Abstract
Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10−11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10−43), alkaline phosphatase (-0.025 SD, 1.2*10−37), total cholesterol (-0.030 SD, p = 1.9*10−36) and LDL cholesterol (-0.027 SD, p = 5.1*10−30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.
Highlights
Discovery of novel protective human genetic variation can identify new therapeutic targets for treatment of a given disease [1]
We analyze twelve thousand individuals with cirrhosis and identify a common missense variant in a gene called MARC1 that protects against cirrhosis
We identify an additional two lowfrequency coding variants in MARC1 that are associated with lower cholesterol levels, lower liver enzyme levels and protection from cirrhosis
Summary
Discovery of novel protective human genetic variation can identify new therapeutic targets for treatment of a given disease [1]. Identification of novel protective variants for cirrhosis may allow for the identification of new therapeutic targets with enhanced likelihood of successful clinical development for treatment of cirrhosis. Cirrhosis is often considered to be the final stage of distinct pathogenic processes including excess alcohol consumption, viral infection and fatty liver secondary to obesity [8]. Analyses of these separate processes have identified similar genetic determinants. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
