Unique motif shared by HLA‐B59:01 and HLA‐B55:02 is associated with methazolamide‐induced Stevens‐Johnson syndrome and toxic epidermal necrolysis in Han Chinese
Unique motif shared by HLA‐B59:01 and HLA‐B55:02 is associated with methazolamide‐induced Stevens‐Johnson syndrome and toxic epidermal necrolysis in Han Chinese
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HLA-B59:01 和 HLA-B55:02 共有的独特基序与汉族人中醋甲唑胺诱导的 Stevens-Johnson 综合征和中毒性表皮坏死松解症有关
DOI：
10.1111/jdv.17980
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Q Xing
中科院分区：
文献类型：
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作者：
Menglin Jiang;F Yang;L Zhang;D Xu;Y Jia;Y Cheng;S Han;T Wang;Z Chen;Y Su;Z Zhu;S Chen;J Zhang;L Wang;L Yang;J Yang;X Luo;Q Xing
醋甲唑胺 (MTZ) 偶尔与致命的史蒂文斯-约翰逊综合征 (SJS) 和中毒性表皮坏死松解症 (TEN) 有关，这些疾病与 HLA-B59:01 相关。然而，一些MTZ诱导的SJS/TEN（MTZ-SJS/TEN）病例的HLA-B59:01呈阴性，这意味着除HLA-B59:01之外的其他遗传因素也有助于MTZ-SJS/TEN。 全面鉴定汉族人群中MTZ-SJS/TEN的HLA和非HLA遗传易感性。 18例MTZ-SJS/TEN患者，806名对照人群和806名人群74 名 MTZ 耐受个体参与了这项研究。进行了全外显子组和基于 HLA 的关联研究。采用分子对接分析来模拟 MTZ 与风险 HLA 蛋白之间的相互作用。我们在 6 号染色体的主要组织相容性复合体区域发现了强信号，其中 22 个 SNP 达到外显子组范围内的显着性。与 MTZ 耐受对照相比，HLA-B59:01 与 MTZ-SJS/TEN 的显着相关性得到验证 [比值比 (OR) = 146.00，95% 置信区间 (CI)：16.12-1321.98； P = 6.19 × 10-10 。此外，66.7% HLA-B59:01 阴性的 MTZ-SJS/TEN 患者是 HLA-B55:02 携带者，而 2.7% 的耐受个体携带 HLA-B55:02（OR = 71.00，95% CI：7.84-643.10；P = 1.43 × 10-4）。在 HLA-B 蛋白中，E45-L116 基序可以完全解释 HLA-B59:01 和 HLA-B55:02 与 MTZ-SJS/TEN 的关联（OR = 119.33，95% CI：29.19-1227.96；P = 4.36 × 10-13）。分子对接分析表明，MTZ 与 HLA-B59:01 和 HLA-B55:02 口袋的结合比与 HLA-B40:01 和 HLA-C01:02 的非风险等位基因的结合更稳定。本研究证实了 HLA-B59:01 与 MTZ-SJS/TEN 的关联，并确定 HLA-B55:02 是汉族中最大的新型风险等位基因。迄今为止的样本量。值得注意的是，编码 E45-L116 的 rs41562914(A)-rs12697944(A) 单倍型能够作为 MTZ-SJS/TEN 的强大遗传预测因子，灵敏度为 89%，特异性为 96%。
Methazolamide (MTZ) has been occasionally linked to the lethal Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are associated with HLA-B59:01. However, some MTZ-induced SJS/TEN (MTZ-SJS/TEN) cases are negative for HLA-B59:01, implying that other genetic factors besides HLA-B59:01 are contributing to MTZ-SJS/TEN.To comprehensively identify HLA and non-HLA genetic susceptibility to MTZ-SJS/TEN in Han Chinese.Eighteen patients with MTZ-SJS/TEN, 806 subjects of the population control and 74 MTZ-tolerant individuals were enrolled in this study. Both exome-wide and HLA-based association studies were conducted. Molecular docking analysis was employed to simulate the interactions between MTZ and risk HLA proteins.We found a strong signal in the major histocompatibility complex region on chromosome 6 with 22 SNPs reaching exome-wide significance. Compared with MTZ-tolerant controls, a significant association of HLA-B59:01 with MTZ-SJS/TEN was validated [odds ratio (OR) = 146.00, 95% confidence interval (CI): 16.12-1321.98; P = 6.19 × 10-10 . Moreover, 66.7% of MTZ-SJS/TEN patients negative for HLA-B59:01 were carriers of HLA-B55:02, whilst 2.7% of the tolerant individuals were observed with HLA-B55:02 (OR = 71.00, 95% CI: 7.84-643.10; P = 1.43 × 10-4 ). Within HLA-B protein, the E45-L116 motif could completely explain the association of HLA-B59:01 and HLA-B55:02 with MTZ-SJS/TEN (OR = 119.33, 95% CI: 29.19-1227.96; P = 4.36 × 10-13 ). Molecular docking analysis indicated that MTZ binds more stably to the pocket of HLA-B59:01 and HLA-B55:02 than to that of non-risk alleles of HLA-B40:01 and HLA-C01:02.This study confirmed the association of HLA-B59:01 with MTZ-SJS/TEN and identified HLA-B55:02 as a novel risk allele in Han Chinese with the largest sample size to date. Notably, the rs41562914(A)-rs12697944(A) haplotype, encoding E45-L116, is capable of serving as a powerful genetic predictor for MTZ-SJS/TEN with a sensitivity of 89% and specificity of 96%.