[Association analysis of polymorphisms of metabolizing enzyme genes with chronic benzene poisoning based on logistic regression and multifactor dimensionality reduction].

OBJECTIVE: To explore the association of polymorphisms of metabolizing enzyme genes with chronic benzene poisoning (CBP) comprehensively by case-control design. METHODS: 152 CBP patients and 152 workers occupationally exposed to benzene without poisoning manifestations were investigated. 30 single nucleotide polymorphisms (SNPs) in 13 genes such as CYP2E1 were tested by PCR-RFLP, sequencing approaches. Logistic regression model was used to detect main effects and 2-order interaction effects of gene and/or environment. Multifactor dimensionality reduction (MDR) was used to detect high-order gene-gene or gene-environment interactions. RESULTS: Based on logistic regression, the main effects of GSTP1 rs947894, EPHX1 rs1051740, CYP1A1 rs4646903, CYP2D6 rs1065852 and rs1135840 were found to be significant (P < 0.05) while the confounding factors of sex, cigarette smoking, alcohol consumption and the intensity of benzene exposure were controlled. EPHX1 rs1051740 might be associated with CBP (P = 0.06). There existed 3 types of interactions were as followed: interactions of GSTP1 rs947894 with alcohol consumption, CYP2E1 rs3813867 with EPHX1 rs3738047, EPHX1 rs3738047 with alcohol consumption(P < 0.05), while the main effects of CYP2E1 rs3813867 and EPHX1 rs3738047 were not significant (P > 0.05). The other SNPs did not show any significant associations with CBP. According to MDR, a 3-order interaction with the strongest combined effect was found, i.e. the 3-factor combination of CYP1A1 rs4646903, CYP2D6 rs1065852 and CYP2D6 rs1135840. CONCLUSION: Gene-gene, gene-environment interactions are important mechanism to genetic susceptibility of CBP.

Central administration of kisspeptin-10 inhibits water and sodium excretion of anesthetized male rats and the involvement of arginine vasopressin.

AIM: To investigate the effect of hypothalamus kisspeptin on water and sodium excretion and the possible mechanism. METHOD: The intracerebroventricular (icv) administration and radioimmunoassay were used to observe the effect of kisspeptin-10 on urine flow, sodium and potassium excretion, plasma arginine vasopressin (AVP), and atrial natriuretic peptide (ANP) concentrations in anesthetized male rats. The mediation of renal sympathetic nerve was also investigated by studies conducted on rats with bilateral renal sympathetic denervation. RESULTS: The urine flow, sodium excretion, and free water clearance decreased significantly by icv injection of 5 nmol kisspeptin-10 (p < 0.05) from 30 to 60 min post-injection. Meanwhile, plasma AVP concentrations increased significantly 30 min after the icv injection of 5 nmol kisspeptin-10 (p < 0.05), whereas the equal dose of kisspeptin-10 did not significantly change plasma ANP concentrations. The mean arterial blood pressure, heart rate, and potassium excretion did not significantly change during the experiment. Furthermore, pretreatment with 5 nmol kisspeptin-10 could still significantly decrease urine flow and sodium excretion in renal sympathetic denervated rats. CONCLUSION: Central administration of kisspeptin-10 could inhibit sodium excretion and urine flow in anesthetized male rats, which is probably mediated by increasing the plasma AVP concentration and is independent of plasma ANP concentration and renal sympathetic nerve activity.

[Genetic susceptibility of DNA damage induced by vinyl chloride monomer exposure].

OBJECTIVE: To explore the association between DNA damage induced by vinyl chloride monomer (VCM) and polymorphisms of DNA repair genes and xenobiotic metabolism genes of VCM. METHODS: Comet assay was employed to detect DNA damage. Based on the status of DNA damage, the VCM exposure workers were divided into two groups: DNA damage group (75) and control group (75). Case-control design was used to investigate the association between the genetic polymorphisms and DNA damage induced by VCM. Genotypes of XRCC1 (Arg194Trp, Arg280His and Arg399Gln), XPD (Ile199Met, Asp312Asn and Lys751Gln) and CYP2E1 were identified by the PCR-RFLP. PCR assay was used to detect positive and null genotype of GSTT1 and GSTM1. RESULTS: Univariate analysis showed that the CYP2E1 c1c2/c2c2 and XPD751 Lys/Gln and Gln/Gln genotypes were significantly associated with the increased levels of DNA damage, XRCCI 339 Arg/Gln and Gln/Gln genotypes were significantly associated with the decreased levels of DNA damage (P < 0.01, P < 0.05, respectively). Logistic regression analysis showed that there was significant association between the genotypes of XRCC1 194, XRCC1 399, XPD 751, CYP2E1 and DNA damages. A prominent risk decreasing of DNA damage was observed for those individuals possessing XRCC1 399Arg/Gln + Gln/Gln genotypes (OR: 0.35, 95%CI: 0.12 approximately 1.01, respectively); The results also showed that there were significant associations between CYP2E1 c1c2/c2c2 and DNA damage both in high and low VCM-exposed groups (OR: 2.57, 95%CI: 1.01 approximately 6.59 and OR: 2.57, 95%CI: 0.99 approximately 6.87). CONCLUSION: Cumulative exposure dose and genotypes of XRCC1 194, XRCC1 399, XPD 751 and CYP2E1 may modulate the DNA damage induced by VCM exposure.

