HLA 基因型与抗甲状腺药物诱导的粒细胞缺乏症的关联：药物基因组学研究的系统评价和荟萃分析。
Associations of HLA genotypes with antithyroid drug-induced agranulocytosis: A systematic review and meta-analysis of pharmacogenomics studies.
机构信息
Department of Dermatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
出版信息
Br J Clin Pharmacol. 2019 Sep;85(9):1878-1887. doi: 10.1111/bcp.13989. Epub 2019 Jul 7.
AIMS
Antithyroid drug (ATD)-induced agranulocytosis is a life-threatening adverse drug reaction. Previous studies suggested that HLA genotypes may play an important role in ATD-induced agranulocytosis. To examine the associations between HLA genotypes and ATD-induced agranulocytosis, we conducted a systematic review and meta-analysis of pharmacogenomics studies.
METHODS
We searched the MEDLINE, Embase and CENTRAL databases on 16 June 2018 for case-control studies on the associations between HLA genotypes with ATD-induced agranulocytosis. The Newcastle-Ottawa scale was used to evaluate the risk of bias of included studies. We conducted random-effects model meta-analysis to obtain pooled odds ratios (ORs) with 95% confidence intervals (CIs) to determine the associations between HLA genotypes and ATD-induced agranulocytosis.
RESULTS
We included 5 studies with 142 ATD-induced agranulocytosis cases, 1529 matched ATD-tolerant controls and 5945 healthy controls. The risk of bias of included studies was generally low. ATD-induced agranulocytosis was associated with HLA-B27:05 (OR 10.97; 95% CI 0.75-159.99), HLA-B38:02 (OR 19.85; 95% CI 7.94-49.57) and HLA-DRB108:03 (OR 5.29; 95% CI 3.44-8.14). After excluding propylthiouracil, the associations of ATD-induced agranulocytosis with HLA-B27:05 and HLA-B38:02 were strengthened (OR being 20.61 (95% CI 5.21-81.58) and 40.59 (95% CI 13.24-124.47), respectively). The associations of ATD-induced agranulocytosis with HLA-B27:05, HLA-B38:02 and HLA-DRB108:03 remained significant when compared to population controls (OR being 7.37 (95% CI 3.86-14.07), 36.43 (95% CI 12.80-103.70) and 5.42 (95% CI 2.36-12.47), respectively). HLA-B27:05, HLA-B38:02, and HLA-DRB1*08:03 alleles were associated with ATD-induced agranulocytosis, especially in carbimazole/methimazole-induced agranulocytosis.
CONCLUSIONS
HLA-B27:05, HLA-B38:02 and HLA-DRB1*08:03 alleles were associated with ATD-induced agranulocytosis, especially in carbimazole/methimazole-induced agranulocytosis.
目的
抗甲状腺药物（ATD）诱导的粒细胞缺乏症是一种危及生命的药物不良反应。先前的研究表明，HLA 基因型可能在 ATD 诱导的粒细胞缺乏症中发挥重要作用。为了研究 HLA 基因型与 ATD 诱导的粒细胞缺乏症之间的关系，我们对药物基因组学研究进行了系统评价和荟萃分析。
方法
我们于 2018 年 6 月 16 日在 MEDLINE、Embase 和 CENTRAL 数据库中搜索了关于 HLA 基因型与 ATD 诱导的粒细胞缺乏症之间关联的病例对照研究。我们使用纽卡斯尔-渥太华量表评估纳入研究的偏倚风险。我们进行了随机效应模型荟萃分析，以获得合并优势比（OR）及其 95%置信区间（CI），以确定 HLA 基因型与 ATD 诱导的粒细胞缺乏症之间的关系。
结果
我们纳入了 5 项研究，共纳入 142 例 ATD 诱导的粒细胞缺乏症病例、1529 例匹配的 ATD 耐受对照和 5945 例健康对照。纳入研究的偏倚风险普遍较低。ATD 诱导的粒细胞缺乏症与 HLA-B27:05（OR 10.97；95%CI 0.75-159.99）、HLA-B38:02（OR 19.85；95%CI 7.94-49.57）和 HLA-DRB108:03（OR 5.29；95%CI 3.44-8.14）相关。排除丙硫氧嘧啶后，ATD 诱导的粒细胞缺乏症与 HLA-B27:05 和 HLA-B38:02 的相关性增强（OR 分别为 20.61（95%CI 5.21-81.58）和 40.59（95%CI 13.24-124.47））。与人群对照相比，ATD 诱导的粒细胞缺乏症与 HLA-B27:05、HLA-B38:02 和 HLA-DRB108:03 的相关性仍然显著（OR 分别为 7.37（95%CI 3.86-14.07）、36.43（95%CI 12.80-103.70）和 5.42（95%CI 2.36-12.47））。HLA-B27:05、HLA-B38:02 和 HLA-DRB1*08:03 等位基因与 ATD 诱导的粒细胞缺乏症相关，尤其是在卡比马唑/甲巯咪唑诱导的粒细胞缺乏症中。
结论
HLA-B27:05、HLA-B38:02 和 HLA-DRB1*08:03 等位基因与 ATD 诱导的粒细胞缺乏症相关，尤其是在卡比马唑/甲巯咪唑诱导的粒细胞缺乏症中。
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