Department of Biostatistics and Bioinformatics, Duke University Medical Center, Duke University, Durham, NC.
Molecular Physiology Institute, Duke University Medical Center, Duke University, Durham, NC.
Hepatology. 2021 Jan;73(1):268-281. doi: 10.1002/hep.31258.
Trimethoprim (TMP)-sulfamethoxazole (SMX) is an important cause of idiosyncratic drug-induced liver injury (DILI), but its genetic risk factors are not well understood. This study investigated the relationship between variants in the human leukocyte antigen (HLA) class 1 and 2 genes and well-characterized cases of TMP-SMX DILI.
European American and African American persons with TMP-SMX DILI were compared with respective population controls. HLA sequencing was performed by Illumina MiSeq (Illumina, San Diego, CA) for cases. The HLA genotype imputation with attribute bagging program was used to impute HLA alleles for controls. The allele frequency difference between case patients and controls was tested by Fisher's exact tests for each ethnic group. For European Americans, multivariable logistic regression with Firth penalization was used to test the HLA allelic effect after adjusting for age and the top two principal components. Molecular docking was performed to assess HLA binding with TMP and SMX. The European American subset had 51 case patients and 12,156 controls, whereas the African American subset had 10 case patients and 5,439 controls. Four HLA alleles were significantly associated in the European American subset, with HLA-B14:01 ranking at the top (odds ratio, 9.20; 95% confidence interval, 3.16, 22.35; P = 0.0003) after covariate adjustment. All carriers of HLA-B14:01 with TMP-SMX DILI possessed HLA-C08:02, another significant allele (P = 0.0026). This pattern was supported by HLA-B14:01-HLA-C08:02 haplotype association (P = 1.33 × 10 ). For the African American patients, HLA-B35:01 had 2.8-fold higher frequency in case patients than in controls, with 5 of 10 patients carrying this allele. Molecular docking showed cysteine at position 67 in HLA-B14:01 and phenylalanine at position 67 in HLA-B35:01 to be the predictive binding sites for SMX metabolites.
HLA-B14:01 is associated with TMP-SMX DILI in European Americans, and HLA-B35:01 may be a potential genetic risk factor for African Americans.
甲氧苄啶（TMP）-磺胺甲恶唑（SMX）是导致药物性肝损伤（DILI）的重要原因，但遗传风险因素尚不清楚。本研究旨在探讨人类白细胞抗原（HLA）I 类和 II 类基因中的变异与 TMP-SMX DILI 确诊病例之间的关系。
对 TMP-SMX DILI 的欧洲裔和非裔美国人患者与各自的人群对照进行比较。通过 Illumina MiSeq（Illumina，圣地亚哥，加利福尼亚州）对病例进行 HLA 测序。使用属性袋装程序进行 HLA 基因型推断，以推断对照的 HLA 等位基因。使用 Fisher 确切检验测试每个种族组中病例患者和对照之间的等位基因频率差异。对于欧洲裔美国人，使用带有 Firth 惩罚的多变量逻辑回归在调整年龄和前两个主成分后测试 HLA 等位基因效应。进行分子对接以评估 TMP 和 SMX 与 HLA 的结合。欧洲裔美国人亚组有 51 例病例患者和 12156 例对照，而非裔美国人亚组有 10 例病例患者和 5439 例对照。在欧洲裔美国人亚组中，有 4 个 HLA 等位基因显著相关，HLA-B14:01 排名最高（比值比，9.20；95%置信区间，3.16，22.35；P=0.0003），在调整协变量后。所有携带 TMP-SMX DILI 的 HLA-B14:01 患者均携带另一个重要等位基因 HLA-C08:02（P=0.0026）。这种模式得到了 HLA-B14:01-HLA-C08:02 单体型关联的支持（P=1.33×10）。对于非裔美国人患者，病例患者中 HLA-B35:01 的频率比对照高 2.8 倍，其中 10 例患者中有 5 例携带该等位基因。分子对接显示 HLA-B14:01 中的半胱氨酸 67 位和 HLA-B35:01 中的苯丙氨酸 67 位是 SMX 代谢物的预测结合位点。
HLA-B14:01 与欧洲裔美国人的 TMP-SMX DILI 相关，HLA-B35:01 可能是非裔美国人的潜在遗传风险因素。
