Analyzing 5770 all-cause cirrhosis cases and 572,850 controls from seven cohorts, we identify a missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene ( MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.88, p=2.1*10 −8 ). 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 (−0.012 SD, 1.4*10 −8 ), alkaline phosphatase (−0.019 SD, 6.6*10 −9 ), total cholesterol (−0.037 SD, p=1*10 −18 ) and LDL cholesterol (−0.035 SD, p=7.3*10 −16 ). Carriers of rare protein-truncating variants in MARC1 had lower liver enzyme levels, cholesterol levels, and reduced odds of liver disease (OR 0.19, p= 0.04) suggesting that deficiency of the MARC1 enzyme protects against cirrhosis.

A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease