markers of liver injury Rip3 -/- compared with WT mice, 28 days after BDL. Interestingly, Casp8 Δhepa /Rip3 -/- displayed improvement of liver function after BDL. Conclusions: CASP8 in LPC, but not RIP3, is an essential mediator of cholestatic liver injury, thus, it might be an interesting pharmacologic target that can be used in the clinic as treatment for cholestatic liver diseases. PS092 PROTEOMIC ANALYSIS OF LIVER FIBROTIC SEPTA AND PERIPORTAL SPACES IN PRIMARY SCLEROSING CHOLANGITIS, PRIMARY BILIARY CHOLANGITIS AND ALCOHOLIC LIVER DISEASE G. Mazza 1 , A. Telese 1 , E. Schrumpf 2–4 , J. Gilbertson 5 , N. Rendell 5 , B. Lombardi 6 , J. Godovac-Zimmermann 6 , G.W. Taylor 5 , D. Thorburn 1 , T.H. Karlsen 2–4,7 , M. Pinzani 1 . 1 UCL Institute for Liver and Digestive Health, Division of Medicine, University College London & Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, United Kingdom; 2 Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; 3 K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 4 Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; 5 Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Royal Free Hospital. University College London, London, United Kingdom; 6 Proteomics and Molecular Cell Dynamics, Center for Nephrology, School of Life and Medical Sciences, University College London, Royal Free Campus, Rowland Hill Street, London, United Kingdom; 7 Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway E-mail: giuseppe.mazza.12@ucl.ac.uk Background and Aims: Primary Sclerosing Cholangitis (PSC) is a chronic, cholestatic liver disease of unknown etiology characterized by periductular inflammation, fibrosis and strictures of bile ducts. There is no medical treatment available for PSC and identification of prognostic biomarkers are crucial for patient counseling and liver transplantation. The aim of this study was to evaluate differences in term of protein composition within fibrotic septa between PSC and other types of liver fibrosis. Methods: Formalin fixed paraffin embedded liver samples were collected from 21 explanted livers (Male 71%; Age 51.5±12.3; MELD 15.3 ± 11.2), including primary sclerosing cholangitis (PSC;11), primary biliary cirrhosis (PBC;5) and alcoholic liver diseases (ALD;5). The slices have been laser microdissected (LMD) by employing a Leica LMD system. Specific fibrotic area (e.g fibrotic bile ducts, portal-to-portal fibrotic septa) were dissected and analyzed with liquid chromatography electrospray tandem mass spectrometry. Furthermore, sub analysis was performed within the PSC patients that were stratified in accordance to the MELD score (cut off value >12). Results: A total of 215 proteins were detected of which 124 were identified within the three groups, including main collagens such as: Collagen α-1(I) chain, Collagen α-1(VI) chain, Collagen α-1(XIV) chain, Collagen α-2(I) chain, Collagen α-2(VI) chain, Collagen α-3(VI) chain. Interestingly, the PSC-PBC combined group showed the peculiar presence of proteoglycans such as: Biglycan, Lumican, Mimecan. Notably, exclusive proteins were detected for each disease (PSC 14, PBC 10, ALD 18). The PSC group was characterized bythe expression of: Transforming growth factor-β-induced protein ig-h3, Fibronectin and Tryptase peptides. However, Collagen IV-α and Pterin 4α were only detected into the ALC group Moreover, the analysis of the PSC group in accordance with the MELD score identified proteins that were exclusively (Betaine-homocysteine S-methyltransferase, Peroxiredoxin-2, Plastin-2) or preferentially (Retinal dehydrogenase 1, Heat shock 70 kDa protein-6 peptides) expressed in patients presenting MELD score <12. Conclusions: This is the first pilot study evaluating fibrotic septa protein composition by employing LMD-proteomic. Quantitative analyses of tissue and serum samples are required in order to validate these findings. However, this study opens new opportunities for the discovery of disease-specific biomarkers. PS093 GENOME-WIDE ASSOCIATION STUDY (GWAS) OF LIVER FIBROSIS PHENOTYPES IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) REVEALS COMMONGENETIC VARIATION INFLUENCING SERUM LEVELS OF LYSYL OXIDASE-LIKE-2 (LOXL2) P.R. Shea 1 , B. Eksteen 2 , G.M. Hirschfield 3 , M.L. Shiffman 4 , H.L. A. Janssen 5 , A.J. Montano-Loza 6 , Z. Goodman 7 , S.E. Kleinstein 1 , R.P. Myers 8 , G.M. Subramanian 8 , J.G. McHutchison 8 , C.L. Bowlus 9 , M. Manns 10 , R. Chapman 11 , C. Levy 12 , A.J. Muir 13 , D.B. Goldstein 1 . 1 Institute for Genomic Medicine, Columbia University, New York, United States; 2 University of Calgary, Calgary, Canada; 3 Center for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, United Kingdom; 4 Liver Institute of Virginia, Richmond, United States; 5 University of Toronto, Toronto; 6 University of Alberta, Edmonton, Canada; 7 Inova Fairfax Hospital, Falls Church; 8 Gilead Sciences, Inc., Foster City; 9 University of California Davis, Sacramento, United States; 10 Hannover Medical School, Hannover, Germany; 11 University of Oxford, Oxford, United Kingdom; 12 University of Miami, Miami; 13 Duke Clinical Research Institute, Durham, United States E-mail: rob.myers@gilead.com Background and Aims: LOXL2 plays a central role in fibrosis by catalyzing collagen cross-linkage and its serum levels (sLOXL2) correlate with fibrosis in PSC patients. In order to better understand the genetic factors that may influence PSC-related fibrosis, we performed a GWAS of common genetic variation among affected patients. Methods: We genotyped PSC patients enrolled in a phase 2b trial of simtuzumab, a monoclonal antibody directed against LOXL2. Genotyping was performed at over 5 million single nucleotide polymorphism (SNP) loci using the Illumina Omni5 high density BeadArray chip. GWAS were conducted using linear or logistic regression of fibrosis-related phenotypes; specifically, advanced fibrosis (Ishak stage 3–6), hepatic collagen content assessed by computer-assisted morphometry on picrosirius red-stained biopsies, and sLOXL2 (VIDAS ® , BioMérieux, Marcy L’Etoile, France). All analyses were Bonferroni adjusted and included age, gender, race, and BMI. Table: Top Results from GWAS for Fibrosis-Related Endpoints in PSC Patients Endpoint Top SNPs Chromosome Nearest Gene p-value sLOXL2 rs17636009 13q32 GPC5 3.416 × 10 -11 rs75294187 11q14 TYR 6.732 × 10 -09 rs7941097 11q14 TENM4 1.216 × 10 -08 rs28820314 14q24 ISM2 1.841 × 10 -08 rs74567273 15q14 C15orf53 1.945 × 10 -08 rs10145540 14q24 ISM2 2.122 × 10 -08 Hepatic collagen rs17035257 4q32 PDGFC 9.828 × 10 -08 * Advanced fibrosis rs35612858 1p32 C1orf87 2.469 × 10 -06 * *p-values do not exceed the threshold for significance. Results: 200 of 234 randomized patients (85%) consented to genetic analysis. The median age was 45 years, 64% were male, 86% were Caucasian, and 47% had ulcerative colitis. 53% of the patients had advanced fibrosis and the median (IQR) hepatic collagen and sLOXL2 levels were 4.5% (2.7–7.0%) and 102 pg/mL (70–145), respectively. We identified four genomic regions with associations with sLOXL2 that exceeded the genome-wide threshold for significance (Table). The strongest association (p = 3.42 × 10 -11 ) was with a region on chromosome 13q31 near the glypican 5 (GPC5) gene. SNPs near the ORAL PRESENTATIONS S180 Journal of Hepatology 2016 vol. 64 | S159–S182