title: Common polymorphisms in FMO1 are associated with nicotine dependence.
abstract: BACKGROUND
  Cigarette smoking and other forms of tobacco use are the leading cause of preventable mortality in the world. A better understanding of the etiology of nicotine addiction may help to increase the success rate of cessation and to decrease the massive morbidity and mortality associated with smoking.
  
  
  METHODS
  To identify genetic polymorphisms that contribute to nicotine dependence, our group undertook a genetic association study including three enzyme families that potentially influence nicotine metabolism: cytochrome P450 enzymes, flavin monooxygenases (FMOs), and UDP-glucuronosyl transferases.
  
  
  RESULTS
  Several polymorphisms in FMO1 showed association in a discovery sample, and were tested in an independent replication sample. One polymorphism, rs10912765, showed an association that remained significant after Bonferroni correction (nominal P=0.0067, corrected P=0.0134). Several additional polymorphisms in linkage disequilibrium with this single nucleotide polymorphism also showed association. Subsequent in-vitro experiments characterized FMO1 as a more efficient catalyst of nicotine N-oxidation than FMO3. In adult humans, FMO1 is primarily expressed in the kidney and is likely to be a major contributor to the renal metabolism and clearance of therapeutic drugs. FMO1 is also expressed in the brain and could contribute to the nicotine concentration in this tissue.
  
  
  CONCLUSIONS
  These findings suggest that polymorphisms in FMO1 are significant risk factors in the development of nicotine dependence and that the mechanism may involve variation in nicotine pharmacology.
authors.affiliation: Departments of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63119, USA. tony@fire.wustl.edu
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Hinrichs
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Murphy
authors.forename: Jen C
authors.initials: JC
authors.lastname: Wang
authors.forename: Scott
authors.initials: S
authors.lastname: Saccone
authors.forename: Nancy
authors.initials: N
authors.lastname: Saccone
authors.forename: Joe Henry
authors.initials: JH
authors.lastname: Steinbach
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Stevens
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D056726:Genetic Association Studies; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010105:Oxygenases / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D012907:Smoking / Q000235:genetics; D014029:Tobacco Use Disorder / Q000201:enzymology / Q000235:genetics*
chemical_list: D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D014453:Glucuronosyltransferase