title: Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms.
abstract: Genome-wide significant associations with cigarettes per day (CPD) and risk for lung cancer and chronic obstructive pulmonary disease (COPD) were previously reported in a region of 19q13, including CYP2A6 (nicotine metabolism enzyme) and EGLN2 (hypoxia response). The associated single nucleotide polymorphisms (SNPs) were assumed to be proxies for functional variation in CYP2A6. Here, we demonstrate that when CYP2A6 and EGLN2 genotypes are analyzed together, the key EGLN2 variant, rs3733829, is not associated with nicotine metabolism independent of CYP2A6, but is nevertheless independently associated with CPD, and with breath carbon monoxide (CO), a phenotype associated with cigarette consumption and relevant to hypoxia. SNPs in EGLN2 are also associated with nicotine dependence and with smoking efficiency (CO/CPD). These results indicate a previously unappreciated novel mechanism behind genome-wide significant associations with cigarette consumption and disease risk unrelated to nicotine metabolism.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: A Joseph
authors.initials: AJ
authors.lastname: Bloom
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Baker
authors.forename: Li-Shiun
authors.initials: LS
authors.lastname: Chen
authors.forename: Naomi
authors.initials: N
authors.lastname: Breslau
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hatsukami
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002248:Carbon Monoxide / Q000032:analysis*; D002888:Chromosomes, Human, Pair 19; D065637:Cytochrome P-450 CYP2A6; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics*; D015810:Linkage Disequilibrium; D009538:Nicotine / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics*
chemical_list: D009538:Nicotine; D002248:Carbon Monoxide; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6
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