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胚系突变与肝脏疾病的保护。

Germline Mutations in and Protection against Liver Disease.

机构信息

From the Regeneron Genetics Center (N.V., M.E.H., J.B.N., O.A.S., M.K., P.A., T.D., G.H., J.B., T.P., L.M., K.W., J. Mbatchou, M.J., M.L., S.B., J.D.O., J.G.R., A.E., M.N.C., G.R.A., M.A.R.F., J. Marchini, H.M.K., K.K., A.R.S., G.D.G., A.E.L., A.B., L.A.L.), Regeneron Pharmaceuticals (M.G., L.P., P.P., J.R.W., B.Z., A.J.M., E.S., V.G., M.S., G.D.Y.), Tarrytown, NY; Indiana University School of Medicine, Indianapolis (C.L.); the Department of Clinical Sciences Malmö, Lund University, and the Department of Emergency and Internal Medicine, Skåne University Hospital - both in Malmö, Sweden (S.E., O.M.); and the Department of Molecular and Functional Genomics, Geisinger Health System, Danville (D.J.C., C.D.S., T.M.), and the Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.) - both in Pennsylvania.

出版信息

N Engl J Med. 2022 Jul 28;387(4):332-344. doi: 10.1056/NEJMoa2117872.

DOI:10.1056/NEJMoa2117872

PMID:35939579

Abstract

BACKGROUND

Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets.

METHODS

We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations.

RESULTS

The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in , , , and were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in , which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 U per liter; 95% confidence interval [CI], -1.66 to -0.83; P = 4.8×10) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P = 9.9×10). Rare coding variants in were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, small interfering RNA knockdown prevented the buildup of large lipid droplets.

CONCLUSIONS

Rare germline mutations in conferred substantial protection from liver disease. (Funded by Regeneron Pharmaceuticals.).

摘要

背景

对数十万人进行外显子组测序可能会识别出与人类疾病（如肝硬化）保护相关的罕见蛋白质编码遗传变异，为发现新的治疗靶点提供策略。

方法

我们进行了多阶段外显子组测序和遗传关联分析，以鉴定与肝脏表型相关的罕见蛋白质编码变异的基因。我们进行了体外实验以进一步表征关联。

结果

多阶段分析涉及 542904 名具有可用的肝转氨酶水平数据的人、24944 名患有各种类型肝病的患者和 490636 名无肝病的对照。我们发现，编码在肝脂滴中发现的结构蛋白的基因中的罕见编码变异与转氨酶水平升高和肝病风险增加有关。我们还发现，编码结构蛋白的基因中的变异具有保护作用。在编码基因中罕见的预测功能丧失变异加错义变异的负担（共同携带者频率为 0.7%）与丙氨酸氨基转移酶水平降低有关（每个等位基因的β值，-1.24 U/L；95%置信区间[CI]，-1.66 至-0.83；P=4.8×10），并且任何原因导致的肝病的几率降低 33%（每个等位基因的优势比，0.67；95%CI，0.57 至 0.79；P=9.9×10）。编码基因中的罕见编码变异与不同潜在原因和不同严重程度的肝病风险降低有关，包括任何原因引起的肝硬化（每个等位基因的优势比，0.50；95%CI，0.36 至 0.70）。在接受减肥手术的 3599 名患者中，编码基因中的罕见编码变异与非酒精性脂肪性肝病活动评分降低有关（每个单位评分的等位基因β值，-0.98；95%CI，-1.54 至-0.41[评分范围为 0 至 8，分数越高表示疾病越严重]）。在油酸挑战的人肝癌细胞系中，小干扰 RNA 敲低可防止大脂滴的堆积。