Identification of novel genes related to airway obstruction in never-smokers

Background: Although a striking proportion (25-45%) of patients with chronic obstructive pulmonary disease (COPD) are never-smokers, most genetic susceptibility studies have not focussed on this group exclusively. Objective: This study aims to identify common genetic variants associated with airway obstruction in never-smokers by performing a genome-wide association (GWA) study on the ratio of FEV 1 to FVC (FEV 1 /FVC). Methods: We used linear regression to analyse the association between 227,981 genotyped single nucleotide polymorphisms (SNPs) and the level of FEV 1 /FVC in 5,070 never-smokers of the LifeLines study. Results were verified in never-smokers of two other cohorts, namely the Vlagtwedde-Vlaardingen study (n = 432) and the Rotterdam study I (n = 408). Results: Seven top SNPs were associated with the level of FEV 1 /FVC (p-value -5 ) in never-smokers of the LifeLines study and were verified in the two other cohorts. Although the SNPs did not reach genome-wide significance in the meta-analysis (p-value -7 ) of the three cohorts, we observed similar directions and magnitudes of effects for four SNPs. We identified two novel SNPs, located in introns of AGAP1 , which is involved in membrane trafficking and cytoskeleton dynamics, and PACSIN2 which plays a role in vesicle formation and transport. The other two SNPs are located nearby HHIP and in an intron of FAM13A , previously identified in GWA studies on COPD (in smokers). Discussion: In never-smokers, we found associations of airway obstruction with both novel genetic variants and with genetic variants previously identified in GWA studies on COPD. This could indicate that these genes play a role in the pathogenesis of non-smoking related COPD.