Genetic determinants of CYP2A6 activity across racial/ethnic groups with different risks of lung cancer and effect on their smoking intensity

Abstract

Genetic variation in cytochrome P450 2A6 (CYP2A6) gene is the primary contributor to the intraindividual and interindividual differences in nicotine metabolism and has been found to influence smoking intensity. 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. This study genotyped 10 known functional CYP2A6 genetic or copy number variants in 2115 current smokers from the multiethnic cohort study [African Americans (AA) = 350, Native Hawaiians (NH) = 288, Whites = 413, Latinos (LA) = 437 and Japanese Americans (JA) = 627] to conduct such an investigation. Here, we found that LA had the highest CYP2A6 activity followed by Whites, AA, NH and JA, who had the lowest levels. Adjusting for age, sex, race/ethnicity and body mass index, we found that CYP2A6 diplotypes were predictive of TNE levels, particularly in AA and JA (P trend < 0.0001). However, only in JA did the association remain after accounting for cigarettes per day. Also, it is only in this population that the lower activity ratio supports lower TNE levels, carcinogen exposure and thereby lower risk of lung cancer. Despite the association between nicotine metabolism (CYP2A6 activity phenotype and diplotypes) and smoking intensity (TNE), CYP2A6 levels did not correlate with the higher TNE levels found in AA nor the lower TNE levels found in LA, suggesting that other factors may influence smoking dose in these populations. Therefore, further study in these populations is recommended.

Figure 1.

CYP2A6 activity and TNE stratified by racial/ethnic group. (A) The urinary ratio of total 3-HCOT to cotinine adjusted for age, sex, CPD and TNE; (B) TNE by racial/ethnic group adjusted for age, sex, BMI and CPD (hatched bars) and additionally adjusted for CYP2A6 activity (black bars). *P < 0.04, **P < 0.001, ***P < 0.0001 for difference between this group and Whites.

Figure 2.

Distribution of CYP2A6 haplotype. Haplotypes, PHASED from eight SNPs and two deletions, are listed in the order of predicted metabolic activity [normal, N (green) to non-functional or deleted, *12 and *4 (red)]. The allele nomenclature is as described at http://www.cypalleles.ki.se/cyp2a6.htm.

Figure 3.

TNE by CYP2A6 diplotype. Diplotypes categories are defined by the functional activity of each allele as follows: N (no variant allele or *1A +*14); I (intermediate activity), *1H, *1A, *9, *17, *23; L (little or no activity), *4, *1A+2, *1H+2, *12, *1H+*7, *7.