Background: 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 of HHIP and FAM13A in 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 genes . HHIP and . FAM13A confer 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.

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Journal of Allergy and Clinical Immunology
Department of Epidemiology

van der Plaat, D.A. (Diana A.), de Jong, K., Lahousse, L., Faiz, A. (Alen), Vonk, J., van Diemen, C., … Boezen, M. (2017). Genome-wide association study on the FEV1/FVC ratio in never-smokers identifies HHIP and FAM13A. Journal of Allergy and Clinical Immunology, 139(2), 533–540. doi:10.1016/j.jaci.2016.06.062