中国汉族人群中芳香族抗癫痫药物所致史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症的遗传预测因素。
Genetic predictors of Stevens-Johnson syndrome and toxic epidermal necrolysis induced by aromatic antiepileptic drugs among the Chinese Han population.
作者信息
Wang Wei, Hu Fa-Yun, Wu Xin-Tong, An Dong-Mei, Yan Bo, Zhou Dong
机构信息
Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
出版信息
Epilepsy Behav. 2014 Aug;37:16-9. doi: 10.1016/j.yebeh.2014.05.025. Epub 2014 Jun 18.
BACKGROUND
Previous studies suggested that one or more HLA alleles participate in the pathogenesis of AED-induced SJS/TEN, but most of these studies focused only on the HLA-B alleles.
PURPOSE
The aim of this study was to investigate the pathogenesis of AED-induced SJS/TEN across a broader spectrum of HLA alleles, including the HLA-A, -B and -DRB1 alleles, to further explore the association between each HLA allele and SJS/TEN induced by aromatic AEDs.
METHODS
A total of 27 patients exhibiting AED-induced SJS/TEN (16 CBZ-SJS/TEN, seven LTG-SJS/TEN, two PHT-SJS/TEN, and two PB-SJS/TEN patients) and 64 patients who exhibited tolerance to AEDs were recruited. High-resolution HLA genotyping was performed to estimate the prevalence of the HLA-A, -B and -DRB1 alleles for each subject.
RESULTS
Fifteen subjects in the SJS/TEN group (12 exhibiting CBZ-SJS/TEN, two exhibiting LTG-SJS, and one exhibiting PB-SJS) carried the HLA-B15:02 allele, whereas only 4/64 subjects in the AED-tolerant group carried this allele; the carrier rate of HLA-B15:02 was significantly different between the groups (P<0.001). Nine patients in the SJS/TEN group carried the HLA-DRB115:01 allele, while 12/64 subjects in the tolerant group carried this allele; considering that two patients in the SJS/TEN group (one exhibiting LTG-SJS and one exhibiting PB-SJS) were homozygous for this allele, the prevalence of HLA-DRB115:01 expression between the two groups was significantly different (P=0.041). Furthermore, the carrier rates of HLA-A33:03, HLA-B58:01, and HLA-DRB1*03:01 were lower in the SJS/TEN group compared with the AED-tolerant group. The carrier rates of these alleles between the two groups were significantly different (P=0.009, 0.016, and 0.009, respectively).
CONCLUSIONS
The HLA-DRB115:01 allele may represent a risk factor for AED-induced SJS/TEN among Han Chinese. The HLA-A33:03, HLA-B58:01, and HLA-DRB103:01 alleles may be "protectors" against AED-induced SJS/TEN, especially CBZ-SJS/TEN.
背景
既往研究提示一个或多个HLA等位基因参与抗癫痫药物（AED）所致史蒂文斯-约翰逊综合征/中毒性表皮坏死松解症（SJS/TEN）的发病机制，但这些研究大多仅聚焦于HLA - B等位基因。
目的
本研究旨在更广泛地研究包括HLA - A、- B和 - DRB1等位基因在内的HLA等位基因在AED所致SJS/TEN发病机制中的作用，进一步探究各HLA等位基因与芳香族AED所致SJS/TEN之间的关联。
方法
共招募27例出现AED所致SJS/TEN的患者（16例卡马西平所致SJS/TEN、7例拉莫三嗪所致SJS/TEN、2例苯妥英钠所致SJS/TEN和2例苯巴比妥所致SJS/TEN患者）以及64例对AED耐受的患者。进行高分辨率HLA基因分型以评估每位受试者HLA - A、- B和 - DRB1等位基因的频率。
结果
SJS/TEN组中有15例受试者（12例卡马西平所致SJS/TEN、2例拉莫三嗪所致SJS和1例苯巴比妥所致SJS）携带HLA - B15:02等位基因，而AED耐受组中仅4/64例受试者携带该等位基因；两组间HLA - B15:02的携带率差异有统计学意义（P<0.001）。SJS/TEN组中有9例患者携带HLA - DRB115:01等位基因，而耐受组中有12/64例受试者携带该等位基因；考虑到SJS/TEN组中有2例患者（1例拉莫三嗪所致SJS和1例苯巴比妥所致SJS）为该等位基因纯合子，两组间HLA - DRB115:01表达频率差异有统计学意义（P = 0.041）。此外，与AED耐受组相比，SJS/TEN组中HLA - A33:03、HLA - B58:01和HLA - DRB1*03:01的携带率较低。两组间这些等位基因的携带率差异有统计学意义（分别为P = 0.009、0.016和0.叭）。
结论
HLA - DRB115:01等位基因可能是汉族人群中AED所致SJS/TEN的一个危险因素。HLA - A33:03、HLA - B58:01和HLA - DRB103:01等位基因可能是AED所致SJS/TEN尤其是卡马西平所致SJS/TEN的“保护因素”。
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