis within the larger context of tissue fibrosis and more specifically in regard to liver and lung fibrosis, were designed to clarify the role of: a) Variants in FNDC5 on the histological severity of NAFLD b) Variants in IFNL3 on lung fibrosis (previous extensive work in our laboratory had confirmed that variants in IFNL3 impact hepatic inflammation and fibrosis in a variety of chronic liver diseases), and c) CNV in the XPO4 gene and the histological severity of NAFLD. The major outcomes of the research were: a) In 987 Caucasian patients with NAFLD, we demonstrated that the FNDC5 rs3480 (G) allele was associated with advanced steatosis (OR 1.29; 95% CI 1.08-1.55; p = 0.004), but not with other histological features through a microRNA-mediated mechanism controlling FNDC5 mRNA stability. This effect was independent but additive to that of variants in PNPLA3 and TM6SF2. Elevated serum irisin was associated with reduced steatosis, and an improved metabolic profile. b) In a cohort of Caucasian patients with systemic sclerosis (SSc) (n=733), we observed an association of the IFNL3 polymorphism with pulmonary fibrosis, but not worsening of skin fibrosis. Functionally, IFN-λ3 serum levels were higher among subjects with pulmonary fibrosis compared to those unaffected (P<0.0001). Lung Ifnl3 mRNA expression was higher in mice with bleomycin-induced PF compared to controls (P