Evidence for large-scale gene-by-smoking interaction effects on pulmonary function.

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 FEV 1 (forced expiratory volume in 1 second) or FEV 1 /FVC (FEV 1 /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 FEV 1 or FEV 1 /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 ( βint  = -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 FEV 1 /FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV /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 FEV 1 /FVC may be more susceptible to the deleterious effects of smoking.

• Authors: Hugues Aschard, Martin D Tobin, Dana B Hancock, David Skurnik, Akshay Sood, Alan James, Albert Vernon Smith, Ani W Manichaikul, Archie Campbell, Bram P Prins, Caroline Hayward, Daan W Loth, David J Porteous, David P Strachan, Eleftheria Zeggini, George T O'Connor, Guy G Brusselle, H Marike Boezen, Holger Schulz, Ian J Deary, Ian P Hall, Igor Rudan, Jaakko Kaprio, James F Wilson, Jemma B Wilk, Jennifer E Huffman, Jing Hua Zhao, Kim de Jong, Leo-Pekka Lyytikäinen, Louise V Wain, Marjo-Riitta Jarvelin, Mika Kähönen, Myriam Fornage, Ozren Polasek, Patricia A Cassano, R Graham Barr, Rajesh Rawal, Sarah E Harris, Sina A Gharib, Stefan Enroth, Susan R Heckbert, Terho Lehtimäki, Ulf Gyllensten, Understanding Society Scientific Group, Victoria E Jackson, Vilmundur Gudnason, Wenbo Tang, Josée Dupuis, María Soler Artigas, Amit D Joshi, Stephanie J London, Peter Kraft
• Journal: International journal of epidemiology (Int J Epidemiol) Vol. 46 Issue 3 Pg. 894-904 (06 01 2017) ISSN: 1464-3685 [Electronic] England
• PMID: 28082375 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association

Topics

• Europe
• Female
• Forced Expiratory Volume (genetics)
• Gene-Environment Interaction
• Humans
• Linear Models
• Male
• Middle Aged
• Multivariate Analysis
• Polymorphism, Single Nucleotide
• Risk Assessment
• Smoking (epidemiology, genetics)
• Spirometry
• Vital Capacity (genetics)