Genetic polymorphisms in CYP1A1, CYP2D6, UGT1A6, UGT1A7, and SULT1A1 genes and correlation with benzene exposure in a Chinese occupational population.

Metabolic enzymes involved in benzene activation or detoxification, including cytochrome P-450 1A1 (CYP1A1), cytochrome P-450 2D6 (CYP2D6), UDP-glucuronosyltransferase 1A6 (UGT1A6), UDP-glucuronosyltransferase1A7 (UGT1A7), and sulfotransferase 1A1 (SULT1A1), were studied for their roles in human susceptibility to benzene poisoning. All 304 subjects were investigated with a unitary questionnaire and their DNA was isolated from blood samples by a routine phenol-chloroform extraction. The study included 152 benzene poisoning patients, and 152 control workers occupationally exposed to benzene in South China. The genotypes were determined by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) technique with genomic DNA. No individuals had the CYP 2D6 c.212 G>A variant alleles in this study. There is no association between the UGT1A6 c.181 T>A, UGT1A7 c.208 Trp>Arg, and SULT1A1 c.638 G>A genotypes and increased risk of benzene-induced carcinogenesis. Although most of the CYP2D6 haplotypes did not show any significant difference, the CYP2D6 haplotype CYP2D6 c.188 C/C, C/T, and c.4268 C/C was significantly overrepresented in the case group (OR 4.02, 95% CI: 2.53-6.39) compared with in controls. Overall, our data suggested that individuals with CYP1A1 c.5639 T/T, CYP2D6 c.188 C/C, C/T, and CYP2D6 c.4268 C/C genotypes tend to be more susceptible to benzene toxicity.

[Relationship between single nucleotide polymorphisms of NRAMP1 gene and susceptibility to pulmonary tuberculosis in workers exposed to silica dusts].

OBJECTIVE: To explore the relationship between polymorphisms of natural resistance-associated macrophage protein 1 (NRAMP1) gene and genetic susceptibility of pulmonary tuberculosis (PTB) in workers exposed to silica dusts. METHODS: A 1:2 case control study of 61 male workers with PTB (50 silicosis patients and 11 unsilicosis workers) as the case group and 122 male PTB-free workers (100 silicosis patients and 22 unsilicosis workers) as the control group was conducted with the frequency matched for age of +/- 5 years, the job, the silica exposure, and the condition of cigarette smoking and alcohol drinking. The polymerase chain reaction-restrained fragment length polymorphism technique (PCR-RFLP) was used to detect the single nucleotide polymorphisms (SNPs) of NRAMP1 INT4 and D543N. RESULTS: There was a 2.73 times (95% CI: 1.32 approximately 5.64) increased risk of silicosis for individuals with C allele of NRAMP1 INT4 compared with individuals carrying homozygote (G/G), while SNPs of NRAMP1 D543N was not associated with PTB (P > 0.05). CONCLUSION: The G > C mutation of intron 4 of NRAMP1 gene might be a susceptible factor of silica for the workers exposed to PTB.

[Genetic polymorphism of CYP-1A1, CYP2D6 and risks of chronic benzene poisoning].

