TY - JOUR
T1 - Common polymorphisms in FMO1 are associated with nicotine dependence
AU - Hinrichs, Anthony L.
AU - Murphy, Sharon E.
AU - Wang, Jen C.
AU - Saccone, Scott
AU - Saccone, Nancy
AU - Steinbach, Joe Henry
AU - Goate, Alison
AU - Stevens, Victoria L.
AU - Bierut, Laura J.
PY - 2011/7
Y1 - 2011/7
N2 - 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.
AB - 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.
KW - flavin monooxygenase 1
KW - nicotine dependence
KW - nicotine metabolism
UR - http://www.scopus.com/inward/record.url?scp=79959800431&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79959800431&partnerID=8YFLogxK
U2 - 10.1097/FPC.0b013e328346886f
DO - 10.1097/FPC.0b013e328346886f
M3 - Article
C2 - 21540762
AN - SCOPUS:79959800431
SN - 1744-6872
VL - 21
SP - 397
EP - 402
JO - Pharmacogenetics and genomics
JF - Pharmacogenetics and genomics
IS - 7
ER -