Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 139, Issue 2, Pages 533-540Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2016.06.062
Keywords
Genome-wide association study; never-smokers; genetics; pulmonary function; chronic obstructive pulmonary disease
Categories
Funding
- Lung Foundation (Longfonds), The Netherlands [4.1.13.007]
- Postdoctoral Fellow of the Research Foundation- Flanders (FWO)
- Dutch Ministry of Health, Welfare, and Sport
- Ministry of EconomicAffairs, Agriculture, and Innovation
- Province of Groningen
- European Union (regional development fund)
- Northern Netherlands Provinces (SNN)
- Scientific Research (NWO)
- University Medical Center Groningen (UMCG)
- University of Groningen, de Nierstichting (the Dutch Kidney Foundation)
- Diabetes Fonds (the Diabetic Foundation)
- Ministry of Health and Environmental Hygiene of The Netherlands
- The Netherlands Asthma Fund [187, 3.2.02.51]
- Stichting Astma Bestrijding, BBMRI- NL (Complementation project)
- European Respiratory Society COPD research award 2011
- Erasmus MC
- Erasmus University Rotterdam
- Netherlands Organisation for Scientific Research (NWO)
- Netherlands Organisation for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Netherlands Genomics Initiative (NGI)
- Ministry of Education, Culture, and Science
- Ministry of Health, Welfare, and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Merck Research Laboratories
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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 3 10 27). 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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