Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS Genet. 2020 Apr 13;16(4):e1008629. doi: 10.1371/journal.pgen.1008629. eCollection 2020 Apr.
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 = 2.310-11). 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, 3.710-43), alkaline phosphatase (-0.025 SD, 1.210-37), total cholesterol (-0.030 SD, p = 1.910-36) 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.
我们分析了来自 8 个队列的 12361 例全因肝硬化病例和 790095 例对照，鉴定出线粒体酰胺氧化还原酶 1 基因（MARC1 p.A165T）中的一个常见错义变异，该变异与全因肝硬化的保护作用相关（OR 0.91，p=2.310-11）。该变异还与 CT 成像上的肝脂肪水平降低以及医生诊断的脂肪肝和丙氨酸转氨酶（-0.025 SD，3.710-43）、碱性磷酸酶（-0.025 SD，1.210-37）、总胆固醇（-0.030 SD，p=1.910-36）和 LDL 胆固醇（-0.027 SD，p=5.1*10-30）水平降低相关。我们还鉴定出一系列 MARC1 等位基因（低频错义 p.M187K 和罕见的蛋白截断 p.R200Ter），这些等位基因也与胆固醇水平降低、肝酶水平降低和肝硬化风险降低相关（238 名 R200Ter 携带者中无 1 例肝硬化病例，而 759027 名非携带者中有 17046 例肝硬化病例，p=0.04），提示 MARC1 酶缺乏可能降低血液胆固醇水平并预防肝硬化。
