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一种产生截短蛋白的HSD17B13变异体对慢性肝病的预防作用
A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease


Noura S. Abul-Husn ... 其他 • 2018.03.22
相关阅读
• 非酒精性脂肪性肝炎的新疗法

外显子测序发现慢性肝病防治新靶点

 

虞朝辉

浙江大学医学院附属第一医院

 

慢性肝病一直是威胁人类健康的主要疾病。尤其是近年来随着肥胖的流行,非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)患病率快速上升,在中国已经达到20%左右,在欧美发达国家更是高达30%以上,成为临床第一大慢性肝病1。NAFLD不仅是导致肝硬化甚至是肝癌等终末期肝病的重要原因,还显著增加糖尿病、冠心病、慢性肾病、结直肠肿瘤等肝外疾病的发病风险,构成日益严峻的公共卫生问题2

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摘要


背景

阐明导致慢性肝病的遗传因素可能会揭示新的治疗靶点。

 

方法

我们利用DiscovEHR这项人类遗传学研究中46,544名参与者的外显子组序列数据和电子健康档案,鉴定出了与血清谷丙氨基转移酶(ALT)和谷草氨基转移酶(AST)水平有关联的基因变异体。对于在另外三个队列(12,527人)中经重复验证的变异体,我们评估了它们与DiscovEHR研究参与者和两个独立队列(共37,173人)中慢性肝病临床诊断之间的关联,以及与2,391份人肝样本中肝病组织病理学严重程度之间的关联。

 

结果

HSD17B13编码肝脏脂滴蛋白17-β-羟基类固醇脱氢酶-13,它的一种剪接变异体(rs72613567:TA)与ALT和AST水平下降有关联(P值分别为4.2×10−12和6.2×10−10)。DiscovEHR研究的参与者中,该变异体与多种肝病风险降低相关。对于酒精性肝病,杂合子的患病风险降低了42%(95%置信区间[CI],20~58),纯合子的患病风险降低了53%(95% CI,3~77);对于非酒精性肝病,杂合子的患病风险降低了17%(95% CI,8~25),纯合子的患病风险降低了30%(95% CI,13~43);对于酒精性肝硬化,杂合子的患病风险降低了42%(95% CI,14~61),纯合子的患病风险降低了73%(95% CI,15~91);对于非酒精性肝硬化,杂合子的患病风险降低了26%(95% CI,7~40),纯合子的患病风险降低了49%(95% CI,15~69)。这些关联在两个独立队列中得到了确证。在人肝样本中,rs72613567:TA变异体与非酒精性脂肪性肝炎风险降低有关联,但是与脂肪变性风险无关。rs72613567:TA变异体减缓了与风险升高性PNPLA3 p.I148M等位基因有关的肝损伤,该变异基因的产物是一个酶活性降低的不稳定截短蛋白。

 

结论

HSD17B13的一种功能缺失变异体与慢性肝病风险降低以及由脂肪变性进展为脂肪性肝炎的风险降低均有关联(由再生元制药 [Regeneron Pharmaceuticals] 等资助)。





作者信息

Noura S. Abul-Husn, M.D., Ph.D., Xiping Cheng, M.D., Ph.D., Alexander H. Li, Ph.D., Yurong Xin, Ph.D., Claudia Schurmann, Ph.D., Panayiotis Stevis, Ph.D., Yashu Liu, Ph.D., Julia Kozlitina, Ph.D., Stefan Stender, M.D., Ph.D., G. Craig Wood, M.S., Ann N. Stepanchick, Ph.D., Matthew D. Still, Shane McCarthy, Ph.D., Colm O’Dushlaine, Ph.D., Jonathan S. Packer, B.S., Suganthi Balasubramanian, Ph.D., Nehal Gosalia, Ph.D., David Esopi, M.S., Sun Y. Kim, B.A., Semanti Mukherjee, Ph.D., Alexander E. Lopez, M.S., Erin D. Fuller, B.S., John Penn, M.S., Xin Chu, Ph.D., Jonathan Z. Luo, B.S., Uyenlinh L. Mirshahi, Ph.D., David J. Carey, Ph.D., Christopher D. Still, D.O., Michael D. Feldman, M.D., Ph.D., Aeron Small, B.A., Scott M. Damrauer, M.D., Daniel J. Rader, M.D., Brian Zambrowicz, Ph.D., William Olson, Ph.D., Andrew J. Murphy, Ph.D., Ingrid B. Borecki, Ph.D., Alan R. Shuldiner, M.D., Jeffrey G. Reid, Ph.D., John D. Overton, Ph.D., George D. Yancopoulos, M.D., Ph.D., Helen H. Hobbs, M.D., Jonathan C. Cohen, Ph.D., Omri Gottesman, M.D., Tanya M. Teslovich, Ph.D., Aris Baras, M.D., Tooraj Mirshahi, Ph.D., Jesper Gromada, Ph.D., D.M.Sc., and Frederick E. Dewey, M.D.
From the Regeneron Genetics Center (N.S.A.-H., A.H.L., C.S., S. McCarthy, C.O., J.S.P., S.B., N.G., S. Mukherjee, A.E.L., E.D.F., J.P., I.B.B., A.R.S., J.G.R., J.D.O., O.G., T.M.T., A.B., F.E.D.) and Regeneron Pharmaceuticals (X. Cheng, Y.X., P.S., Y.L., D.E., S.Y.K., B.Z., W.O., A.J.M., G.D.Y., J.G.), Tarrytown, NY; the University of Texas Southwestern Medical Center at Dallas, Dallas (J.K., S.S., H.H.H., J.C.C.); and Geisinger Health System, Danville (G.C.W., A.N.S., M.D.S., X. Chu, J.Z.L., U.L.M., D.J.C., C.D.S., T.M.), and Perelman School of Medicine, University of Pennsylvania, Philadelphia (M.D.F., A.S., S.M.D., D.J.R.) — both in Pennsylvania. Address reprint requests to Dr. Dewey at the Regeneron Genetics Center, 777 Old Saw Mill River Rd., Tarrytown, NY 10591, or at frederick.dewey@regeneron.com.

 

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