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目的探讨CYP2D6和CYP2E1基因多态性与慢性锰接触工人神经毒性易感性的关联。方法采用巢式病例-对照研究的方法,对同一车间的电焊作业工人通过为期1年的健康监护,根据神经系统检查结果,确定63例有早期神经系统异常的工人作为病例组。根据个人资料对每1例病例进行3～5名对照的匹配,确定240例未见任何神经系统异常的工人为对照组。采用限制性片段聚合酶链反应(PCR-RFLP)技术检测CYP2D6酶基因的2938位C/T突变多态性和CYP2E1第6内含子7668位T/A突变产生DraⅠ酶切多态性及5’非编码区1019C/T基因突变产生PstⅠ酶切多态性。结果以各基因位点的野生型为参照,调整吸烟、饮酒、工龄、年龄和性别影响因素后,病例组CYP2D6基因突变型纯合子LL基因型和等位基因频率均低于对照组。具有LL突变的个体锰接触作业时受神经系统损伤的危险性与具有野生型纯合子WtWt的个体相比下降了79%(OR=0.21,95%CI=0.05～0.93,P=0.04)。病例组CYP2E1PstⅠ酶切位点突变型等位基因C2C2频率(22.2%)略高于对照组(15.0%),但差异无统计学意义(P>0.05),基因型分布差异亦无统计学意义(P>0.05)。CYP2E1DraⅠ酶切位点基因型分布和等位基因频率在病例组和对照组中差异亦无统计学意义(P>0.05)。结论携带CYP2D6LL基因型的个体对职业性慢性锰中毒产生的神经损伤不易感,CYP2D6酶基因的2938位C/T突变可能为职业性慢性锰接触致神经系统损害的保护因素之一。
Objective To investigate the association between CYP2D6 and CYP2E1 gene polymorphisms and the susceptibility to chronic toxicity of manganese exposed workers. Methods A nested case-control study was conducted in which 63 workers with early neurological abnormalities were identified as case group by a one-year health monitoring of workers in the same workshop based on the results of neurological examination. According to the personal data, we matched 3 to 5 control cases for each case, and 240 workers who did not find any neurological abnormalities were selected as the control group. The 2938 C / T mutation of CYP2D6 gene and the T / A mutation of 7668 T / A in intron 6 of CYP2E1 were detected by restriction fragment length polymorphism (PCR-RFLP) Mutations in the non-coding region 1019C / T resulted in PstI digestion polymorphism. Results The genotypes of CYP2D6 homozygous LL genotypes and alleles were all lower than those of the control group after adjusting for smoking, drinking, length of service, age and gender. Individuals with LL mutations had a 79% reduction in the risk of nervous system injury during contact work with individuals with the wild type homozygote WtWt (OR = 0.21, 95% CI = 0.05-0.93, P = 0.04). The frequency of C2C2 allele in the CYP2E1PstⅠ restriction site was slightly higher in the case group than in the control group (22.2% vs 15.0%), but the difference was not statistically significant (P> 0.05) P> 0.05). CYP2E1Dra Ⅰ restriction site genotype distribution and allele frequencies in the case group and control group, the difference was not statistically significant (P> 0.05). Conclusions Individuals carrying CYP2D6LL genotype are not susceptible to the neurological damage caused by occupational chronic manganese poisoning. The C / T mutation of CYP2D6 gene at CYP2D6 may be one of the protective factors of nervous system damage induced by occupational chronic manganese exposure.