HLA-A-B-DRB1单倍型与抗癫痫药物所致皮肤不良反应间的关系  

The study of the relationship between HLA-A,-B,-DRB1 monoploid and adverse reaction induced by anti-epileptic drugs

作　　者：吴欣桐[1] 胡发云[1] 周东[1] 王强[2] 

机构地区：[1]四川大学华西医院神经内科,四川成都610041 [2]四川大学华西医院精神科,四川成都610041

出　　处：《西部医学》2015年第6期816-821,共6页Medical Journal of West China

基　　金：国家自然科学基金面上项目(81171301)

摘　　要：目的探讨HLA-A,-B,-DRB1单倍型与抗癫痫药物(AEDs)引发皮肤不良反应(cADRs)的关系。方法本研究一共纳入74例cADRs[包括13例患有Steven-Johnson综合征(SJS)和中毒性表皮坏死松解症(TEN)]的癫痫患者、70例对AEDs耐受的癫痫患者和71名健康对照者。HLA基因分型采用的是polymerase chain reaction(PCR)-sequence-based-typing(SBT)法。结果通过基因分型检测,一共发现27个HLA-A、46个HLA-B和33个HLA-DRB1等位基因。4个高频出现的单倍型为:HLA-A*3303-B*5801-DRB1*0301,HLA-A*0207-B*4601-DRB1*0901,HLA-A*3001-B*1302-DRB1*0701和HLA-A*1101-B*1502-DRB1*1202。基于整个人群分析,单倍型HLA-A*3303-B*5801-DRB1*0301在耐受AEDs的癫痫患者中出现的频率(10/70)高于在AEDs诱发皮疹的癫痫患者中出现的频率(3/74),差异有统计学意义(P<0.05)。2例耐受AEDs的患者携带了单倍型HLA-A*1101-B*1502-DRB1*1202。健康对照与AEDs诱发皮疹的癫痫患者之间差异无统计学意义(P>0.05)。在AEDs引发的重症皮疹(SJS和/或TEN)患者中,有7例患者携带单倍型HLA-A*1101-B*1502-DRB1*1202和HLA-A*1101-B*1502-DRB1*1501,并且这7例患者均服用卡马西平(CBZ)。CBZ-cADRs的患者与CBZ耐受及健康对照组相比,上述两个单倍型的分布差异均具有统计学意义(均P<0.05)。结论单体型HLA-A*3303-B*5801-DRB1*0301可能是保护性基因因素之一。在中国大陆癫痫患者中,单倍型HLA-A*1101-B*1502-DRB1*1202和HLA-A*1101-B*1502-DRB1*1501与AEDs诱发皮疹的发生有极大的关系。Objective This study aimd to investigate the association between antiepileptic drugs （AEDs）-induced cutaneous adverse drug reactions （cADRs） and human leukocyte antigen （HLA）-A, -B, -DRB1 in patients from mainland of China. Methods 74 patients with cADRs, including 13 with Stevens-Johnson syndrome （SJS）, and toxic epidermal necrolysis （TEN）, 70 AEDs -tolerant controls and 71 healthy volunteers were recruited. HLA genotyping was performed by the polymerase chain reaction （PCR）-sequence-base＆typing （SBT） method. Results 27 HLA-A, 46 HLA-B and 33 HLA-DRB1 alleles were detected in genotyping. 4 high frequency haplotypes were reconstructed： HLA-A ＊ 3303-B ＊ 5801-DRB1 ＊ 0301, HLA-A＊ 0207-B＊ 4601-DRB1 ＊ 0901, HLA-A＊ 3001-B＊ 1302-DRB1 ＊ 0701, HLA-A ＊ ll01-B ＊ 1502-DRB1 ＊ 1202. The former one was found with higher percentage （10/70） among AEDs-tolerant controls than cADRs patients （3/74） with statistic significance （P^0.05） in whole enrolled population. Two of those tolerant controls also took haplotype HLA-A ~ 1101-B ＊ 1502-DRB1 ＊ 1202. No similar phenomenon was found in healthy volunteer and cADRs groups, even among patients with SJS/TEN. The latter and other haplotype HLA-A ＊ 1101-B ＊ 1502 DRB1 ＊ 1501 was merely found in seven different patients, who exactly had carbamazepin （CBZ）-induced SJS/TEN, in all patients with severe cADRs, both with significant difference in the frequency comparing with CBZ-tolerant controls and healthy volunteers （P〈0.05）. Conclusion these data suggested that haplotype HLA-A＊ 3303-B＊ 5801-DRB1 ＊ 0301 might be one of the protective genetic factors for AEDs-induced cADRs. HLA-A ~ 1101-B ~ 1502-DRB1 ~ 1202 and HLA-A ~ 1101-B ~ 1502-DRB1 ~ 1501 had strong association with CBZ-induced SJS/TEN among patients from mainland of China.

关 键 词：人类白细胞抗原 单倍型 抗癫痫药物 皮疹 

分 类 号：R742.1[医药卫生—神经病学与精神病学] R971.6[医药卫生—临床医学]