Interplay of genetic risk factors (CHRNA5-CHRNA3-CHRNB4) and cessation treatments in smoking cessation success.
OBJECTIVE
Smoking is highly intractable, and the genetic influences on cessation are unclear. Identifying the genetic factors affecting smoking cessation could elucidate the nature of tobacco dependence, enhance risk assessment, and support development of treatment algorithms. This study tested whether variants in the nicotinic receptor gene cluster CHRNA5-CHRNA3-CHRNB4 predict age at smoking cessation and relapse after an attempt to quit smoking.


METHODS
In a community-based, crosssectional study (N=5,216) and a randomized comparative effectiveness smoking cessation trial (N=1,073), the authors used Cox proportional hazard models and logistic regression to model the relationships of smoking cessation (self-reported quit age in the community study and point-prevalence abstinence at the end of treatment in the clinical trial) to three common haplotypes in the CHRNA5-CHRNA3-CHRNB4 region defined by rs16969968 and rs680244.


RESULTS
The genetic variants in the CHRNA5-CHRNA3-CHRNB4 region that predict nicotine dependence also predicted a later age at smoking cessation in the community sample. In the smoking cessation trial, haplotype predicted abstinence at end of treatment in individuals receiving placebo but not among individuals receiving active medication. Haplotype interacted with treatment in affecting cessation success.


CONCLUSIONS
Smokers with the high-risk haplotype were three times as likely to respond to pharmacologic cessation treatments as were smokers with the low-risk haplotype. The high-risk haplotype increased the risk of cessation failure, and this increased risk was ameliorated by cessation pharmacotherapy. By identifying a high-risk genetic group with heightened response to smoking cessation pharmacotherapy, this work may support the development of personalized cessation treatments.
Department of Psychiatry and the Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. chenli@psychiatry.wustl.edu
Li-Shiun
LS
Chen
Timothy B
TB
Baker
Megan E
ME
Piper
Naomi
N
Breslau
Dale S
DS
Cannon
Kimberly F
KF
Doheny
Stephanie M
SM
Gogarten
Eric O
EO
Johnson
Nancy L
NL
Saccone
Jen C
JC
Wang
Robert B
RB
Weiss
Alison M
AM
Goate
Laura Jean
LJ
Bierut
D000367:Age Factors; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*; D012307:Risk Factors; D016540:Smoking Cessation / Q000379:methods*; D014029:Tobacco Use Disorder / Q000188:drug therapy / Q000235:genetics*
D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human