A Screening Test for HLA-B*15:02 in a Large United States Patient Cohort Identifies Broader Risk of Carbamazepine-Induced Adverse Events
A Screening Test for HLA-B*15:02 in a Large United States Patient Cohort Identifies Broader Risk of Carbamazepine-Induced Adverse Events
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DOI：
10.3389/fphar.2019.00149
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发表时间：
2019-03-26
影响因子：
5.6
通讯作者：
Moreno, Tanya A.
中科院分区：
文献类型：
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作者：
Fang, Hua;Xu, Xiequn;Moreno, Tanya A.
目的：HLA-B*15:02 与接受卡马西平 (CBZ) 和结构相关药物治疗的患者中危及生命的严重皮肤过敏反应密切相关。 FDA 批准的标签建议亚洲血统患者在 CBZ 治疗前进行 HLA-B*15:02 筛查。在本研究中，我们的目的是 (a) 确定筛查 HLA-B*15:02 的直接方法，以及 (b) 评估大量美国患者的患病率。方法：通过挖掘公共数据来确定候选遗传标记。通过将 SNP 结果与高分辨率 HLA 分型进行比较，对 28,897 名个体进行了关联测试。对 130,460 名个体的去识别 SNP 和种族数据进行回顾性分析，以评估 HLA-B*15:02 在美国的种族分布。结果：28,897 名美国个体显示 HLA-B*15:02 与 rs144012689 次等位基因之间 100% 一致性（100% 敏感性/99.97% 特异性）。对 160 名阳性个体（其中 66 名具有医生报告的种族）的回顾性分析主要包括 28 名亚洲人 (42%)、15 名非裔美国人 (22%)、11 名白种人 (17%)、2 名西班牙裔 (3%) 和 10 名“其他”人 (15%)。 结论：在没有基于种族的预选的情况下对美国患者进行 HLA-B*15:02 筛查，发现了两倍多与单独筛查亚洲血统患者相比，面临 CBZ 相关不良事件风险的携带者数量。基于种族假设的风险评估可能无法识别美国不同种族人口中的大部分高危患者。
Purpose: HLA-B*15:02 is strongly associated with life-threatening severe skin hypersensitivity reactions in patients treated with carbamazepine (CBZ) and structurally related medications. FDA-approved labeling recommends HLA-B*15:02 screening before CBZ therapy in patients of Asian ancestry. In this study, we aimed to (a) identify a direct method for screening HLA-B*15:02, and (b) evaluate prevalence in a large cohort of United States patients.Methods: Candidate genetic markers were identified by mining public data. Association was tested in 28,897 individuals by comparing SNP results with high-resolution HLA typing. Retrospective analysis of de-identified SNP and ethnicity data from 130,460 individuals was performed to evaluate the ethnic distribution of HLA-B*15:02 in the United States.Results: 28,897 United States individuals showed 100% concordance between HLA-B*15:02 and the minor allele of rs144012689 (100% sensitivity/99.97% specificity). Retrospective analysis of 160 positive individuals (66 with physician-reported ethnicity) notably included 28 Asians (42%), 15 African Americans (22%), 11 Caucasians (17%), 2 Hispanics (3%), and 10 "Other" (15%).Conclusion: Screening United States patients for HLA-B*15:02 without ethnicity-based preselection identifies more than twice the number of carriers at risk of CBZ-related adverse events than screening patients of Asian ancestry alone. Risk assessment based on ethnicity assumptions may not identify a large portion of at-risk patients in the ethnically diverse United States population.