A r tic le Interplay of Genetic Risk Factors (CH R N A 5 -CH R N A 3 -CH R N B 4 ) and Cessation tre atm e n ts in Smoking Cessation Success Li-Shiun Chen, M.D., M.P.H., Sc.D. O b je c tiv e : Smoking is highly intractable, R e su lts: The genetic variants in the and the genetic influences on cessation CHRNA5-CHRNA3-CHRNB4 region that pre- Timothy B. Baker, Ph.D. are unclear. Identifying the genetic factors dict nicotine dependence also predicted a affecting smoking cessation could eluci- later age at smoking cessation in the com - date the nature of tobacco dependence, munity sample. In the smoking cessation Megan E. Piper, Ph.D. enhance risk assessment, and support de- trial, haplotype predicted abstinence at velopment of treatment algorithms. This end of treatment in individuals receiving Naomi Breslau, Ph.D. study tested whether variants in the nico- placebo but not among individuals re- tinic receptor gene cluster CHRNA5- ceiving active medication. Haplotype in- Dale S. Cannon, Ph.D. CHRNA3-CHRNB4 predict age at smoking teracted with treatment in affecting ces- cessation and relapse after an attempt to sation success. Kimberly F. Doheny, Ph.D. quit smoking. Conclusions: Smokers with the high-risk M e th o d : In a community-based, cross- haplotype were three times as likely to re- Stephanie M. Gogarten, Ph.D. sectional study (N=5,216) and a random - spond to pharmacologic cessation treat- ized comparative effectiveness smoking ments as were smokers with the low-risk Eric O. Johnson, Ph.D. cessation trial (N=1,073), the authors used haplotype. The high-risk haplotype in- Cox proportional hazard models and lo- creased the risk of cessation failure, and Nancy L. Saccone, Ph.D. gistic regression to model the relation- this increased risk was ameliorated by ships of smoking cessation (self-reported cessation pharmacotherapy. By identify- quit age in the community study and ing a high-risk genetic group with height- Jen C. Wang, Ph.D. point-prevalence abstinence at the end ened response to smoking cessation phar- of treatment in the clinical trial) to three macotherapy, this work may support the Robert B. Weiss, Ph.D. common haplotypes in the CHRNA5- development of personalized cessation CHRNA3-CHRNB4 region defined by treatments. Alison M. Goate, D.Phil. rs16969968 and rs680244. Laura Jean Bierut, M.D. (Am J Psychiatry 2012; 169:735–742) Tobacco smoking is a serious public health problem. tity, defined by cigarettes per day; the most robust asso- Unfortunately, smoking is a quintessential dependence ciations have been reported for rs16969968 and rs1051730, disorder, evidenced by a characteristic withdrawal syn- two highly correlated variants (p<5.57×10–72) (10). In the drome and heavy, uncontrolled use (1). Cardinal mani- CHRNA5-A3-B4 region, at least two independent signals festations of uncontrolled use are persistent use and an have been identified (9, 12). The first signal, tagged by inability to quit successfully in a cessation attempt (1–3). rs16969968, a variant that results in an amino acid change Nicotine dependence is associated with both a reduced in the a5 nicotinic cholinergic receptor (CHRNA5), alters likelihood of quitting over time (4) and a rapid return to nicotinic receptor conductance in vitro (13, 14). A second, smoking following a quit attempt (3, 5–7). Therefore, iden- distinct signal, tagged by rs680244, is associated with vari- tification of the factors that contribute to either sustained ability in CHRNA5 mRNA levels (15). Resequencing of the smoking or more rapid smoking relapse should help eluci- CHRNA5-CHRNA3-CHRNB4 locus in subjects of European date the causal basis of tobacco dependence, permit more ancestry identified three common haplotypes in the region accurate prediction of dependence and relapse risk, and spanning CHRNA5 and the 3( end of CHRNA3 (12), which support more effective application of treatment. can be defined by rs16969968 and rs680244 (15). Recent meta-analyses (8–11) based on tens of thousands The CHRNA5-CHRNA3-CHRNB4 variants have been of subjects of European descent have confirmed the asso- less consistently associated with cessation outcomes than ciation of chromosome region 15q25.1 with smoking quan- with measures of smoking quantity. Five studies have This article is featured in this month’s AJP A u d io, is discussed in an ed ito rials by Dr. Lotrich (p. 681), is an article that provides Clinical Guidance (p. 742), and is the subject of a CM e course (p. 767) Am J Psychiatry 169:7, July 2012 ajp.psychiatryonline.org 7 3 5 G eN etic Facto rs an d SM o K IN G CessatIo N Success shown an association between the CHRNA5-CHRNA3- sample and failed abstinence at the end of treatment in a CHRNB4 region and successful smoking cessation (16– treatment trial. Analyses addressed three major questions: 20). All five found that the same genetic risk variants that 1) Does the natural history of smoking cessation vary by contribute to smoking quantity and nicotine dependence genetic variants in the chromosome 15q25 region? 