4.2 Article

New CYP2A6 gene deletion and conversion variants in a population of Black African descent

期刊

PHARMACOGENOMICS
卷 11, 期 2, 页码 189-198

出版社

FUTURE MEDICINE LTD
DOI: 10.2217/PGS.09.144

关键词

CYP2A6; deletion; gene conversion; nicotine; trans-3 '-hydroxycotinine/cotinine ratio

资金

  1. Centre for Addiction and Mental Health
  2. Canadian Institutes of Health Research (CIHR) [MOP-86471]
  3. Canada Research Chair in Pharmacogenetics (RFT)
  4. National Institute oil Drug Abuse [DA02277, DA20830]
  5. Tobacco Use in Special Populations awards

向作者/读者索取更多资源

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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