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

• Published in: PLoS genetics 2020-04, Vol.16 (4), p.e1008629
• Main Authors: Emdin, Connor A, Haas, Mary E, Khera, Amit V, Aragam, Krishna, Chaffin, Mark, Klarin, Derek, Hindy, George, Jiang, Lan, Wei, Wei-Qi, Feng, Qiping, Karjalainen, Juha, Havulinna, Aki, Kiiskinen, Tuomo, Bick, Alexander, Ardissino, Diego, Wilson, James G, Schunkert, Heribert, McPherson, Ruth, Watkins, Hugh, Elosua, Roberto, Bown, Matthew J, Samani, Nilesh J, Baber, Usman, Erdmann, Jeanette, Gupta, Namrata, Danesh, John, Saleheen, Danish, Chang, Kyong-Mi, Vujkovic, Marijana, Voight, Ben, Damrauer, Scott, Lynch, Julie, Kaplan, David, Serper, Marina, Tsao, Philip, Mercader, Josep, Hanis, Craig, Daly, Mark, Denny, Joshua, Gabriel, Stacey, Kathiresan, Sekar
• Format: Article
• Language: English
• Subjects: Alanine; Alanine transaminase; Alkaline phosphatase; Alleles; Biology and Life Sciences; Biomedical research; Blood levels; Cardiology; Cholesterol; Cholesterol, LDL - blood; Cirrhosis; Computed tomography; Coronary Artery Disease - genetics; Datasets as Topic; Departments; Epidemiology; Fatty liver; Fatty Liver - blood; Fatty Liver - enzymology; Fatty Liver - genetics; Fatty Liver - prevention & control; Female; Funding; Gene frequency; Genetic Predisposition to Disease; Homozygote; Hospitals; Humans; Informatics; Liver - enzymology; Liver cirrhosis; Liver Cirrhosis - blood; Liver Cirrhosis - enzymology; Liver Cirrhosis - genetics; Liver Cirrhosis - prevention & control; Liver Cirrhosis, Alcoholic - blood; Liver Cirrhosis, Alcoholic - enzymology; Liver Cirrhosis, Alcoholic - genetics; Liver Cirrhosis, Alcoholic - prevention & control; Liver diseases; Loss of Function Mutation - genetics; Low density lipoprotein; Male; Medical schools; Medicine; Medicine and Health Sciences; Middle Aged; Mitochondria; Mitochondrial Proteins - genetics; Mutation, Missense - genetics; Oxidoreductases - genetics; Population genetics; Public health; Social Sciences; Transaminase
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008629

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.