Common polymorphisms in FMO1 are associated with nicotine dependence

Anthony L. Hinrichs, Sharon E. Murphy, Jen C. Wang, Scott Saccone, Nancy Saccone, Joe Henry Steinbach, Alison Goate, Victoria L. Stevens, Laura J. Bierut

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)397-402
Number of pages6
JournalPharmacogenetics and genomics
Volume21
Issue number7
DOIs
StatePublished - Jul 2011

Keywords

  • flavin monooxygenase 1
  • nicotine dependence
  • nicotine metabolism

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