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2015 DEPARTMENT OF MEDICINE RESEARCH DAY Title of Poster: Genome-wide association analysis of liver fibrosis in mice identifies a novel fibrosis susceptibility locus on chromosome 13 Presenter: Simon W. Beaven Division: Digestive Diseases ☒Faculty ☐Fellow ☐Resident ☐Post-doc Research Fellow ☐Graduate Student ☐Medical Student ☐Other Principal Investigator/Mentor: Simon W. Beaven Co-Investigators: Iina Tuominen, Kevin Wroblewski, Mete Civelek, Kara Clerkin, Ashot Asaryan, Sara Haroutunian, Samuel French, Calvin Pan, Brian W. Parks, Margarete Mehrabian, Clara Magyar, Aldons J Lusis Thematic Poster Category: Infections, Injury and Repair, Inflammation, Host Defense, Immunology, Hemostasis and Atherosclerosis Abstract Background and Aims: Liver fibrosis, characterized by excess deposition of collagen within the hepatic parenchyma, is a multifactorial trait that develops in response to all types of chronic liver injury, including fatty liver (NAFLD/NASH), viral hepatitis (B & C), and alcohol abuse. The Hybrid Mouse Diversity Panel (HMDP) is a collection of 100 genetically distinct mouse strains that can be used to model diseases, including liver fibrosis, for genome-wide association analysis. Our aim was to characterize the genetic background of liver fibrosis in the HMDP strains subjected to chemicallyinduced liver damage. Methods: Chronic liver injury was induced by serial carbon tetrachloride (CCl 4) injections twice weekly for six weeks. A total of 437 CCl4-treated (1-9 mice per strain) and 256 vehicle-treated (1-7 per strain) mice were harvested for liver histology and gene expression. Liver sections were stained with picrosirius red as a specific marker of pathologic fibrillar collagen. Slides were digitally scanned at 20x magnification. Using Definiens Tissue Studio, we designed an algorithm to quantify fibrosis as the collagen proportionate area % (CPA%) of the whole section, excluding normal vascular wall and liver capsular collagen. This algorithm was designed in conjunction with a pathologist at UCLA. The association of 208,514 single nucleotide polymorphisms (SNPs) to CPA% was analyzed using a linear mixed model that has previously been shown to allow correction for population structure, which is extensive in mice. Liver gene expression was studied with quantitative PCR. Results: Variation in fibrosis was broad between resistant and susceptible mouse strains, with estimated heritability of 39%. The mean CPA% ranged from 0.28 to 3.33 in the CCl 4-treated mice. A locus on chromosome 13, with a peak SNP identified as rs36783842, reached genome-wide significance in the association analysis (P=1.78 x 10-7). Conditioning on this SNP identified a 3.5 Mb region containing 17 protein-coding genes that where further analyzed for differences in liver expression. Of the twelve genes that were expressed in the liver, only one gene, Stard3nl, was significantly downregulated in the ten most fibrosis-susceptible strains, compared with all the other strains (P=0.0002 in CCl4-treated mice). Conclusions: This is the largest genome-wide association study of liver fibrosis in mice. By using CPA% as a robust quantitative measure, we identified a novel pro-fibrotic locus that influences the differences in fibrosis susceptibility in the 100 mouse strains of the HMDP. Ongoing work aims to test the causative role of Stard3nl in fibrosis. Our results also demonstrate significant heritability of the trait, define automated CPA% as an unbiased quantitative measure for fibrosis, and provide a road map for rational strain selection when testing anti-fibrotic drugs.