Nicotinic acetylcholine receptor variation and response to... : Pharmacogenetics and Genomics (original) (raw)

ORIGINAL ARTICLES

Nicotinic acetylcholine receptor variation and response to smoking cessation therapies

Bergen, Andrew W.; Javitz, Harold S.; Krasnow, Ruth; Nishita, Denise; Michel, Martha; Conti, David V.; Liu, Jinghua; Lee, Won; Edlund, Christopher K.; Hall, Sharon; Kwok, Pui-Yan; Benowitz, Neal L.; Baker, Timothy B.; Tyndale, Rachel F.; Lerman, Caryn; Swan, Gary E.

aCenter for Health Sciences, SRI International, Menlo Park

bDepartment of Preventive Medicine, University of Southern California, Los Angeles

Departments of cPsychiatry

dDermatology

eMedicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California

fDepartment of Medicine, University of Wisconsin, Madison, Wisconsin

gDepartment of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA

hDepartments of Psychiatry, Pharmacology and Toxicology, Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.pharmacogeneticsandgenomics.com).

Correspondence to Andrew W. Bergen, PhD, Center for Health Sciences, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA Tel:+1 240 463 1430; fax:+1 650 859 5099; e-mail: [email protected]

Received August 6, 2012

Accepted November 20, 2012

Abstract

Objective

To evaluate the association of nicotinic acetylcholine receptor (nAChR) single nucleotide polymorphism (SNP) with 7-day point prevalence abstinence (abstinence) in randomized clinical trials of smoking cessation therapies in individuals grouped by pharmacotherapy randomization to inform the development of personalized smoking cessation therapy.

Materials and methods

We quantified association of four SNPs at three nAChRs with abstinence in eight randomized clinical trials. Participants were 2633 outpatient treatment-seeking, self-identified European ancestry individuals smoking at least 10 cigarettes/day, recruited through advertisement, prescribed pharmacotherapy, and provided with behavioral therapy. Interventions included nicotine replacement therapy (NRT), bupropion, varenicline, placebo (PLA), or combined NRT and bupropion, and five modes of group and individual behavioral therapy. Outcome measures tested in multivariate logistic regression were end of treatment and 6 month (6MO) abstinence, with demographic, behavioral, and genetic covariates.

Results

‘Risk’ alleles previously associated with smoking heaviness were significantly (P<0.05) associated with reduced abstinence in the PLA pharmacotherapy group (PG) at 6MO [for rs588765, odds ratio (95% confidence interval) 0.41 (0.17–0.99)], and at end of treatment and at 6MO [for rs1051730, 0.42 (0.19–0.93) and 0.31 (0.12–0.80)], and with increased abstinence in the NRT PG at 6MO [for rs588765, 2.07 (1.11–3.87) and for rs1051730, 2.54 (1.29–4.99)]. We observed significant heterogeneity in rs1051730 effects (_F_=2.48, _P_=0.021) between PGs.

Conclusion

chr15q25.1 nAChR SNP risk alleles for smoking heaviness significantly increase relapse with PLA treatment and significantly increase abstinence with NRT. These SNP–PG associations require replication in independent samples for validation, and testing in larger sample sizes to evaluate whether similar effects occur in other PGs.