HLA-B*1502等位基因与中国南方汉族癫痫患者拉莫三嗪皮肤不良反应关联性的Meta分析

目的:系统评价HLA-B*1502等位基因与中国南方汉族拉莫三嗪所致皮肤不良反应(LTG-cADRs)的关联性。方法:通过计算机全面检索PubMed、Embase、The Cochrane Library、中国期刊全文数据库(CNKI)、中国科技期刊全文数据库(VIP)、万方数字化期刊全文库(WanFang Data),检索时间截止2015年 5月31日,并采用STATA SE 12.0软件进行Meta分析。结果:共纳入7个病例对照研究,107例LTG-cADRs癫痫患者,包括25例史蒂文斯-约翰逊综合征/中毒性表皮坏死松解症(SJS/TEN)患者,1例药物超敏反应(HSS)患者,81例斑丘疹(MPE)患者,213例拉莫三嗪耐受(LTG-Tolerant)癫痫患者,Meta分析结果显示,在中国南方汉族癫痫患者中HLA-B*1502等位基因与LTG-SJS/TEN存在显著相关性(OR=4.44,95% CI:1.66~11.87, P=0.003)。而HLA-B*1502等位基因与LTG-MPE不存在显著相关性(OR=0.85,95% CI:0.29~2.48, P=0.759)。结论:在中国南方汉族人群中,HLA-B*1502等位基因与LTG-cADRs存在一定的关联性。     

HLA基因与新疆维吾尔族癫痫患者中拉莫三嗪所致药疹的关联性

目的探讨HLA-A*3001,HLA-A*3101,HLA-B*1502,HLA-B*38,HLA-B*5801等位基因与新疆地区维吾尔族癫痫患者中拉莫三嗪(LTG)诱发的药疹的相关性。方法用序列特异性引物-聚合酶链式反应技术对新疆地区28例服用拉莫三嗪的维吾尔族癫痫患者[其中10例出现斑丘疹(LTG-MPE组),18例未出现皮肤不良反应(LTG-tolerant组)],以及30例维吾尔族健康受试者(对照组)进行HLA-A*3001,HLA-A*3101,HLA-B*1502,HLA-B*38,HLA-B*5801等位基因的检测。分析HLA基因与拉莫三嗪所致皮肤不良反应的相关性。结果 HLA-B*1502,HLA-B*38,HLA-B*5801,HLA-A*3001,HLA-A*3101的等位基因阳性率在3组间比较差异无统计学意义(P>0.05)。结论拉莫三嗪诱发的药疹与HLA-A*3001,HLA-A*3101,HLA-B*1502,HLA-B*38,HLA-B*5801等位基因无显著相关性。     

抗癫痫药物致皮肤型药物不良反应与HLA基因关系的研究进展

摘 要为了解近年来芳香族抗癫痫药物致皮肤型不良反应（cADRs）与各国不同人群、种族中HLA基因多态性之间的关系,为抗癫痫药物合理应用和风险管理实施个体化治疗提供信息服务,本文通过8个主要关键词联机检索2004～2013年全球发表的英文及中文文献。通过纳入排除标准后提取出密切相关文献32篇。对这些异质性论文报告的研究结果进行汇总分析,系统综述相关领域的研究进展。研究发现,对亚洲、欧洲地区人群HLA基因与抗癫痫药物致cADRs相关性：①HLA-B*1502基因在亚洲部分地区及汉族人群中（除日本、韩国外）与CBZ-cADRs中的SJS/TEN强相关,与CBZ HSS/MPE无相关性;②HLA-B*1502基因与其他芳香族AEDs导致的SJS/TEN的关系不确定;③HLA-B*1511基因与日本、韩国人群CBZ SJS/TEN的发生有一定联系;④HLA-A*3101基因与欧洲、日本、韩国人群中CBZ导致各种类型的cADRs密切相关;⑤在不同人群、种族中进行HLA-B*1502基因筛查其意义及成本效益分析存在差异;⑥HLA-B*1502基因在严重皮肤不良反应的药理作用机制仍不明确。表明对亚裔人（除外日本、韩国）使用CBZ治疗前需要进行HLA-B*1502基因筛查,而对日本、韩国人需要检测HLA-B*1511基因,能有效避免在使用CBZ过程中发生严重药物不良反应,规避CBZ的用药风险,杜绝经济损失。     

