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Aschard, Hugues and Tobin, Martin D. and Hancock, Dana B. and Skurnik, David and Sood, Akshay and James, Alan and Vernon Smith, Albert and Manichaikul, Ani W. and Campbell, Archie and Prins, Bram P. and Hayward, Caroline and Loth, Daan W. and Porteous, David J. and Strachan, David P. and Zeggini, Eleftheria and O’Connor, George T. and Brusselle, Guy G. and Boezen, H. Marike and Schulz, Holger and Deary, Ian J. and Hall, Ian P. and Rudan, Igor and Kaprio, Jaakko and Wilson, James F. and Wilk, Jemma B. and Huffman, Jennifer E. and Hua Zhao, Jing and de Jong, Kim and Lyytikäinen, Leo-Pekka and Wain, Louise V. and Jarvelin, Marjo-Riitta and Kähönen, Mika and Fornage, Myriam and Polasek, Ozren and Cassano, Patricia A. and Barr, R. Graham and Rawal, Rajesh and Harris, Sarah E. and Gharib, Sina A. and Enroth, Stefan and Heckbert, Susan R. and Lehtimäki, Terho and Gyllensten, Ulf and Gudnason, Vilmundur and Jackson, Victoria E. and Tang, Wenbo and Dupuis, Josée and Soler Artigas, María and Joshi, Amit D. and London, Stephanie J. and Kraft, Peter (2017) Evidence for large-scale gene-by-smoking interaction effects on pulmonary function. International Journal of Epidemiology . dyw318. ISSN 0300-5771

Abstract

Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking.

Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia.

Results: We identified an interaction (bint=–0.036, 95% confidence interval, -0.040 to -0.032, P=0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV1/FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect.

Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.

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