1. deCODE Genetics, 101 Reykjavik, Iceland
2. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA
3. Department of Medical Oncology,
4. Department of Pathology,
5. Department of Cardiothoracic Surgery,
6. Department of General Adult Psychiatry, and,
7. Department of Medicine, Landspitali University Hospital, 101 Reykjavik, Iceland
8. Department of Surgery, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand
9. Department of Laboratory Medicine, Konventhospital Barmherzige Brueder, 4020 Linz, Austria
10. Center for Vascular Diseases, University Hospital, MAS, 205 02 Malmö, Sweden
11. Laboratory of Vascular Biology and Genetics, A. Gemelli University Hospital, Universita Cattolica del Sacro Cuore School of Medicine, 00168 Rome, Italy
12. Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands
13. Comprehensive Cancer Center East, 6501 BG Nijmegen, The Netherlands
14. Department of Urology, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands
15. Division of Medical Oncology, University Hospital, 5009 Zaragoza, Spain
16. Nanotechnology Institute of Aragon, 5009 Zaragoza, Spain
17. Health Science Institute, 5009 Zaragoza, Spain
18. Division of Medical Oncology, Hospital Reina Sofia, 31500 Tudela, Spain
19. Department of Lung Disease, Primary Health Care Centre, 101 Reykjavik, Iceland
20. Vogur SAA Addiction Treatment Center, 112 Reykjavik, Iceland
21. OASI Institute for Research and Care (IRCCS), 94018 Troina (EN), Italy
22. School of Medicine, University of Iceland, 101 Reykjavik, Iceland
23. Therapeia, 101 Reykjavik, Iceland
24. These authors contributed equally to this work.

Correspondence to: Thorgeir E. Thorgeirsson^1,24Kari Stefansson^1,22 Correspondence and requests for materials should be addressed to T.E.T. (Email: thorgeir@decode.is) or K.S. (Email: kari.stefansson@decode.is).

Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year^{1, 2}. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND)^{3, 4, 5, 6, 7, 8} has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health^{9, 10}. Smoking is the major risk factor for lung cancer (LC)^{11, 12, 13, 14} and is one of the main risk factors for peripheral arterial disease (PAD)^{15, 16, 17}. Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls^{18, 19}, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene–environment interaction²⁰, highlighting the role of nicotine addiction in the pathology of other serious diseases.

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