Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study.
Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study.
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DOI：
10.1053/j.gastro.2016.12.016
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发表时间：
2017-04
期刊：
影响因子：
29.4
通讯作者：
International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium
中科院分区：
文献类型：
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作者：
Nicoletti P;Aithal GP;Bjornsson ES;Andrade RJ;Sawle A;Arrese M;Barnhart HX;Bondon-Guitton E;Hayashi PH;Bessone F;Carvajal A;Cascorbi I;Cirulli ET;Chalasani N;Conforti A;Coulthard SA;Daly MJ;Day CP;Dillon JF;Fontana RJ;Grove JI;Hallberg P;Hernández N;Ibáñez L;Kullak-Ublick GA;Laitinen T;Larrey D;Lucena MI;Maitland-van der Zee AH;Martin JH;Molokhia M;Pirmohamed M;Powell EE;Qin S;Serrano J;Stephens C;Stolz A;Wadelius M;Watkins PB;Floratos A;Shen Y;Nelson MR;Urban TJ;Daly AK;International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium
我们进行了一项全基因组关联研究（GWAS），以确定药物性肝损伤（DILI）的遗传风险因素，这些药物来自以前没有报道过遗传风险因素的许可药物。我们对862名DILI患者和10588名人群匹配的对照者进行了GWAS。第一组病例于2009年5月之前在欧洲（n=137）或美国（n=274）招募。第二组病例是从2009年5月至2013年5月在欧洲、美国和南美洲进行的国际合作研究中确定的。对于GWAS，我们仅纳入了与特定药物（但不包括氟氯西林或阿莫西林-克拉维酸）相关的欧洲血统病例。我们使用所有受试者的DNA样本分析人类白细胞抗原（HLA）基因和单核苷酸多态性（SNP）。在发现分析结束后，我们使用来自283名诊断为与各种药物相关的DILI的欧洲患者的数据验证了我们的发现。我们将DILI与rs 114577328（代表A*33：01 HLA I类等位基因;比值比[OR]，2.7; 95%CI，1.9-3.8; P=2.4×10−8）和2号染色体上的rs72631567（OR，2.0; 95%CI，1.6-2.5; P=9.7×10−9）相关联。与A*33：01的相关性由特比萘芬、非诺贝特和噻氯匹定相关DILI的大效应介导。2号染色体上的变异与多种药物的DILI相关。进一步的表型分析表明，对于胆汁淤积性和混合性DILI，DILI和A*33：01之间的相关性在全基因组范围内是显著的，但对于肝细胞DILI则不显著; 2号染色体上的多态性与胆汁淤积性和混合性DILI以及肝细胞DILI相关。我们发现rs 28521457（在LRBA基因内）仅与肝细胞DILI相关（OR，2.1; 95%CI，1.6-2.7; P=4.8×10−9）。我们没有将任何特定的药物类别与遗传多态性相关联，除了他汀类药物相关的DILI，其与18号染色体上的rs 116561224相关（OR=5.4; 95%CI，3.0-9.5; P=7.1×10−9）。我们验证了A*33：01特比萘芬和舍曲林诱导的DILI之间的关联。我们无法验证DILI与rs72631567、rs 28521457或rs 116561224之间的关联。在一个欧洲血统的DILI患者的GWAS中，我们将HLA-A*33：01与特比萘芬、可能的非诺贝特和噻氯匹定引起的DILI相关联。我们确定了与他汀类药物DILI相关的多态性，以及2个非药物特异性风险因素。
We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. We performed a GWAS of 862 persons with DILI and 10588 population-matched controls. The first set of cases was recruited prior to May 2009 in Europe (n=137) or the USA (n=274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the USA and South America. For the GWAS, we included only cases of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze human leukocyte antigen (HLA) genes and single nucleotide polymorphisms (SNPs). After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% CI, 1.9–3.8; P=2.4×10−8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6–2.5; P=9.7×10−9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant, genome wide, for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the LRBA gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6–2.7; P=4.8×10−9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR=5.4; 95% CI, 3.0–9.5; P=7.1×10−9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non–drug-specific risk factors.