Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand.
Clin Transl Sci. 2022 Aug;15(8):1887-1905. doi: 10.1111/cts.13291. Epub 2022 May 22.
Aggregated risk of carbamazepine (CBZ)-induced cutaneous adverse drug reactions (cADRs) with different HLA variants are unclear and limited in terms of the power of studies. This study aimed to assess the aggregated risk of CBZ-induced cADRs associated with carrying the following HLA variants: HLA-B15:02, HLA-B15:11, HLA-B15:21, HLA-B38:02, HLA-B40:01, HLA-B46:01, HLA-B58:01, HLA-A24:02, and HLA-A31:01. Literature was searched in different databases following PRISMA guidelines. The outcomes were measured as odds ratio (OR) using RevMan software by a random/fixed effects model, where p < 0.05 was set as statistical significance. In total, 46 case-control studies met the inclusion criteria and were included in this analysis consisting of 1817 cases and 6614 controls. It was found that case-patients who carried the HLA-B15:02 allele were associated with a significantly increased risk of CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) compared to controls (OR 26.01; 95% CI 15.88-42.60; p < 0.00001). The aggregated risk of cADRs was slightly higher in Asian compared to Caucasian patients (Asians: OR 14.84; 95% CI 8.95-24.61; p < 0.00001; Caucasians: OR 11.65; 95% CI 1.68-80.70; p = 0.01). Further, HLA-B15:11, HLA-B15:21, or HLA-A31:01 allele was also associated with significantly increased risk of CBZ-induced cADRs (HLA-B15:11: OR 6.08; 95% CI 2.28-16.23; p = 0.0003; HLA-B15:21: OR 5.37; 95% CI 2.02-14.28; p = 0.0008; HLA-A31:01: OR 5.92; 95% CI 4.35-8.05; p < 0.00001). Other HLA variants were not found to have any significant associations with CBZ-induced cADRs. Strong associations between the HLA-B15:02, HLA-B15:11, HLA-B15:21, or HLA-A31:01 allele with CBZ-induced cADRs have been established in this analysis. Pharmacogenetic testing of particular HLA alleles before initiation of CBZ therapy may be beneficial to patients and may help to eradicate cADRs substantially.
卡马西平（CBZ）诱导的皮肤不良反应（cADR）与不同 HLA 变体相关的累积风险尚不清楚，而且研究的效力有限。本研究旨在评估携带以下 HLA 变体的 CBZ 诱导的 cADR 相关的累积风险：HLA-B15:02、HLA-B15:11、HLA-B15:21、HLA-B38:02、HLA-B40:01、HLA-B46:01、HLA-B58:01、HLA-A24:02 和 HLA-A31:01。根据 PRISMA 指南在不同的数据库中进行文献检索。使用 RevMan 软件通过随机/固定效应模型测量结果为比值比（OR），其中 p<0.05 被设定为统计学意义。共有 46 项病例对照研究符合纳入标准，并纳入了本分析，其中包括 1817 例病例和 6614 例对照。结果发现，与对照相比，携带 HLA-B15:02 等位基因的病例患者与 CBZ 诱导的史蒂文斯-约翰逊综合征/中毒性表皮坏死松解症（SJS/TEN）的风险显著增加相关（OR 26.01；95%CI 15.88-42.60；p<0.00001）。与高加索患者相比，亚洲患者的 cADR 累积风险略高（亚洲人：OR 14.84；95%CI 8.95-24.61；p<0.00001；高加索人：OR 11.65；95%CI 1.68-80.70；p=0.01）。此外，HLA-B15:11、HLA-B15:21 或 HLA-A31:01 等位基因也与 CBZ 诱导的 cADR 的风险显著增加相关（HLA-B15:11：OR 6.08；95%CI 2.28-16.23；p=0.0003；HLA-B15:21：OR 5.37；95%CI 2.02-14.28；p=0.0008；HLA-A31:01：OR 5.92；95%CI 4.35-8.05；p<0.00001）。其他 HLA 变体与 CBZ 诱导的 cADR 之间未发现任何显著关联。本分析确立了 HLA-B15:02、HLA-B15:11、HLA-B15:21 或 HLA-A31:01 等位基因与 CBZ 诱导的 cADR 之间的强烈关联。在开始 CBZ 治疗之前对特定 HLA 等位基因进行遗传药理学检测可能对患者有益，并有助于显著消除 cADR。
