| 20136358 |
Mwenifumbo JC, Zhou Q, Benowitz NL, Sellers EM, Tyndale RF: New CYP2A6 gene deletion and conversion variants in a population of Black African descent. Pharmacogenomics. 2010 Feb;11(2):189-98.
AIMS: Cytochrome P450 2A6 (CYP2A6) is a human enzyme best known for metabolizing nicotine and nitrosamine precarcinogens. Our aim was to discover and characterize new CYP2A6 alleles in a population of Black African descent. MATERIALS & METHODS: We used cloning, sequencing and genotyping of genomic DNA to discover new variants, and in vivo nicotine pharmacokinetic phenotyping to characterize the functional effect of the new alleles. RESULTS: Four new CYP2A6 alleles, CYP2A6*4G, *4H, *1B4 and *1L, were discovered and characterized in a population of Black African descent. The two new deletion alleles, CYP2A6*4G and *4H, are distinguished by different crossover junctions at 7.9 and 7.8 kb downstream of the CYP2A6 +1ATG start site, respectively; their combined allele frequency is 1.6%. The new gene conversion alleles, CYP2A6*1B4 and CYP2A6*1L, contain 27 and 10 bp of CYP2A7 sequence in the CYP2A6 3 -flanking region, respectively; their combined allele frequency is 7.3%. CYP2A6*4 appears to associate with lower CYP2A6 activity in vivo, while CYP2A6*1L does not; however, CYP2A6*1L confounds genotyping assays that use the 2A6R3 and 2A6R4 primers. CONCLUSION: As new variants are discovered, the relationships between CYP2A6 genotype, nicotine metabolism, smoking behaviors and tobacco-related cancer risk will be further clarified. |
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