Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism

Abstract

Aims Several single nucleotide polymorphisms (SNPs) of the cytochrome P450 enzyme 1A2 gene ( CYP1A2 ) have been reported. Here, frequencies, linkage disequilibrium and phenotypic consequences of six SNPs are described. Methods From genomic DNA, 114 British Caucasians (49 colorectal cancer cases and 65 controls) were genotyped for the CYP1A2 polymorphisms -, and 1545T AE C (alleles CYP1A2 * 1B , * 1G , * 1H and * 3 ), using polymerase chain reaction-restriction fragment length polymorphism assays. All patients and controls were phenotyped for CYP1A2 by h.p.l.c. analysis of urinary caffeine metabolites. Results In 114 samples, the most frequent CYP1A2 SNPs were 1545T AE C (38.2% of tested chromosomes), -164A AE C ( CYP1A2 * 1F , 33.3%) and -2464T AE delT ( CYP1A2 * 1D , 4.82%). The SNPs were in linkage disequilibrium: the most frequent constellations were found to be -3858G/ -2464T/ -740T/ -164A/63C/1545T (61.8%), -3858G/ -2464T/ -740T/ -164C/63C/1545C (33.3%), and -3858G/ -2464delT/ -740T/ -164A/63C/1545C (3.51%), with no significant frequency differences between cases and controls. In the phenotype analysis, lower caffeine metabolic ratios were detected in cases than in controls. This was significant in smokers ( n = 14, P = 0.020), and in a subgroup of 15 matched case-control pairs ( P = 0.007), but it was not significant in nonsmokers ( n = 100, P = 0.39). There was no detectable association between CYP1A2 genotype and caffeine phenotype. Conclusions (i) CYP1A2 polymorphisms are in linkage disequilibrium. Therefore, only -164A AE C ( CYP1A2 * 1F ) and -2464T AE delT ( CYP1A2 * 1D ) need to be analysed in the routine assessment of CYP1A2 genotype; (ii) in vivo CYP1A2 activity is lower in colorectal cancer patients than in controls, and (iii) CYP1A2 genotype had no effect on phenotype (based on the caffeine metabolite ratio). However, this remains to be confirmed in a larger study.

Estrogen-metabolizing gene polymorphisms in the assessment of female hormone-dependent cancer risk

“…20 In our study, the frequency of C allele of CYP1A2*1F was higher in women with hormone-dependent cancer, in agreement with a previous study. 21 These results suggest that women with C allele of CYP1A2*1F, which is associated with a decrease in CYP1A2 enzyme activity, have a higher risk of developing endometrial or OCs.…”

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

“…[13][14][15] Some data exist on higher drug concentrations and higher risks for tardive dyskinesia in schizophrenic patients who are smokers and carriers of CYP1A2 genotypes with reduced inducibility (C/A polymorphism at position 734 in intron 1 and G/A polymorphism at position À2964 in the 5 0 -flanking region of CYP1A2), but those results have not been fully replicated. [16][17][18] Polymorphisms in CYP2B6 might be relevant for the antidepressant bupropion, but the differences due to genotype are small.…”

Polymorphisms in Metabolic Genes Related to Tobacco Smoke and the Risk of Gastric Cancer in the European Prospective Investigation into Cancer and Nutrition

“…CYP1A2 seems to be mainly expressed in the liver and is involved in the activation of heterocyclic amines and aromatic amines; its activity can be determined by measuring the excretion of caffeine metabolites. The allele C of IVS1-154A>C seems to be associated with decreased caffeine metabolism among smokers, whereas the effect on enzymatic activity of À3859G>A is not clear (19).…”