有机磷杀虫剂中毒致中间期肌无力综合征的遗传易感性研究

Genetic susceptibility to intermediate myasthenia syndrome following organophosphate insecticides poisoning

目的 探讨代谢酶基因多态性与有机磷杀虫剂 (OPs)中毒致中间期肌无力综合征(IMS)遗传易感性的关系 ,为IMS易感人群的筛选和保护提供依据。方法 以山东省某地区医院收治入院的 14 7位急性OPs中毒患者为研究对象 ,采集外周静脉血 ,检测全血胆碱酯酶 (ChE)活力 ,并以限制性片段长度多态性、等位基因特异性扩增和单链构象多态性PCR技术 ,分别对CYP2E1(10 91C→T)和GSTP1(313A→G )、CYP1A1(4889A→G)、PON1第 5 5位点 (L→M )、GSTM1和GSTT1进行基因分型。结果 急性OPs中毒者入院时全血ChE活力IMS患者为 (38 2 2±17 5 6 ) % ,非IMS患者为 (42 4 9± 16 2 3) % ,差异无显著性 ,但IMS患者入院后全血ChE活力恢复速度明显慢于非IMS患者。PON1第 5 5位点杂合子和突变纯合子、GSTM1缺失及其与GSTT1均缺失者在IMS患者的分布百分率分别为 4 1 7%、2 2 2 %、6 9 4 %和 4 1 7% ,显著多于非IMS患者的30 6 %、3 6 %、4 5 9%和 19 8%。结论 在有机磷及其混剂中毒患者中 ,PON1第 5 5位点含有突变型等位基因、GSTM1及其与GSTT1均缺失者发生IMS的危险性增高。

Objective To explore the association of gene polymorphism of organophosphate insecticides (OPs) metabolic enzymes with intermediate myasthenia syndrome (IMS) following acute OPs poisoning. Methods Thirty six of 147 acute OPs poisoning patients developed IMS one to four days after poisoning. Peripheral blood samples were collected from all the patients and whole blood cholinesterase (ChE) activity was determined by DTNB spectrometry. The genetic polymorphism of CYP2E1 (1091C→T) and GSTP1(313A→G) were analyzed by polymerase chain reaction (PCR)-restrict fragment length polymorphism, CYP1A1 (4889A→G), GSTM1 and GSTT1 by allele-specific PCR, and PON1 at 55 codon (55L→M) by PCR-single strand conformation polymorphism. Results The whole blood ChE activity in IMS patients was not significantly different from non-IMS patients at admission (38.22±17.56)% and (42.49±16.23)%, respectively, P >0.05, but recovered much slower in IMS patients than that in non-IMS patients. The frequencies of heterozygote and variant homozygote of PON1 at 55 codon, GSTM1 null, and both GSTM1 and GSTT1 null were higher in IMS patients than those in non-IMS patients ( P <0.05), with odds ratios and their 95% confident intervals of 2.48 (1.06-5.78), 11.23 (2.95-42.76), 2.53 (1.14-5.61) and 2.68 (1.20-5.97), respectively. Conclusions Patients of OPs and its mixture poisoning with genotype of variant allele at 55 codon of PON1,GSTM1 null and both GSTM1 and GSTT1 null probably had higher risk for IMS.