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


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.


CONCLUSIONS
As new variants are discovered, the relationships between CYP2A6 genotype, nicotine metabolism, smoking behaviors and tobacco-related cancer risk will be further clarified.
Department of Pharmacology, Room 4326 Medical Sciences Building, 1 King's College Circle, CAMH & University of Toronto, Toronto, ON M5S 1A8, Canada.
Jill C
JC
Mwenifumbo
Qian
Q
Zhou
Neal L
NL
Benowitz
Edward M
EM
Sellers
Rachel F
RF
Tyndale
D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001483:Base Sequence; D044383:Black People; D003001:Cloning, Molecular; D018592:Cross-Over Studies; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D004247:DNA / Q000235:genetics; D005091:Exons; D005785:Gene Conversion / Q000235:genetics*; D017353:Gene Deletion; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D009538:Nicotine / Q000493:pharmacokinetics / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000493:pharmacokinetics / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000235:genetics*
D018722:Nicotinic Agonists; D009538:Nicotine; D004247:DNA; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C423964:CYP2A7 protein, human; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2