芳香族类抗癫痫药诱发Stevens-Johnson综合征与HLA-B*1502基因的相关性研究

Association between antiepileptic drug-induced Stevens-Johnson syndrome and HLA-B*1502

目的 HLA-B*1502基因与芳香族类抗癫痫药(AEDs)诱发的Stevens-Johnson综合征(Stevens-Johnsonsyndrome,SJS)在华中地区汉族研究对象的相关性研究。方法 2007—2009年武汉市儿童医院神经内科住院就诊的因服用AEDs而导致药物副反应(cADRs)的16例癫痫患儿为cADRs组,其中5例表现为SJS,高敏综合征(HSS)2例和斑丘疹(MPE)9例。同时,按1∶2的比例收集32例服AEDs无副反应的患儿为AED-耐受组,其年龄、性别及所服用药物与cADRs组匹配;选取38名正常儿童为正常对照组。采用等位基因特异性多重PCR分型技术(ARMS-PCR)检测HLA-B*1502的基因型。结果 5例由芳香族类AEDs所诱导的SJS皆为HLA-B*1502基因阳性,而在AED-耐受组中2例、正常对照组中3例HLA-B*1502基因阳性。HLA-B*1502基因频率在cADRs组(33.3%)明显高于AED-耐受组(6.25%,P<0.05;OR=7.5,95%CI1.25～44.89)和正常对照组(7.89%,P<0.05;OR=5.30,95%CI1.09～25.84)。若以SJS或表皮性红斑(TEN)为研究对象则检测到HLA-B*1502基因与SJS或TEN有更强的相关性(P<0.0001;OR=247.99,95%CI5.87～3831.70)。若以AED-耐受组为对照组,HLA-B*1502基因预测芳香族类AEDs诱发SJS的敏感性为100%(95%CI81.5%～100%),特异性为71.4%(95%CI30%～95%)。HLA-B*1502基因与MPE及HSS无相关性。结论 HLA-B*1502基因与芳香族类AEDs诱导的SJS在华中地区汉族研究对象呈强相关,HLA-B*1502基因可作为由卡马西平为代表的芳香族类AEDs诱发SJS的易感基因,筛查该基因有助于指导癫痫患儿临床个体化药物治疗。

Objective We mainly aimed to examine whether HLA-B＊1502 gene is assac.iated with Stevens-Johnson Syndrome （SJS） induced by antiepileptic drugs （AEDs） association in Hun children in South China mainland. Methods We enrolled 16 patients with cutaneous adverse drug reactions （cADRs）induced by antiepileptic drugs, including 5 patients with SJS, 2 with hypersensitivity syndrome （HSS）and 9 with maculopapular eruption （MPE）, from 2007 to 2009. We also included 32 AED-tolerant controls in 2 ： 1 ratio with cases in age, sex, and AED prescribed. We also included 38 healthy controls. Multiplex amplification refractory mutation system （ARMS-PCR）was used to determine their genotypes. Results We found that 5 patients with SJS were HLA-B＊1502 positive while only 2 individuals were positive in AED-tolerant and healthy controls, respectively. The allele frequency of HLA-B＊1502 in patients with cADRs was significantly higher compared with AED-tolerant controls （33.3% vs 6.25%, P 〈 0.05, OR = 7.5,95% CI 1.25 - 44.89）or with general population（33.3% vs 7.89%, P 〈 0.05, OR = 5.30,95%CI 1.09 - 25.84）. If we confined patients with AED-induced SJS alone, stronger association between HLA-B＊1502 and AED-induced SJS was found in patients （P 〈 0.0001, OR = 247.99,95%CI 5.87 ~ 3831.70）. When the AED-tolerant group was used as the control, HLA-B＊ 1502 allele had 100% sensitivity （95% CI： 81.5% -100%） and 71.4% specificity （95% CI： 30% - 95%） for testing AED-induced SJS. HLA-B1502 was not associated with MPE and HSS. Conclusion Our findings have further confirmed the strong association of HLA-B＊1502 with AED-induced SJS/TEN in Chinese Hart children in South China and HLA-B＊1502 is a valuable marker for testing AED-indueed SJS. This knowledge could be used to guide personalized medicine for children with epilepsy by screening HLA-B＊ 1502 before prescribing AEDs.