A variant associated with nicotine dependence, lung cancer and peripheral arterial disease

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Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year1,2. 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 health9,10. 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 controls18,19, 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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We thank the participants in the genetic studies whose contributions made this work possible, the staff at Noatun (deCODE’s recruitment centre), and personnel at deCODE’s core facilities. This work was supported in part by funds from the National Institute of Drug Abuse and the European Commission.

Author Contributions T.E.T., F.G., P.S., and T.R. contributed equally to this work. T.E.T., F.G., P.S, T.R., A.W., D.F.G., A.K. and K.S. wrote the first draft of the paper. Ha.S., H.J.I., T.G. and S.J. recruited and diagnosed the Icelandic lung cancer patients. S.E.M. recruited and diagnosed the Icelandic peripheral arterial disease patients. T.B., H.K., J.G.S., I.H, V.R., H.O., T.T. and S.J. recruited and diagnosed nicotine addiction subjects. K.K.H.A., F.d.V., P.F.A.M. and L.A.K. recruited and diagnosed the subjects from The Netherlands. D.I., M.J.V., L.A., B.S., L.M. and J.I.M. recruited and diagnosed the Spanish subjects. G.T.J. and A.M.v.R. recruited and diagnosed the subjects from New Zealand. T.M., B.P. and M.H. recruited and diagnosed subjects from Austria. A.G. and B.L. recruited and diagnosed subjects from Sweden. A.F. and R.P. recruited and diagnosed subjects from Italy. A.W., A.I., S.N.S., J.T.B., S.T., J.G., M.J., J.S., O.O. and S.N.S. performed genotyping and experimental work. L.J.G., G.B. and K.K. incorporated phenotypic data into a database and analysed it. T.E.T., F.G., P.S., T.R., A.W., K.P.M., A.M., G.T., D.F.G. and A.K. analysed the data. T.E.T., F.G., P.S., T.R., K.P.M., Hr.S., T.J., J.I.M., L.K., H.O., T.T., J.R.G., S.J., D.G., U.T., A.K. and K.S. planned, supervised and coordinated the work. All authors contributed to the final version of the paper.

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Correspondence to Thorgeir E. Thorgeirsson or Kari Stefansson.

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Some of the authors employed by deCODE genetics own stock or stock options in the company

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This file contains Supplementary Methods, Supplementary Results, Supplementary Figure 1, Supplementary Tables 1-6, and additional references. (PDF 292 kb)

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