亚洲人群HLA-B*1502等位基因与卡马西平引起SJS/TEN的关联性荟萃分析

目的 探讨亚洲人群人类白细胞抗原(HLA)-B*1502等位基因对卡马西平引起Stevens-Johnson综合征和中毒性表皮坏死松解症(Stevens-Johnson syndrome/toxic epidermal necrolysis,SJS/TEN)的影响.方法 检索Pubmed 、Embase、中国期刊网、万方和维普等数据库,按照纳入标准纳入有关HLA-B*1502等位基因与卡马西平引起SJS/TEN的病例对照研究,应用Review Manager 4.2和Stata 10.0进行荟萃分析.结果 共纳入10篇文献(10个病例对照研究),共计卡马西平引起的SJS/TEN患者208例,对照者829例.荟萃分析显示合并RR(95% CI)为10.95(8.30 ~ 14.45)(Z = 16.93,P < 0.000 01).结论 HLA-B*1502等位基因与卡马西平引起SJS/TEN存在明显关联.     

中国东北地区汉族癫痫患者HLA-B*1502等位基因分布频率

目的研究中国东北地区汉族癫痫患者HLA-B*1502等位基因分布的频率。方法用聚合酶链反应DNA序列分析法,对125例中国东北地区汉族癫痫患者DNA标本进行HLA-B基因分型。结果 125例DNA标本中,共检测出34种不同的HLA-B等位基因。其中,2例患者携带HLA-B*1502等位基因。HLA-B*1502等位基因在中国东北地区癫痫患者中的分布频率为1.6%。其他分布频率较高的等位基因分别为HLA-B*4001、B*4601、B*4801、B*1302和B*4002。结论东北地区癫痫患者中HLA-B*1502等位基因分布频率(1.6%)与其在北京地区健康汉族人群中的分布频率近似(1.5%);但远低于其在中国中部、西部及南部地区的分布频率。     

HLA-A*31:01等位基因与拉莫三嗪所致皮肤不良反应关联性的Meta分析

目的：近年来,多项研究探讨了人类白细胞抗原HLA-A*31：01等位基因与抗癫痫药拉莫三嗪（LTG）所致皮肤型药物不良反应（cADRs）的关联性,但目前尚无确定的结论。因此,本研究拟通过一项Meta分析来系统评价HLA-A*31：01等位基因与拉莫三嗪所致皮肤不良反应（LTG-cADRs）的关联性。方法：通过计算机全面检索生物医学文献库PubMed、Embase、The Cochrane Library、Medline、CNKI、VIP和万方数据库,检索时间截止至2018年7月24日,纳入探讨了HLA-A*31：01与LTG-cADRs相关性的研究,并采用RevMan 5.3软件进行Meta分析。结果：共纳入5项病例对照研究,123例LTG-cADRs癫痫患者,137例拉莫三嗪耐受（LTG-Tolerant）癫痫患者,2 837例正常人群。Meta分析结果显示,在与LTG-Tolerant组的比较中,HLA-A*31：01基因型与LTG所致的cADRs存在显著相关性（OR=2.87,95% CI：1.11~7.40,P=0.03）。而在与正常人群组的比较中,HLA-A*31：01基因型与LTG所致的cADRs不存在显著相关性（OR=1.34,95% CI：0.34~5.28,P=0.67）。结论：本研究证明,HLA-A*31：01基因型可能是LTG所致cADRs的遗传风险因素。     

