Gene polymorphism

Abstract: Aims The cytochrome P450 enzyme CYP1A2 metabolises several drugs and carcinogens. We wanted to determine how much of the variability of CYP1A2 activity is explained by a newly discovered gene polymorphism in intron 1. Methods A single nucleotide polymorphism in intron 1 of the CYP1A2 gene at position 734 downstream of the first transcribed nucleotide was identified by DNA sequence analysis. The functional significance of this C/A polymorphism was assessed in 185 healthy Caucasian non-smokers and in 51 smokers by genotyping and phenotyping using caffeine (100 mg oral dose). Results Out of the total sample, 46% were homozygous for the variant A, 44% were heterozygous, and 10% were homozygous for the variant C. The ratio of 1,7-dimethylxanthine (17X) plus 1,7-dimethyluric acid divided by caffeine in 0–5 h urine samples from 185 non-smokers did not differ significantly between the three CYP1A2 genotypes. In the 51 smokers, analysis of variance revealed significant differences in the 5 h plasma 17X/caffeine ratios between the genotypes (P=0.008, F-test). The mean ratio was 1.37 in carriers of the A/A genotype, 0.88 in heterozygotes and 0.82 in carriers of C/C. The mean difference between the A/A and C/A groups was 0.48 (95% confidence interval 0.15–0.81; P=0.01). Conclusions The A/A genotype, which may represent a CYP1A2 high inducibility genotype, may either be a direct cause of increased CYP1A2 activity, or be genetically linked to polymorphisms conferring high inducibility. Further studies are needed to define the role of this polymorphism on the pharmacokinetics of drugs metabolised by CYP1A2 and in the activation of carcinogens.

Abstract: Thymidylate synthase (TS) catalyses the conversion of deoxy-uridylate to deoxy-thymidylate and is essential for DNA synthesis. The human TS gene promoter is polymorphic, having either double or triple tandem repeats of a 28-bp sequence. Here we determined the significance of this polymorphism in humans and its prediction for clinical outcome of patients with metastatic colorectal cancer treated with 5-fluorouracil. The TS mRNA level was analyzed using RT-PCR. Individuals homozygous for the triple repeat variant (L/L) had 3.6 times higher TS mRNA levels compared to those homozygous for the double repeat variant (S/S) in tumor tissue (P = 0.004). We tested 50 patients with disseminated colorectal cancer who received 5-FU treatment to determine whether this TS polymorphism will predict clinical outcome. We found individuals with S/S genotype had a response rate of 50% (4/8) when compared to 9% (2/22) in those with L/L and 15% (3/20) in those with S/L genotype (P = 0.041). Patients with L/L had less severe side effects to 5-FU (P = 0.008). The data suggest that genotyping for the TS polymorphism may have the potential to identify patients more likely to respond to 5-FU based chemotherapy.

Abstract: BACKGROUND/AIMS To explore the association between polymorphism of myeloperoxidase (MPO) gene and the susceptibility to gastric cancer. METHODOLOGY A case control study of 117 gastric cancer patients and 105 controls was conducted to investigate the polymorphism of MPO gene 463G-A using the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The association between polymorphism and the risk of gastric cancer was examined by a multivariate analysis. Stratification analysis by age, gender, smoking status, H. pylori (Hp) infection and family history of gastric cancer was performed. RESULTS In gastric cancer group the frequencies of the cases caring genotype G/G, G/A, A/A were 70.94%, 25.64% and 3.42%, respectively. In healthy control group, the frequency of genotype G/G, G/A, A/A was 51.43%, 37.14% and 11.43%, respectively. The frequency of genotype G/A and A/A in cancer group was found significantly higher than that in healthy control group (p<0.05). Compared with the MPO-463 G/G genotype, individuals with GA/AA genotype had a significantly decreased risk of gastric cancer (OR=0.50, 95%CI=0.28-0.90). In the stratification analysis, patients younger than 60 years old, male, Hp-IgG negative and with no family history of gastric cancer with genotype GA/AA had lower risk than those with genotype G/G. CONCLUSIONS MPO gene polymorphism is associated with susceptibility of gastric cancer. It is conceivable that carriers of the A allele may be at reduced risk of gastric cancer.