Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.
Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.
复制标题
DOI：
10.1053/j.gastro.2011.04.001
复制
发表时间：
2011-07
期刊：
影响因子：
29.4
通讯作者：
International SAEC
中科院分区：
文献类型：
--
作者：
Lucena MI;Molokhia M;Shen Y;Urban TJ;Aithal GP;Andrade RJ;Day CP;Ruiz-Cabello F;Donaldson PT;Stephens C;Pirmohamed M;Romero-Gomez M;Navarro JM;Fontana RJ;Miller M;Groome M;Bondon-Guitton E;Conforti A;Stricker BH;Carvajal A;Ibanez L;Yue QY;Eichelbaum M;Floratos A;Pe'er I;Daly MJ;Goldstein DB;Dillon JF;Nelson MR;Watkins PB;Daly AK;Spanish DILI Registry;EUDRAGENE;DILIN;DILIGEN;International SAEC
药物性肝损伤（DILI），尤其是抗菌药物引起的药物性肝损伤，是严重肝病的重要原因。阿莫西林-克拉维酸（AC）是特异质DILI的主要原因，但对这种不良反应的遗传易感性知之甚少。我们使用来自201例白色欧洲和美国AC-DILI病例和532例人群对照的822，927个单核苷酸多态性（SNP）标记进行了全基因组关联研究，与遗传背景匹配。AC-DILI与主要组织相容性复合体中的许多位点相关。最强的效应是人类白细胞抗原（HLA）II类SNP（rs 9274407，P=4.8×10−14），与rs3135388相关，rs3135388是HLA-DRB 1 *1501-DQB 1 *0602的标签SNP，先前与AC-DILI相关。在rs3135388的条件下，rs 9274407仍然显著（P=1.1×10−4）。在I类区域（rs 2523822，P=1.8×10−10）观察到与HLA-A*0201相关的独立关联。最显著的I类和II类SNP显示统计学交互作用（P=0.0015）。高分辨率HLA基因分型（177例和219例对照）证实了HLA-A*0201（P=2×10−6）和HLA-DQB 1 *0602（P=5×10−10）的相关性，以及它们的相互作用（P=0.005）。此外，在具有名义显著性的HLA等位基因中观察到群体依赖性效应。在对自身免疫相关基因的分析中，PTPN 22基因中的rs 2476601与自身免疫相关（P=1.3×10−4）。I类和II类HLA基因型影响AC-DILI的易感性，表明适应性免疫应答在发病机制中的重要性。鉴定的HLA基因型将在AC-DILI的发病机制的研究中有用，但由于阳性预测值低，作为预测或诊断生物标志物的效用有限。
Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. We performed a genome-wide association study using 822,927 single-nucleotide polymorphism (SNP) markers from 201 White European and US cases of AC-DILI and 532 population controls, matched for genetic background. AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with a human leukocyte antigen (HLA) class II SNP (rs9274407, P=4.8×10−14), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10−4). An independent association was observed in the class I region (rs2523822, P=1.8×10−10), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=0.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10−6) and HLA-DQB1*0602 (P=5×10−10), and their interaction (P=0.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of auto-immunerelated genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10−4). Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI, but have limited utility as predictive or diagnostic biomarkers because of the low positive-predictive values.
登录
查看更多内容
影响因子：
13.5
作者：
Isabel Lucena, M.;Andrade, Raul J.;Avila, Susana
通讯作者：
Avila, Susana
影响因子：
13.5
作者：
Andrade, RJ;Lucena, MI;Hidalgo, R
通讯作者：
Hidalgo, R
影响因子：
168.9
作者：
Ashley, Euan A.;Butte, Atul J.;Wheeler, Matthew T.;Chen, Rong;Klein, Teri E.;Dewey, Frederick E.;Dudley, Joel T.;Ormond, Kelly E.;Pavlovic, Aleksandra;Morgan, Alexander A.;Pushkarev, Dmitry;Neff, Norma F.;Hudgins, Louanne;Gong, Li;Hodges, Laura M.;Berlin, Dorit S.;Thorn, Caroline F.;Sangkuhl, Katrin;Hebert, Joan M.;Woon, Mark;Sagreiya, Hersh;Whaley, Ryan;Knowles, Joshua W.;Chou, Michael F.;Thakuria, Joseph V.;Rosenbaum, Abraham M.;Zaranek, Alexander Wait;Church, George M.;Greely, Henry T.;Quake, Stephen R.;Altman, Russ B.
通讯作者：
Altman, Russ B.
影响因子：
4.2
作者：
Fontana RJ;Watkins PB;Bonkovsky HL;Chalasani N;Davern T;Serrano J;Rochon J;DILIN Study Group
通讯作者：
DILIN Study Group
稀有变体会产生整个基因组的关联。
影响因子：
9.8
作者：
Dickson SP;Wang K;Krantz I;Hakonarson H;Goldstein DB
通讯作者：
Goldstein DB