Although a striking proportion (25% to 45%) of patients with chronic obstructive pulmonary disease are never-smokers, most genetic susceptibility studies have not focused on this group exclusively.Objective:
The aim of this study was to identify common genetic variants associated with FEV1 and its ratio to forced vital capacity (FVC) in never-smokers.Methods:
Genome-wide association studies were performed in 5070 never-smokers of the identification cohort LifeLines, and results (P< 10−5) were verified by using a meta-analysis of the Vlagtwedde-Vlaardingen study and the Rotterdam Study I-III (total n = 1966). Furthermore, we aimed to assess the effects of the replicated variants in more detail by performing genetic risk score, expression quantitative trait loci, and variant*ever-smoking interaction analyses.Results:
We identified associations between the FEV1/FVC ratio and 5 common genetic variants in the identification cohort, and 2 of these associations were replicated. The 2 variants annotated to the genes hedgehog interacting protein(HHIP)and family with sequence similarity 13 member A(FAM13A)were shown to have an additive effect on FEV1/FVC levels in the genetic risk score analysis; were associated with gene expression ofHHIPandFAM13Ain lung tissue, respectively; and were genome-wide significant in a meta-analysis including both identification and 4 verification cohorts (P< 2.19 × 10−7). Finally, we did not identify significant interactions between the variants and ever smoking. Results of the FEV1 identification analysis were not replicated.Conclusion:
The genesHHIPandFAM13Aconfer a risk for airway obstruction in general that is not driven exclusively by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease.