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目的探讨δ-氨基-γ-酮戊酸脱水酶(ALAD)和维生素D受体(VDR)基因多态性以及基因-基因、基因-环境之间的联合作用对铅肾毒性的作用。方法选择233名铅作业工人,根据工人接触铅水平是否超过职业接触限值将其分为两组,分别测定血铅、尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、尿β2-微球蛋白(β2-MG)和尿肌酐,全血提取DAN基因组,多聚酶链反应-限制性片段长度多态性(PCR-RFLP)法分析ALAD和VDR基因多态性。结果超职业限值组,ALAD1-2/2-2基因型和ALAD1-1基因型工人尿NAG的浓度分别为(2.12±0.07)U/mmol Cr和(1.73±0.03)U/mmol Cr,差异具有显著性P<0.05;VDR-Bb基因型的工人尿β2-MG浓度[(20.94±0.12)μg/mmol Cr]高于携带VDR-bb基因型工人的尿β2-MG浓度[(15.28±0.09)μg/mmol Cr](P=0.01)。多因素Logistic回归分析发现,铅接触、高血铅等环境因素以及环境-基因的联合作用都是铅作业工人肾损害的危险因素,接铅水平、血铅水平、ALAD基因型和接铅水平的联合作用引起尿NAG异常的OR值分别为6.85(2.51～10.87)、2.41(1.70～3.41)、3.01(1.10～8.19)。结论在高铅浓度接触下ALAD和VDR基因型与铅肾毒性有关,ALAD-2等位基因和高铅接触是加重铅肾毒性的危险因素。
Objective To investigate the effects of the combination of δ-aminolevulinic acid dehydratase (ALAD) and vitamin D receptor (VDR) gene polymorphism and gene-gene, gene-environment on lead nephrotoxicity. Methods A total of 233 lead workers were selected and divided into two groups based on whether the level of lead exposed by workers exceeded the occupational exposure limits. Blood lead, urine NAG, urine β2 DNA microarray (β2-MG) and urinary creatinine were extracted from the whole blood to extract the DNA of ALAD and VDR. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to analyze the polymorphisms of ALAD and VDR genes. Results The urine NAG concentrations of ALAD1-2 / 2-2 genotype and ALAD1-1 genotype workers were (2.12 ± 0.07) U / mmol Cr and (1.73 ± 0.03) U / mmol Cr, respectively, in the over- (20.94 ± 0.12) μg / mmol Cr] in workers with VDR-Bb genotype was significantly higher than that of the workers with VDR-bb genotype ([15.28 ± 0.09 ) μg / mmol Cr] (P = 0.01). Multivariate logistic regression analysis found that environmental factors such as lead exposure and hyperkalemia, and environmental-gene combination were risk factors for renal damage in lead workers, followed by lead level, blood lead level, ALAD genotype and lead level The combined OR of urine NAG abnormalities were 6.85 (2.51-10.87), 2.41 (1.70-3.41) and 3.01 (1.10-8.19) respectively. Conclusions ALAD and VDR genotypes are associated with lead nephrotoxicity at exposure to high lead concentrations and ALAD-2 alleles and lead exposure are risk factors that exacerbate lead toxicity.