title: 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.
authors.forename: Sungshim L
authors.initials: SL
authors.lastname: Park
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center , Honolulu, HI 96813 , USA and.
authors.forename: Maarit I
authors.initials: MI
authors.lastname: Tiirikainen
authors.forename: Yesha M
authors.initials: YM
authors.lastname: Patel
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center , Honolulu, HI 96813 , USA and.
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Wilkens
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center , Honolulu, HI 96813 , USA and.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, University of Minnesota , 2231 6th Street SE, 2-127 CCRB, Minneapolis, MN 55455 , USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Murphy
mesh_terms: D000328:Adult; D000368:Aged; D002853:Chromatography, Liquid; D015331:Cohort Studies; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000208:ethnology* / Q000209:etiology / Q000235:genetics*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009538:Nicotine / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000235:genetics*
chemical_list: D009538:Nicotine; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6
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