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Gender-stratified gene and gene–treatment interactions in smoking cessation

The Pharmacogenomics Journal volume 12, pages 521–532 (2012)Cite this article

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Abstract

We conducted gender-stratified analyses on a systems-based candidate gene study of 53 regions involved in nicotinic response and the brain—reward pathway in two randomized clinical trials of smoking cessation treatments (placebo, bupropion, transdermal and nasal spray nicotine replacement therapy). We adjusted P-values for multiple correlated tests, and used a Bonferroni-corrected α-level of 5 × 10−4 to determine system-wide significance. Four single-nucleotide polymorphisms (rs12021667, rs12027267, rs6702335, rs12039988; r2>0.98) in erythrocyte membrane protein band 4.1 (EPB41) had a significant male-specific marginal association with smoking abstinence (odds ratio (OR)=0.5; 95% confidence interval (CI): 0.3–0.6) at end of treatment (adjusted P<6 × 10−5). rs806365 in cannabinoid receptor 1 (CNR1) had a significant male-specific gene–treatment interaction at 6-month follow-up (adjusted P=3.9 × 10−5); within males using nasal spray, rs806365 was associated with a decrease in odds of abstinence (OR=0.04; 95% CI: 0.01–0.2). While the role of CNR1 in substance abuse has been well studied, we report EPB41 for the first time in the nicotine literature.

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Acknowledgements

We thank the participants of the two randomized clinical trials for their contributions to research. We acknowledge the contributions of Faith Allen, Ruth Krasnow, Huaiyu Mi, and Chris Edlund for data curation and management. This research was supported by a grant from NIDA, NCI, NIGMS and NHGRI U01 DA020830, NIDA R01 DA002277 and NCI P50 CA084735.

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Authors and Affiliations

  1. Department of Preventive Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA

    W Lee, D Li, J Liu, P Thomas & D V Conti

  2. Center for Health Sciences, SRI International, Menlo Park, CA, USA

    A W Bergen & G E Swan

  3. Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    R F Tyndale

  4. Departments of Medicine, Biopharmaceutical Sciences, Psychiatry, and Clinical Pharmacy, University of California at San Francisco, San Francisco, CA, USA

    N L Benowitz

  5. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

    C Lerman

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  1. W Lee
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Correspondence to D V Conti.

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Competing interests

Drs. Swan and Conti have served as consultants for Pfizer. Dr. Lerman has served as a consultant for and/or received research support from Pfizer, AstraZeneca, Novartis, Targacept and Glaxo SmithKline. Dr. Tyndale owns shares and participates in Nicogen Research, a company focused on novel smoking cessation treatment approaches. No Nicogen funds were used in this work and no other Nicogen participants reviewed the manuscript. Dr. Tyndale has also consulted for Novartis. Dr. Benowitz is a paid consultant for several pharmaceutical companies that market smoking cessation medications and has been a paid expert witness against tobacco companies in litigation related to nicotine addiction. This research was not supported by industry funds.

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Lee, W., Bergen, A., Swan, G. et al. Gender-stratified gene and gene–treatment interactions in smoking cessation. Pharmacogenomics J 12, 521–532 (2012). https://doi.org/10.1038/tpj.2011.30

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