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Human Molecular Genetics Advance Access originally published online on July 23, 2009
Human Molecular Genetics 2009 18(20):4007-4012; doi:10.1093/hmg/ddp322
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15

Kaisu Keskitalo1,*, Ulla Broms1,3, Markku Heliövaara3, Samuli Ripatti3,4, Ida Surakka3,4, Markus Perola2,3,4, Janne Pitkäniemi1, Leena Peltonen2,3,4,5,6, Arpo Aromaa3 and Jaakko Kaprio1,3,4

1 Department of Public Health and 2 Department of Medical Genetics, University of Helsinki, University of Helsinki 00014, Finland, 3 National Institute for Health and Welfare, Helsinki 00271, Finland, 4 Institute for Molecular Medicine Finland, FIMM, Helsinki 00290, Finland, 5 Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK and 6 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA 02138, USA

* To whom correspondence should be addressed at: Department of Public Health, University of Helsinki, PO Box 41, University of Helsinki 00014, Finland. Tel: +358 919127541; Fax: +358 919127570; Email: kaisu.keskitalo{at}helsinki.fi

Received May 28, 2009; Revised July 2, 2009; Accepted July 13, 2009

A cluster of three nicotinic acetylcholine receptor genes on chromosome 15 (CHRNA5/CHRNA3/CHRNB4) has been shown to be associated with nicotine dependence and smoking quantity. The aim of this study was to clarify whether the variation at this locus regulates nicotine intake among smokers by using the level of a metabolite of nicotine, cotinine, as an outcome. The number of cigarettes smoked per day (CPD) and immune-reactive serum cotinine level were determined in 516 daily smokers (age 30–75 years, 303 males) from the population-based Health2000 study. Association of 21 SNPs from a 100 kb region of chromosome 15 with cotinine and CPD was examined. SNP rs1051730 showed the strongest association to both measures. However, this SNP accounted for nearly a five-fold larger proportion of variance in cotinine levels than in CPD (R2 4.3% versus 0.9%). The effect size of the SNP was 0.30 for cotinine level, whereas it was 0.13 for CPD. Variation at CHRNA5/CHRNA3/CHRNB4 cluster influences nicotine level, measured as cotinine, more strongly than smoking quantity, measured by CPD, and appears thus to be involved in regulation of nicotine levels among smokers.


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