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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.

Original publication




Journal article


J Allergy Clin Immunol

Publication Date





533 - 540


Genome-wide association study, chronic obstructive pulmonary disease, genetics, never-smokers, pulmonary function, Adolescent, Adult, Aged, Aged, 80 and over, Carrier Proteins, Cohort Studies, Female, Forced Expiratory Volume, GTPase-Activating Proteins, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Lung, Male, Membrane Glycoproteins, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, Risk, Smoking, Spirometry, Vital Capacity, Young Adult