Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, New York.
Duke Molecular Physiology Institute, Duke University, Durham, North Carolina.
Gastroenterology. 2023 Mar;164(3):454-466. doi: 10.1053/j.gastro.2022.11.036. Epub 2022 Dec 7.
BACKGROUND & AIMS: Drug-induced liver injury (DILI) due to amoxicillin-clavulanate (AC) has been associated with HLA-A∗02:01, HLA-DRB1∗15:01, and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS).
Transcriptome-wide association study and genome-wide association study analyses were performed on 444 AC-DILI cases and 10,397 population-based controls of European descent. Associations were confirmed in a validation cohort (n = 133 cases and 17,836 population-based controls). Discovery and validation AC-DILI cases were also compared with 1358 and 403 non-AC-DILI cases.
Transcriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10), coding for an aminopeptidase involved in antigen presentation. The lead eQTL single nucleotide polymorphism, rs1363907 (G), was associated with AC-DILI risk in the discovery (odds ratio [OR], 1.68; 95% CI, 1.23-1.66; P = 1.7 × 10) and validation cohorts (OR, 1.2; 95% CI, 1.04-2.05; P = .03), following a recessive model. We also identified HLA-B∗15:18 as a novel AC-DILI risk factor in both discovery (OR, 4.19; 95% CI, 2.09-8.36; P = 4.9 × 10) and validation (OR, 7.78; 95% CI, 2.75-21.99; P = .0001) cohorts. GRS, incorporating rs1363907, rs2476601, HLA-B∗15:18, HLA-A∗02:01, and HLA-DRB1∗15:01, was highly predictive of AC-DILI risk when cases were analyzed against both general population and non-AC-DILI control cohorts. GRS was the most significant predictor in a regression model containing known AC-DILI clinical risk characteristics and significantly improved the predictive model.
We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B∗15:18. GRS based on the 5 risk variants may assist AC-DILI causality assessment and risk management.
阿莫西林克拉维酸（AC）引起的药物性肝损伤（DILI）与 HLA-A∗02:01、HLA-DRB1∗15:01 和 rs2476601 有关，rs2476601 是 PTPN22 中的错义变体。本研究旨在确定 AC-DILI 的新风险因素并构建遗传风险评分（GRS）。
对 444 例 AC-DILI 病例和 10397 名欧洲裔人群对照进行全转录组关联研究和全基因组关联研究分析。在验证队列（n=133 例病例和 17836 名人群对照）中确认了关联。发现和验证的 AC-DILI 病例还与 1358 例和 403 例非 AC-DILI 病例进行了比较。
全转录组关联研究显示，AC-DILI 风险与 ERAP2 肝表达降低显著相关（P=3.7×10），ERAP2 编码一种参与抗原呈递的氨肽酶。rs1363907（G）是主要的 eQTL 单核苷酸多态性，与发现（比值比[OR]，1.68；95%CI，1.23-1.66；P=1.7×10）和验证队列（OR，1.2；95%CI，1.04-2.05；P=0.03）中的 AC-DILI 风险相关，符合隐性模型。我们还在发现（OR，4.19；95%CI，2.09-8.36；P=4.9×10）和验证（OR，7.78；95%CI，2.75-21.99；P=0.0001）队列中确定了 HLA-B∗15:18 作为新的 AC-DILI 风险因素。纳入 rs1363907、rs2476601、HLA-B∗15:18、HLA-A∗02:01 和 HLA-DRB1∗15:01 的 GRS 对病例与一般人群和非 AC-DILI 对照队列进行分析时，对 AC-DILI 风险具有高度预测性。在包含已知 AC-DILI 临床风险特征的回归模型中，GRS 是最显著的预测因子，并且显著改善了预测模型。
我们确定了与 ERAP2 低表达和 HLA-B∗15:18 相关的 AC-DILI 风险的新关联。基于 5 个风险变体的 GRS 可能有助于 AC-DILI 的因果关系评估和风险管理。
