Nicoletti Paola, Aithal Guruprasad P, Bjornsson Einar S, Andrade Raul J, Sawle Ashley, Arrese Marco, Barnhart Huiman X, Bondon-Guitton Emmanuelle, Hayashi Paul H, Bessone Fernando, Carvajal Alfonso, Cascorbi Ingolf, Cirulli Elizabeth T, Chalasani Naga, Conforti Anita, Coulthard Sally A, Daly Mark J, Day Christopher P, Dillon John F, Fontana Robert J, Grove Jane I, Hallberg Pär, Hernández Nelia, Ibáñez Luisa, Kullak-Ublick Gerd A, Laitinen Tarja, Larrey Dominique, Lucena M Isabel, Maitland-van der Zee Anke H, Martin Jennifer H, Molokhia Mariam, Pirmohamed Munir, Powell Elizabeth E, Qin Shengying, Serrano Jose, Stephens Camilla, Stolz Andrew, Wadelius Mia, Watkins Paul B, Floratos Aris, Shen Yufeng, Nelson Matthew R, Urban Thomas J, Daly Ann K
Department of Systems Biology, Columbia University, New York, New York.
National Institute for Health Research, Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospital, National Health Service Trust, and University of Nottingham, Nottingham, United Kingdom.
Gastroenterology. 2017 Apr;152(5):1078-1089. doi: 10.1053/j.gastro.2016.12.016. Epub 2016 Dec 30.
BACKGROUND & AIMS: 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 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. 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 A33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10). The association with A33:01 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 A33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10). 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). We validated the association between A33:01 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.
我们开展了一项全基因组关联研究（GWAS），以确定来自未报告过遗传风险因素的已获许可药物所致药物性肝损伤（DILI）的遗传风险因素。
我们对862例DILI患者和10588例人群匹配对照进行了GWAS。第一组病例于2009年5月前在欧洲（n = 137）和美国（n = 274）招募。第二组病例是从2009年5月至2013年期间在欧洲、美国和南美洲开展的国际合作研究中确定的。对于GWAS，我们仅纳入与特定药物（但不包括氟氯西林或阿莫西林 - 克拉维酸）相关的欧洲血统患者的病例。我们使用所有受试者的DNA样本分析HLA基因和单核苷酸多态性。在发现分析结束后，我们使用来自283例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。
我们发现DILI与rs114577328（HLA I类等位基因A33:01的替代物；比值比[OR]，2.7；95%置信区间[CI]，1.9 - 3.8；P = 2.4×10）以及2号染色体上的rs72631567（OR，2.0；95% CI，1.6 - 2.5；P = 9.7×10）相关。与A33:01的关联是由特比萘芬、非诺贝特和噻氯匹定相关的DILI的显著效应介导的。2号染色体上的变异与多种药物所致的DILI相关。进一步的表型分析表明，DILI与A33:01之间的关联在胆汁淤积性和混合型DILI中全基因组范围内显著，但在肝细胞性DILI中不显著；2号染色体上的多态性与胆汁淤积性和混合型DILI以及肝细胞性DILI均相关。我们发现rs28521457（在含脂多糖反应性囊泡运输、beach和锚定蛋白的基因内）仅与肝细胞性DILI相关（OR，2.1；95% CI，1.6 - 2.7；P = 4.8×10）。除了他汀类药物相关的DILI与18号染色体上的rs116561224相关（OR，5.4；95% CI，3.0 - 9.5；P = 7.1×10）外，我们未发现任何特定药物类别与基因多态性相关。我们验证了A33:01与特比萘芬和舍曲林所致DILI之间的关联。我们未能验证DILI与rs72631567、rs28521457或rs116561224之间的关联。
在一项针对欧洲血统DILI患者的GWAS中，我们发现HLA - A*33:01与特比萘芬以及可能与非诺贝特和噻氯匹定所致的DILI相关。我们确定了似乎与他汀类药物所致DILI相关的多态性，以及2个非药物特异性风险因素。
