Nicotinic acetylcholine receptor variants are associated with cigarette smoking

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Original Article

The Pharmacogenomics Journal advance online publication 17 March 2009; doi: 10.1038/tpj.2009.6

Association of nicotinic acetylcholine receptor subunit 4 polymorphisms with nicotine dependence in 5500 Germans

L P Breitling¹, N Dahmen², K Mittelstra³, D Rujescu⁴, J Gallinat⁵, C Fehr², I Giegling⁴, C Lamina^3,6, T Illig^3,7, H Müller¹, E Raum¹, D Rothenbacher¹, H-E Wichmann³, H Brenner¹ and G Winterer⁸

1. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
2. Department of Psychiatry, University of Mainz, Mainz, Germany
3. Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
4. Department of Psychiatry, Ludwig Maximilians University, Munich, Germany
5. Department of Psychiatry, Charité University Medicine Berlin, Campus Mitte, Berlin, Germany
6. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbrnuck, Austria
7. Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany
8. Department of Psychiatry, Heinrich Heine University, Düsseldorf, Germany

Correspondence: Dr LP Breitling, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Bergheimer Street 20, D-69115 Heidelberg, Germany. Email: L.Breitling@dkfz.de

Received 12 November 2008; Revised 6 February 2009; Accepted 9 February 2009; Published online 17 March 2009.

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Abstract

Polymorphisms in the CHRNA4 gene coding the nicotinic acetylcholine receptor subunit 4 have recently been suggested to play a role in the determination of smoking-related phenotypes. To examine this hypothesis, we conducted a genetic association study in three large samples from the German general population (N₁=1412; N₂=1855; N₃=2294). Five single-nucleotide polymorphisms in CHRNA4 were genotyped in 5561 participants, including 2707 heavily smoking cases (regularly smoking at least 20 cigarettes per day) and 2399 never-smoking controls (100 cigarettes over lifetime). We examined associations of the polymorphisms with smoking case–control status and with the extent of nicotine dependence as measured by the Fagerstrom test of nicotine dependence (FTND) score (N=1030). The most significant association was observed between rs2236196 and FTND (P=0.0023), whereas the closely linked rs1044396 had most statistical support in the case–control models (P=0.0080). The consistent effect estimates across three independent cohorts elaborate on recently published functional studies of rs2236196 from the CHRNA4 3'-untranslated region and seem to converge with accumulating evidence to firmly implicate the variant G allele of this polymorphism in the intensification of nicotine dependence.