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

• DOI: 10.1371/journal.pgen.1008629
• Publication Date: 2020-04-13T17:33:43Z
• Authors: Connor A. Emdin; Mary E. Haas; Amit V. Khera; Krishna Aragam; Mark Chaffin; Derek Klarin; George Hindy; Lan Jiang; Wei-Qi Wei; Qiping Feng; Juha Karjalainen; Aki Havulinna; Tuomo Kiiskinen; Alexander Bick; Diego Ardissino; James G. Wilson; Heribert Schunkert; Ruth McPherson; Hugh Watkins; Roberto Elosua; Matthew J. Bown; Nilesh J. Samani; Usman Baber; Jeanette Erdmann; Namrata Gupta; John Danesh; Danish Saleheen; Kyong-Mi Chang; Marijana Vujkovic; Ben Voight; Scott Damrauer; Julie Lynch; David Kaplan; Marina Serper; Philip Tsao; ; Josep Mercader; Craig Hanis; Mark Daly; Joshua Denny; Stacey Gabriel; Sekar Kathiresan
• Keywords: Liver disease

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 (OR 0.91, p = 2.3*10−11). This same also lower levels of hepatic fat on computed tomographic imaging odds physician-diagnosed fatty liver as well blood alanine transaminase (-0.025 SD, 3.7*10−43), alkaline phosphatase 1.2*10−37), total cholesterol (-0.030 1.9*10−36) LDL (-0.027 5.1*10−30) levels. We identified series additional MARC1 alleles (low-frequency p.M187K rare protein-truncating p.R200Ter) associated levels, enzyme reduced risk (0 for 238 R200Ter carriers versus 17,046 among 759,027 non-carriers, 0.04) suggesting deficiency may protect against cirrhosis.