2) Do also predicted smoking cessation. Other studies, howev- these variants predict cessation in a treatment trial? 3) er, failed to confirm this association (21–23). A genome- Does the relation between the genetic variants and cessa- wide association study of three treatment cohorts did tion depend on treatment status? The results are relevant not identify any nicotinic receptor genes as predictors of to understanding the nature of risk posed by the targeted prospectively measured smoking cessation (23). One large variants for cessation and whether the variants have phar- genome-wide association meta-analysis that strongly macogenetic implications in treatment assignment or ap- supported the association between 15q25.1 and smoking plication. quantity failed to find an association with smoking cessa- tion (current versus former smoking) at a genome-wide M e th o d level of significance (10). A logical case can be made for a relation between the Community Study CHRNA5-CHRNA3-CHRNB4 variants and smoking cessa- We used the ARIC study to examine the genetic association tion. These variants are consistently related to measures with age at cessation in a nontreatment setting. It is a prospec- of smoking quantity and nicotine dependence (12, 16), tive epidemiologic study conducted in four U.S. communities and there is copious evidence that measures of nicotine to investigate atherosclerosis. In 1987, each ARIC field center dependence predict cessation likelihood (4, 5, 24). These recruited a cohort sample ages 45–64 from a defined population findings encourage examination of the involvement of in its community, and almost 16,000 subjects participated. Self- reported age at cessation was assessed with the question “How the CHRNA5-CHRNA3-CHRNB4 variants in cessation old were you when you stopped smoking?” Genotyping was per- and further suggest that this relation is mediated by de- formed on the Affymetrix 6.0 chip at the Broad Institute of the pendence. If evidence for mediation is not found and yet Massachusetts Institute of Technology and Harvard University. the variants are related to cessation, it would suggest that Genetic and phenotype data were available for 12,771 subjects; the variants influence cessation through routes that are data were obtained from the National Center for Biotechnol- ogy Information database of Genotypes and Phenotypes (http:// independent of their influence on dependence. More- www.ncbi.nlm.nih.gov/sites/entrez?db=gap; dbGaP accession over, previous research suggests that the relation between number phs000090.v1.p1). the CHRNA5-CHRNA3-CHRNB4 variants and cessation should be examined with regard to pharmacotherapy. Smoking Cessation Clinical Trial There is mounting evidence that pharmacotherapies work We used a randomized, placebo-controlled smoking cessa- by mitigating the risks for cessation failure that are related tion trial at the University of Wisconsin Center for Tobacco Re- to severity of nicotine dependence (25, 26). This suggests search and Intervention (31) to examine the genetic association with time to relapse after quitting in a treatment trial setting. This that the connection between the variants and cessation study group has not been previously examined for the association may be strongest among individuals who do not receive of genetic risk with smoking cessation. The institutional review pharmacotherapy for smoking cessation. board at the University of Wisconsin–Madison approved this trial, Using data from a community-based project, the Ath- and all subjects provided written informed consent. erosclerosis Risk in Communities (ARIC) study (27), and Participants were eligible to participate if they were 18 years of age or older, smoked 10 or more cigarettes per day, and were mo- a smoking cessation clinical trial at the University of Wis- tivated to quit smoking. Before randomization, the participants consin Transdisciplinary Tobacco Use Research Center, we completed baseline assessments of demographic characteristics, extended the research on the CHRNA5-CHRNA3-CHRNB4 smoking history (including cigarettes smoked per day), and to- region and smoking cessation success. This research was bacco dependence, which included the Fagerström Test for Nico- predicated on hypotheses about the relations of CHRNA5- tine Dependence (32). Each participant provided a breath sample for alveolar carbon monoxide analysis to verify smoking status CHRNA3-CHRNB4 variants, tobacco dependence, and and estimate the quantity of smoking. smoking cessation. The two types of studies differ in study The participants (N=1,073) were randomly assigned to six duration, amount of experimental contact and monitor- conditions: placebo (N=132), nicotine patch (N=187), nicotine ing, and type of participants. However, complementary lozenge (N=183), sustained-release bupropion (N=188), nicotine hypotheses were developed for these two types of research patch and nicotine lozenge (N=193), or bupropion and nicotine lozenge (N=190).