Abul-Husn Noura S, Cheng Xiping, Li Alexander H, Xin Yurong, Schurmann Claudia, Stevis Panayiotis, Liu Yashu, Kozlitina Julia, Stender Stefan, Wood G Craig, Stepanchick Ann N, Still Matthew D, McCarthy Shane, O'Dushlaine Colm, Packer Jonathan S, Balasubramanian Suganthi, Gosalia Nehal, Esopi David, Kim Sun Y, Mukherjee Semanti, Lopez Alexander E, Fuller Erin D, Penn John, Chu Xin, Luo Jonathan Z, Mirshahi Uyenlinh L, Carey David J, Still Christopher D, Feldman Michael D, Small Aeron, Damrauer Scott M, Rader Daniel J, Zambrowicz Brian, Olson William, Murphy Andrew J, Borecki Ingrid B, Shuldiner Alan R, Reid Jeffrey G, Overton John D, Yancopoulos George D, Hobbs Helen H, Cohen Jonathan C, Gottesman Omri, Teslovich Tanya M, Baras Aris, Mirshahi Tooraj, Gromada Jesper, Dewey Frederick E
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.
N Engl J Med. 2018 Mar 22;378(12):1096-1106. doi: 10.1056/NEJMoa1712191.
Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets.
We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples.
A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10) and AST (P=6.2×10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity.
A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.).
阐明慢性肝病的遗传因素可能会揭示新的治疗靶点。
我们使用了来自DiscovEHR人类遗传学研究中46544名参与者的外显子组序列数据和电子健康记录，以识别与血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平相关的基因变异。在另外三个队列（12527人）中得到复制的变异，在DiscovEHR研究参与者和两个独立队列（共37173人）中评估其与慢性肝病临床诊断的关联，并在2391份人类肝脏样本中评估其与肝病组织病理学严重程度的关联。
编码肝脏脂质滴蛋白羟基类固醇17-β脱氢酶13的HSD17B13中的一个剪接变异（rs72613567:TA）与ALT水平降低（P=4.2×10）和AST水平降低（P=6.2×10）相关。在DiscovEHR研究参与者中，该变异与酒精性肝病风险降低相关（杂合子中降低42%[95%置信区间{CI}，20%至58%]，纯合子中降低53%[95%CI，3%至77%]）、非酒精性肝病（杂合子中降低17%[95%CI,8%至25%]，纯合子中降低30%[95%CI,13%至43%]）、酒精性肝硬化（杂合子中降低42%[95%CI,14%至61%]，纯合子中降低73%[95%CI,15%至91%]）以及非酒精性肝硬化（杂合子中降低26%[95%CI,7%至40%]，纯合子中降低49%[95%CI,15%至69%]）相关。在两个独立队列中证实了这些关联关系。rs72613567:TA变异与人类肝脏样本中非酒精性脂肪性肝炎风险降低相关，但与脂肪变性无关；rs72613567:TA变异减轻了与增加风险的PNPLA3 p.I148M等位基因相关的肝损伤，并导致一种不稳定且截短且酶活性降低的蛋白质。
HSD17B13中的一个功能丧失变异与慢性肝病风险降低以及从脂肪变性进展为脂肪性肝炎的风险降低相关。（由再生元制药公司等资助。）
