The purpose of the current study is to assess the contribution of the CYP2A6*2 rs1801272 and CYP2A6*9 rs28399433 gene polymorphisms and tobacco smoking in the risk of lung cancer in an Egyptian population.
Yet only in Asian populations, both Japanese and Chinese, which have a high prevalence of genetic variants, has a link between CYP2A6, smoking dose, and lung cancer been established.
These findings suggest that CYP2A6 activity provides information on lung cancer risk that is not captured by smoking history or a (short-term) biomarker of dose.
We aimed to compare CYP2A6 genetic variation and CYP2A6 enzyme activity (representative of the rate of nicotine metabolism) between the two tribal populations as these have previously been associated with differences in smoking, quitting, and lung cancer risk.
Thus the reduced risk of lung cancer in smokers with lower CYP2A6 activity may be explained by lower consumption of cigarettes, less intense smoking and reduced CYP2A6-catalyzed activation of the tobacco-specific lung carcinogen NNK.
The present data support the hypothesis that a greater CYP2A6 activity causes smokers to smoke more extensively and be exposed to higher levels of carcinogens, resulting in an increased risk for lung cancer.
However, no study has evaluated the relationship between CYP2A6 genetic variants and the CYP2A6 activity ratio (total 3-hydroxycotinine/cotinine) and their influence on smoking intensity [total nicotine equivalents (TNE)], across five racial/ethnic groups found to have disparate rates of lung cancer.
We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk.
These findings support a contribution of genetic variation in CYP2A6 to lung cancer risk among African American smokers, particularly men, whereby CYP2A6 genotypes associated with reduced metabolic activity confer a lower risk of developing lung cancer.
We and others have previously reported that CYP2A6*4, a whole-gene deletion polymorphism, is associated with lower risk of lung cancer than the wild-type allele.
Genome-wide significant associations with cigarettes per day (CPD) and risk for lung cancer and chronic obstructive pulmonary disease (COPD) were previously reported in a region of 19q13, including CYP2A6 (nicotine metabolism enzyme) and EGLN2 (hypoxia response).
Previously we found that variation in CYP2A6 and CHRNA5-CHRNA3-CHRNB4 combined to increase lung cancer risk in a case-control study in European American ever-smokers (n = 860).
These results indicated that the three-order interaction of CYP2A6, CYP1A1, and CYP2D6 polymorphisms might increase genetic susceptibility to lung cancer.
In 2005, we examined functional CYP2A6 variants associated with reduced metabolism (CYP2A6*2, CYP2A6*9, CYP2A6*4), smoking history, and change in smoking in 878 adult smokers undergoing lung cancer screening in an urban setting.
Overall, we found that CYP2A6 *1/*1 genotype was associated with an increased risk of lung cancer relative to *4/*4 genotype (OR = 2.65, 95 % CI: 1.84-3.81, P < 0.001).
When stratified by smoking, the effects of CYP1A1 and CYP2A6 polymorphisms on lung cancer susceptibility were found to be significant only in heavy smokers who had smoked 40 pack years or more (54% of all cases) but no associations were seen for lighter smokers.
It has been reported that the plasma concentration of cotinine, a major metabolite of nicotine, in carriers of wild-type alleles of CYP2A6 is considerably higher than that in carriers of null or reduced-function alleles of CYP2A6, raising the possibility that cotinine plays an important role in the development of lung cancer.
Heterozygote carriers of SNPs in CYP1A2 1545T>C, -164C>A and -740T>G; CYP2A6 -47A>C; MDR1 3435T>C; NAT1 1088T>A and 1095A>C; GSTA2 S112T; GSTM3 V224I and MTHFR A222V had altered risk of developing lung cancer.