拉莫三嗪联合丙戊酸钠治疗脑卒中继发性癫痫的疗效分析

目的 探讨拉莫三嗪联合丙戊酸钠治疗脑卒中继发性癫痫的效果。方法 脑卒中继发性癫痫患者98例按照随机数字表法分为治疗组与对照组各49例,两组都给予脑卒中常规治疗,对照组予口服丙戊酸钠,治疗组在此基础上予拉莫三嗪。记录发作情况、发作次数及每次持续时间,监测药物不良反应。治疗期间每月随访1次,复查血、尿常规,血电解质,血脂,肝肾功能等。结果 治疗后治疗组的总有效率为95.8%,对照组为76.6%,治疗组的总有效率明显高于对照组(P<0.05)。治疗后两组的癫痫发作次数以及持续时间有明显下降,与治疗前对比差异明显(P<0.05);同时治疗后治疗组的癫痫发作次数以及持续时间也明显少于对照组(P<0.05)。治疗后1年,两组脑电图有痫样放电及累及导联数减少,组内及组间差异均有统计学意义(P<0.05)。治疗期间治疗组的皮疹、感觉异常、胃肠道反应等不良反应的总发生率与对照组比较,差异无统计学意义(P>0.05)。结论 拉莫三嗪联合丙戊酸钠治疗脑卒中继发性癫痫能提高治疗效果,促进癫痫症状的消失,不良反应少,值得推广应用。     

药物性皮肤损害与HLA-B相关性研究进展

近期文献研究表明,人类白细胞抗原B等位基因多态性与一些药物的严重皮肤损害有关。本文重点介绍了HLA-B*1502与卡马西平, HLA-B*5801与别嘌呤醇,HLA-B*5701与阿卡巴韦所致严重皮肤损害的相关性研究进展,HLA-B具种族特异性和区域限制性,HLA-B*1502可作为特异性生物标志物用于东南亚裔人群卡马西平不良反应的预防性检测。     

别嘌醇所致严重皮疹与HLA-B*5801等位基因的相关性

目的探讨服用别嘌醇后发生严重皮疹与人类白细胞抗原(HLA)-B*5801等位基因之间的相关性。方法 12例服用别嘌醇后发生严重皮疹的患者作为别嘌醇皮疹组,17例服用别嘌醇后6个月未发生严重皮疹的患者作为别嘌醇对照组,15例健康志愿者作为健康组,采用序列特异性引物引导的聚合酶链反应与直接测序方法分别对三组研究对象的外周静脉血进行HLA-B*5801等位基因检测,分析严重皮疹的发生与HLA-B*5801等位基因之间的联系。结果别嘌醇皮疹组的HLA-B*5801等位基因阳性率为91.67%(11/12),别嘌醇对照组的HLA-B*5801等位基因阳性率为5.88%(1/17),健康组的HLAB*5801等位基因阳性率为13.33%(2/15),别嘌醇皮疹组HLA-B*5801等位基因阳性率明显高于其他两组,差异有统计学意义(P<0.05)。HLA-B*5801等位基因阳性者服用别嘌醇后发生严重皮疹的风险显著高于阴性者。结论 HLA-B*5801等位基因阳性者服用别嘌醇后发生严重皮疹的风险非常高,用药前需行HLA-B*5801等位基因筛查以减少皮疹的发生,提高用药安全。     

抗癫痫药物等引发药疹与人类白细胞抗原基因的相关性研究

目的探讨抗癫痫药物等引发药疹与HLA基因多态性的相关性,以期为药疹的预防和治疗提供依据。方法收集48例药疹患者,采用PCR-SSP方法检测HLA-B*1502、HLA-A*0206、HLA-A*3101、HLA-A*1101、HLA-B*5901、HLA-Cw*0704、HLA-Cw*0801、HLA-DRB1*1202等8个等位基因。采用RT-PCR检测HLA-B*1502基因阳性者中mRNA表达水平。结果药物引发的药疹可能与HLA-B*1502、HLA-Cw*0801、HLA-A*0206和HLA-Cw*0704等位基因相关(P<0.05);其中抗癫痫药物引发的重症药疹与HLA-B*1502等位基因的相关性最强(P<0.01);且抗癫痫药物引发的重症药疹HLA-B*1502 mRNA的表达水平明显高于耐受组及对照组(P<0.01)。结论抗癫痫药物引发的重症药疹与HLA-B*1502等位基因密切相关。HLA-B*1502mRNA表达水平可以作为预测抗癫痫药物诱发重症药疹的重要指标。     

Pharmacogenetics of toxic epidermal necrolysis

Importance of the field: Toxic epidermal necrolysis (TEN) and Stevens–Johnson Syndrome (SJS) are two of the most severe drug-induced cutaneous reactions. Advances in genome technologies have allowed researchers to identify genetic markers associated with this drug-associated event and these have provided a potential tool for prevention.

