Chunk #28 — From large-effect risk loci to disease biology — The CHRNA5–CHRNA3–CHRNB4 nicotinic receptor gene cluster and the CYP2A6 nicotine-metabolising gene.
Nicotine biological effects are also modulated by metabolism, with multiple steps and several enzymatic pathways63. Cytochrome P450 family 2 subfamily A member 6 (CYP2A6) accounts for up to 80% of nicotine clearance. In particular, CYP2A6 is involved in two key reactions, nicotine oxidation to nicotine iminium ion, and cotinine oxidation to hydroxycotinine. The hydroxycotinine/cotinine ratio (known as nicotine metabolic ratio (NMR)) is a biomarker of CYP2A6 activity and nicotine clearance66. NMR heritability is about 60–80%, and CYP2A6 variants account for up to 30% of the phenotypic variantion67. In line with this functional effect, CYP2A6 variation showed consistent associations with nicotine dependence, smoking, smoking cessation, lung cancer, and other related traits68–71. A brain imaging study showed that in smokers the CYP2A6 effect on brain concentration of nicotine influences circuits involved in reward and impulsivity processes72.
