title: CYP2B6 non-coding variation associated with smoking cessation is also associated with differences in allelic expression, splicing, and nicotine metabolism independent of common amino-acid changes.
abstract: The Cytochrome P450 2B6 (CYP2B6) enzyme makes a small contribution to hepatic nicotine metabolism relative to CYP2A6, but CYP2B6 is the primary enzyme responsible for metabolism of the smoking cessation drug bupropion. Using CYP2A6 genotype as a covariate, we find that a non-coding polymorphism in CYP2B6 previously associated with smoking cessation (rs8109525) is also significantly associated with nicotine metabolism. The association is independent of the well-studied non-synonymous variants rs3211371, rs3745274, and rs2279343 (CYP2B6*5 and *6). Expression studies demonstrate that rs8109525 is also associated with differences in CYP2B6 mRNA expression in liver biopsy samples. Splicing assays demonstrate that specific splice forms of CYP2B6 are associated with haplotypes defined by variants including rs3745274 and rs8109525. These results indicate differences in mRNA expression and splicing as potential molecular mechanisms by which non-coding variation in CYP2B6 may affect enzymatic activity leading to differences in metabolism and smoking cessation.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: A Joseph
authors.initials: AJ
authors.lastname: Bloom
authors.forename: Maribel
authors.initials: M
authors.lastname: Martinez
authors.forename: Li-Shiun
authors.initials: LS
authors.lastname: Chen
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Murphy
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
mesh_terms: D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D003367:Cotinine / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D009538:Nicotine / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D016540:Smoking Cessation
chemical_list: D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D003367:Cotinine