Areas covered in this review: Current updates of genetic biomarkers that have been identified as being associated with TEN/SJS induced by several drugs, and the associations of these markers in different populations, are discussed.

What the reader will gain: The strong association of HLA-B*1502 and carbamazepine (CBZ)-induced TEN/SJS have been reported by several independent studies. This association was mostly observed in patients of Southeast Asian ancestry; it was not observed in populations with low HLA-B*1502 allele frequency. Studies also suggest that drugs with a similar chemical structure to CBZ might also induce TEN/SJS in patients with HLA-B*1502. In addition to CBZ, HLA-B*5801 was also found to associate with allopurinol-induced TEN/SJS. This strongly suggests that the associations of these markers with TEN/SJS are drug specific.

Take home message: The strong association between CBZ and HLA-B*1502 has prompted the US Food and Drug Administration to update the label for CBZ to include genetic information and to recommend genetic testing before prescribing CBZ. Patients with Asian ancestry or who are from regions prevalent in HLA-B*1502 should be screened before CBZ treatment.     

Cost minimization of HLA-B*1502 screening before prescribing carbamazepine in Thailand

Background Carbamazepine (CBZ) is broadly used for the treatment of epilepsy, neuropathic pain and other neurological diseases, owing to its effectiveness and low price. CBZ can induce Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). There are several studies that found an association between HLA-B*1502 and CBZ-induced SJS/TEN, especially in people of Thai origin. In Thailand the prevalence of HLA-B*1502 was found to be in the range 8.1–14 %. Objective This study aimed to determine if screening for HLA-B*1502 in Thai patients who were to receive CBZ is cost effective. Setting Srinagarind Hospital, Khon Kaen University, Thailand. Method A comparison between treatment cost of CBZ induced SJS/TEN and the HLAB*1502 screening costs in the Thai population. Main outcome measure Comparison of the costs of treatment of CBZ induced SJS/TEN and costs of HLA-B*1502 screening test. Results When persons having the HLA-B*1502 allele receive CBZ, the chance of developing SJS/TEN is as high as 88.1 %, while persons without the HLA-B*1502 allele do not develop SJS/TEN. Therefore, a model was calculated to compare the cost of treatment between HLA-B*1502 testing before giving CBZ and if the patients were not tested for HLAB*1502. It was found that screening 100 patients before giving CBZ would save an amount of 98,549.94 baht per 100 cases of CBZ-prescribed patients. Conclusion The screening for HLA-B*1502 allele before giving carbamazepine is cost effective. The results of the present study may also apply to other populations if the HLA-B*1502 frequency is high enough.     

Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions

The anticonvulsant carbamazepine (CBZ) frequently causes cutaneous adverse drug reactions (cADRs), including maculopapular eruption (MPE), hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We reported that SJS/TEN caused by CBZ is strongly associated with the HLA-B*1502 gene in Han Chinese. Here, we extended our genetic study to different types of CBZ-cADRs (91 patients, including 60 patients with SJS/TEN, 13 patients with hypersensitivity syndrome and 18 with maculopapular exanthema versus 144 tolerant controls). We used MALDI-TOF mass spectrometry to screen the genetic association of 278 single nucleotide polymorphisms (SNPs), which cover the major histocompatibility complex (MHC) region, tumor necrosis factor-alpha, heat shock protein and CBZ-metabolic enzymes, including CYP3A4, 2B6, 2C8, 2C9, 1A2 and epoxide hydrolase 1. In addition, we genotyped 20 microsatellites in the MHC region and performed HLA-typing to construct the recombinant map. We narrowed the susceptibility locus for CBZ-SJS/TEN to within 86 kb flanking the HLA-B gene on the extended B*1502 haplotype, and confirmed the association of B*1502 with SJS/TEN [Pc=1.6x10, odds ratio (OR)=1357; 95% confidence interval (CI)=193.4-8838.3]. By contrast to CBZ-SJS/TEN, HLA-B*1502 association was not observed in the MPE or HSS groups: MPE was associated with SNPs in the HLA-E region and a nearby allele, HLA-A*3101 (Pc=2.2x10, OR=17.5; 95% CI=4.6-66.5), and HSS with SNPs in the motilin gene (Pc=0.0064, OR=7.11; 95% CI=3.1-16.5) located terminal to the MHC class II genes. No SNPs in genes involved in CBZ metabolism were associated with CBZ-induced cADRs. Our data suggest that HLA-B*1502 could contribute to the pathogenesis of CBZ-SJS/TEN, and that genetic susceptibility to CBZ-induced cADRs is phenotype-specific.     

福建汉族人群服用别嘌醇引起严重皮肤不良反应与HLA-B*5801关联性

目的:探讨福建汉族人群服用别嘌醇引起严重皮肤不良反应(SCADRs)与标志基因HLA-B*5801关联性。方法:收集2012年1月—2013年5月期间福建汉族人群中有服用别嘌醇史住院患者的血液样本,经皮肤科确诊为单一别嘌醇所致SCADRs的患者8例归入别嘌醇重症药疹组,包括剥脱性皮炎(ED)3例,斯-约综合征(SJS)1例,中毒性表皮坏死松解症(TEN)1例,SJS /TEN 3例。期间抽取服用别嘌醇14 d以上未出现皮肤不良反应的患者16例归入耐受组。健康人群318名归入健康对照组。入组患者DNA用聚合酶链-限制性长度多态性法进行标志基因检测,聚合酶链-直接测序法验证检测结果。分析该地区人群服用别嘌醇致SCADRs与HLA-B*5801的关联性。结果:重症药疹组与耐受组患者在性别、年龄、药物过敏史、肾功能、日剂量及药物暴露天数之间均无统计学差异(P>0.05)。别嘌醇重症药疹组100.0%(8/8)患者携带HLA-B*5801基因,别嘌醇耐受组18.8%(3/16)携带(OR=65.57,95% CI:6.7~641.94,敏感度100%,特异度81%,P=0.000 2),福建健康汉族人群20.4%(65/318)携带(OR=65.79,95% CI:13.71-315.77,P=0.000 1)。结论:福建汉族人群服用别嘌醇所致SCADRs与携带HLA-B*5801关联性较高,提示该基因检测结果阳性患者应尽量避免服用别嘌醇,以降低发生严重不良反应的风险。     

A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs

BACKGROUND: Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are rare but life-threatening cutaneous adverse reactions to drugs, especially to allopurinol, carbamazepine, lamotrigine, phenobarbital, phenytoine, sulfamethoxazole, oxicam and nevirapine. Recently, a strong association between carbamazepine and allopurinol induced SJS or TEN has been described with respectively, HLA-B*1502 and HLA-B*5801 in a Han Chinese population from Taiwan and other Asian countries. OBJECTIVE: The objective is to further investigate the relationship between SJS/TEN and HLA-B in a large number of patients in a European population. METHODS: HLA-B genotyping was performed on 150 patients included in a European study (RegiSCAR) of SJS and TEN. We focused on patients related to 'high-risk' drugs including: 31 cases related to allopurinol, 28 to sulfamethoxazole, 19 to lamotrigine and 14 to oxicam. RESULTS: Sixty-one percent of 31 allopurinol-induced SJS/TEN patients carried the HLA-B*5801 allele and the figure was 55% for 27 patients of European ancestry [odds ratio=80 (34-187)], (P<10(-6)) as previously observed in Han Chinese. For other drugs, two rare alleles showed a weaker association with SJS/TEN in a limited number of patients: B*38 for sulfamethoxazole or lamotrigine-related patients, and B*73 for oxicam. CONCLUSION: At variance with prior results in Asia, this study shows that even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease. Further investigations are necessary to delineate the exact role of the HLA region in SJS/TEN, and to look for other associations in other regions of the genome.     

