Genetic variants associated with ALT elevation from therapeutic acetaminophen.
Genetic variants associated with ALT elevation from therapeutic acetaminophen.
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DOI：
10.1080/15563650.2022.2117053
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发表时间：
2022-11
影响因子：
3.3
通讯作者：
Heard, Kennon J.
中科院分区：
文献类型：
--
作者：
Monte, Andrew A.;Mackenzie, Ian Arriaga;Pattee, Jack;Kaiser, Sasha;Willems, Emileigh;Rumack, Barry;Reynolds, Kate M.;Dart, Richard C.;Heard, Kennon J.
几项研究表明，遗传变异与过量服用对乙酰氨基酚引起的肝损伤（DILI）相关。尚未对治疗给药期间与对乙酰氨基酚诱导的丙氨酸转氨酶升高相关的遗传变异进行检查。我们对摄入治疗剂量4克对乙酰氨基酚长达16天的患者进行了遗传分析。我们使用Illumina多种族全球阵列2检查了先前与对乙酰氨基酚代谢或免疫介导的DILI发展有关的20个基因。使用TOPMed对常染色体进行比对和插补。通过使用连锁不平衡（LD）修剪变体和aSPU R包中的自适应幂分数总和（aSPU）检验单独测试每个基因，进行候选基因区域分析。治疗期间测量的最高ALT（最大ALT）用作结局。192名服用治疗性APAP的受试者被纳入遗传分析。136例（70.8%）为女性，133例（69.2%）为白人，中位年龄为34岁（IQR：26，46）。年龄> 50岁是与ALT最大升高相关的唯一临床因素。SULT1E1（负责磺基转移酶家族1E成员1酶产生的基因）的变异与最大ALT相关。没有单一的变异驱动这种关联，而是这种关联是由于基因内许多变异的累加效应。在该队列中，没有其他基因与最大ALT升高相关。在该队列中，治疗剂量的对乙酰氨基酚诱导的ALT升高与大多数与对乙酰氨基酚代谢或免疫诱导的DILI相关的基因变异无关。SULT1E1多态性在醋氨酚引起的ALT升高中的作用有待进一步研究。
Several studies have suggested genetic variants associated with acetaminophen induced liver injury (DILI) following overdose. Genetic variation associated with acetaminophen induced alanine aminotransferase elevation during therapeutic dosing has not been examined. We performed genetic analyses on patients that ingested therapeutic doses of 4 grams of acetaminophen for up to 16 days. We examined 20 genes previously implicated in the metabolism of acetaminophen or the development of immune mediated DILI using the Illumina Multi-Ethnic Global Array 2. Autosomes were aligned and imputed using TOPMed. A candidate gene region analysis was performed by testing each gene individually using linkage disequilibrium (LD) pruned variants with the adaptive sum of powered scores (aSPU) test from the aSPU R package. The highest measured ALT during therapy, the maximum ALT, was used as the outcome. 192 subjects taking therapeutic APAP were included in the genetic analysis. 136 (70.8%) were female, 133 (69.2%) were Caucasian race, and the median age was 34 years (IQR: 26, 46). Age > than 50 years was the only clinical factor associated with maximum ALT increase. Variants in SULT1E1, the gene responsible for Sulfotransferase Family 1E Member 1 enzyme production, was associated with maximum ALT. No single variant drove this association, but rather the association was due to the additive effects of numerous variants within the gene. No other genes were associated with maximum ALT increase in this cohort. Acetaminophen induced ALT elevation at therapeutic doses was not associated with variation in most genes associated with acetaminophen metabolism or immune induced DILI in this cohort. The role of SULT1E1 polymorphism in acetaminophen induced elevated ALT needs further examination.
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影响因子：
5.8
作者：
Gogarten, Stephanie M.;Sofer, Tamar;Conomos, Matthew P.
通讯作者：
Conomos, Matthew P.
影响因子：
2
作者：
Levano KS;Jaramillo-Valverde L;Tarazona DD;Sanchez C;Capristano S;Vásquez-Loarte T;Solari L;Mendoza-Ticona A;Soto A;Rojas C;Zegarra-Chapoñan R;Guio H
通讯作者：
Guio H
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
DOI：
10.1124/jpet.112.202010
发表时间：
2013-05-01
影响因子：
3.5
作者：
Court, Michael H.;Freytsis, Marina;Lee, William M.
通讯作者：
Lee, William M.
疾病中的膜联蛋白 A11
影响因子：
5
作者：
Wang, Jiasheng;Guo, Chunmei;Greenaway, Frederick T.
通讯作者：
Greenaway, Frederick T.