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 increase the success rate of cessation and decrease the massive morbidity and mortality associated with smoking. METHODS In order 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 (CYP P450s), flavin monooxygenases (FMOs) and UDP-glucuronosyl transferases (UGTs). RESULTS Several polymorphisms in FMO1 showed association in a discovery sample and were tested in an independent replication sample. One polymorphism, rs10912765, showed association that remained significant after Bonferroni correction (nominal p=0.0067, corrected p=0.0134). Several additional polymorphisms in linkage disequilibrium with this SNP 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.

Variation in P450 oxidoreductase (POR) A503V and flavin-containing monooxygenase (FMO)-3 E158K is associated with minor alterations in nicotine metabolism, but does not alter cigarette consumption

“…FMO1 is the major fetal hepatic FMO isoform, but in adults is expressed in extra-hepatic tissues, likely including brain [12]. FMO1 also catalyzes nicotine metabolism [12], and variation in FMO1 is associated with nicotine dependence, perhaps through altered brain metabolism of nicotine [12]; further study of associations between this enzyme family and smoking behaviors may be warranted.…”

Targeted sequencing identifies genetic polymorphisms of flavin‐containing monooxygenase genes contributing to susceptibility of nicotine dependence in European American and African American

“…Hinrichs et al. () has identified significant association between SNPs of FMO1 and nicotine dependence. Although a recent study has shown that common polymorphisms in FMO3 can influence nicotine clearance (Bloom et al., ), no study has provided direct evidence of the association between FMO3 polymorphisms and nicotine dependence.…”

Pathway Analysis of Smoking Quantity in Multiple GWAS Identifies Cholinergic and Sensory Pathways

“…The UGT complex of genes, which catalyze nicotine and cotinine glucuronidation [34], were significant in both the OZALC-NAG and SAGE studies, and were identified among the other retinoid binding genes. Furthermore, the flavin monooxygenase 1 gene ( FMO1 ) is also associated with nicotine metabolism [42] and was tagged in the three studies. There is one KEGG pathway (hsa00982 “ Drug metabolism – cytochrome P450 ”) and two GO terms (GO:0005792 “ microsome ” and GO:0042598 “ vesicular fraction ”) with less than 500 genes that include FMO1 and UGT1A4.…”