Association between HLA and Stevens–Johnson Syndrome Induced by Carbamazepine in Southern Han Chinese: Genetic Markers besides B*1502?

Previous studies have demonstrated a strong association between carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (CBZ-induced SJS/TEN) and HLA-B*1502 in Chinese, and HLA-A*3101 but not HLA-B*1502 in Caucasians and Japanese. Cases with CBZ-induced SJS/TEN negative for HLA-B*1502 were reported recently in Southeast Asia. Negative correlations between CBZ-induced SJS/TEN and B*0702 or B*4001 have also been reported, suggesting a possible protective role. Here, we genotyped HLA-B and HLA-A in 18 cases with CBZ-induced SJS/TEN, in comparison with CBZ-tolerant and normal controls in Southern Han Chinese. A strong association between HLA-B*1502 and CBZ-induced SJS/TEN was found, with 72.2% sensitivity and 87.1% specificity. However, we also found five patients with SJS (5/18, 27.78%) who were negative for HLA-B*1502. HLA-A*2402 was present in nine of 16 cases with SJS (56.25%, including three of five cases negative for HLA-B*1502), which was significantly more frequent than that of CBZ-tolerant controls or the general southern population. Only one case with SJS carried HLA-A*3101. No statistical difference in the mean age, sex ratio and CBZ usage was found between the CBZ-induced SJS/TEN group and the CBZ-tolerant group. In search for possible protective genetic markers in HLA-B*1502-positive but CBZ-tolerant patients, we failed to find any significant factors in the HLA alleles observed. Given the association between HLA-B*1502 and CBZ-induced SJS/TEN, genetic testing before initiating CBZ therapy is suggested in Han Chinese population. However, physicians should also be vigilant about SJS/TEN in those negative for HLA-B*1502. Other factors for the development of CBZ-induced SJS/TEN in HLA-B*1502-negative patients and protective factors in CBZ-tolerant patients should be investigated further.     

Hla-B alleles and lamotrigine-induced cutaneous adverse drug reactions in the Han Chinese population

Abstract: Lamotrigine (LTG) is a commonly used antiepileptic drug. However, the use of LTG is limited because of its cutaneous adverse drug reactions (cADRs) ranging from mild maculopapular eruption (MPE) to severe Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between HLA‐B*1502 and carbamazepine‐induced SJS/TEN has been identified in Chinese and Thai. Although three of seven cases with HLA‐B*1502 have been reported in LTG‐induced SJS/TEN so far, the relationship between HLA‐B*1502 and LTG‐induced SJS/TEN needs further investigation. It is also unclear whether there is a specific genetic marker associated with LTG‐induced MPE in Chinese. In this study, we genotyped 43 Han Chinese patients treated with LTG (14 cases with LTG‐induced cADRs and 29 LTG‐tolerant controls), using PCR‐SSP for HLA‐B*1502 testing and low‐resolution genotyping, as well as sequencing for four‐digit genotyping. The two cases with SJS were negative for HLA‐B*1502, with B1301/1301 and 4601/5610, respectively. Combining the data with previous studies, there was no significant difference in the frequency of subjects with HLA‐B*1502 between the LTG‐induced SJS/TEN group and the LTG‐tolerant group (p = 0.08, OR 4.23, 95% CI 0.94–18.97). In the MPE group, only one was positive for HLA‐B*1502. There was no significant difference in the frequency of a specific HLA‐B allele between the MPE group and the LTG‐tolerant group either. In this study, no significant association between HLA‐B*1502 and LTG‐induced SJS or MPE was found. Given the small sample size and only HLA‐B locus genotyping, further large‐scale studies are required to explore genetic associations with LTG‐induced cADRs.