OBJECTIVE: To explore the relationship between genetic polymorphisms of CYP-1A1 and CYP2D6 and risks of chronic benzene poisoning (BP). METHODS: A case control study was conducted. 152 BP patients and 152 workers occupationally exposed to benzene without poisoning manifestations were involved. Polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) technology was used for detecting the single nucleotide polymorphisms (SNPs) of MspI in the non-coding region of CYP-1A1 gene and c.188, g.212 position in the first extron of CYP2D6 gene. RESULTS: The individuals with CYP1A1 MspI T/T genotype had a 1.32 times (95% CI: 1.05 approximately 1.65, P = 0.02) increased risk of BP compared with those carrying T/C and C/C genotypes. In no-smoking population, there was a 1.56 times (95% CI: 1.15 approximately 2.12, P = 0.003) increased risk of BP for subjects carrying CYP1A1 MspIT/T genotype compared with those carrying T/C and C/C genotypes. The individuals carrying CYP2D6 c.188 C/C or C/T genotype had a 1.23 times (95% CI: 1.05 approximately 1.42, P = 0.01) increased risk compared with those carrying T/T genotypes. In no-smoking population, there was a 1.23 times (95% CI: 1.04 approximately 1.47, P = 0.01) increased risk of BP for subjects carrying CYP2D6 c.188 C/C or C/T genotypes compared with those carrying T/T genotype. The single nucleotide polymorphism of g.212 position in the first extron of CYP2D6 gene had not been validated. CONCLUSION: The individuals with CYP2D6 c.188 C/C, CYP2D6 c.188 C/T and CYP1A1 MspIT/T genotypes tend to be more susceptible to benzene toxicity.

[Relationship between genetic polymorphism in hMTH1c.83, hOGG1c.326 and hMYHc.335 and risks of chronic benzene poisoning].

OBJECTIVE: To explore the relationship between genetic polymorphisms in hMTH1, hOGG1 and hMYH and risks of chronic benzene poisoning (CBP). METHODS: A case control study was conducted. One hundred and fifty-two BP patients and 152 workers occupationally exposed to benzene without poisoning manifestations were investigated. The polymerase chain reaction restrained fragment length polymorphism technique (PCR-RFLP) was applied to detect the single nucleotide polymorphisms (SNPs) on c.83 of hMTH1 gene, c.326 of hOGG1 gene and c.335 of hMYH gene. RESULTS: There were 2.51 times (OR(adj) = 2.51, 95% CI: 1.14-5.49, P = 0.02) and 2.49 times (OR(adj) = 2.49, 95% CI: 1.52-4.07, P < 0.01) risks of BP for individuals carrying genotypes of hMTH1c.83Val/Met + Met/Met or hOGG1c.326Cys/Cys compared with individuals carrying genotypes of hMTH1c.83Val/Val or hOGG1c.326Ser/Cys + Ser/Ser, respectively. Compared with individuals carrying genotypes of hOGG1c.326Cys/Cy and hMYHc.335 is/His at the same time, there was 0.33 times (OR(adj) = 0.33, 95% CI = 0.15-0.72, P = 0.01) risks of BP for these with genotypes of hOGG1c.326Ser/Cys + Ser/Ser and hMYHc.335His/Gln + Gln/Gln simultaneously. In the smoking group, there was 0.15 times (OR(adj) = 0.15, 95% CI: 0.03-0.68, P = 0.01) risks of BP for subjects carrying genotypes of hMYHc.335His/Gln + Gln/Gln compared with these carrying genotypes of hMYHc.335His/His. CONCLUSION: Polymorphisms of hMTH1 Val83 Met and hOGG1 Ser326Cys may contribute to altered risks of CBP, and potential interaction may exist among polymorphisms of hOGG1 Ser326Cys and hMYH His335Gln.

[Relationship of genetic polymorphism of microsomal epoxide hydrolase with susceptibility of chronic benzene poisoning].

OBJECTIVE: To explore the relationship between genetic polymorphisms of microsomal epoxide hydrolase (mEH) and susceptibility of chronic benzene poisoning (BP). METHOD: A case-control study was conducted. 152 BP patients and 152 workers occupationally exposed to benzene without poisoning manifestations were investigated. Polymerase chain reaction-restrained fragment length polymorphism technique (PCR-RFLP) was applied to detect the single nucleotide polymorphisms (SNPs) on c.113 and c.139 of mEH gene. RESULTS: The risk of BP for individuals carrying mEHc.113 C/C genotype was 0.60 (OR = 0.60, 95% CI: 0.37 - 0.97, P = 0.04) of those carrying T/T and T/C genotypes. In non-smoking population, the risk of BP for subjects carrying mEHc.113 C/C genotype was 0.56 (OR = 0.56, 95% CI: 0.33 - 0.96, P = 0.03) of those carrying T/T and T/C genotypes, and in non-drinking population, the individuals carrying mEHc.113 C/C genotype was 0.51 (OR = 0.51, 95% CI: 0.30 - 0.86, P = 0.01) of those carrying T/T and T/C genotypes. CONCLUSION: The subjects carrying mEHc.113 C/C genotype and together with non-smoking or non-drinking habit may have lower risk of chronic benaene poisoning.