Genome-wide association study on the FEV1/FVC ratio in never-smokers identifies HHIP and FAM13A

Diana A van der Plaat; Kim de Jong; Lies Lahousse; Alen Faiz; Judith M Vonk; Cleo C van Diemen; Ivana Nedeljkovic; Najaf Amin; Guy G Brusselle; Albert Hofman; Corry-Anke Brandsma; Yohan Bossé; Don D Sin; David C Nickle; Cornelia M van Duijn; Dirkje S Postma; H Marike Boezen

doi:10.1016/j.jaci.2016.06.062

Genome-wide association study on the FEV₁/FVC ratio in never-smokers identifies HHIP and FAM13A

J Allergy Clin Immunol. 2017 Feb;139(2):533-540. doi: 10.1016/j.jaci.2016.06.062. Epub 2016 Sep 6.

Authors

Diana A van der Plaat¹, Kim de Jong¹, Lies Lahousse², Alen Faiz³, Judith M Vonk¹, Cleo C van Diemen⁴, Ivana Nedeljkovic⁵, Najaf Amin⁵, Guy G Brusselle⁶, Albert Hofman⁵, Corry-Anke Brandsma³, Yohan Bossé⁷, Don D Sin⁸, David C Nickle⁹, Cornelia M van Duijn⁵, Dirkje S Postma¹⁰, H Marike Boezen¹¹

Affiliations

¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
² Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
³ Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁴ Department of Genetics, University of Groningen, University Medical Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁵ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
⁶ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
⁷ Department of Molecular, Medicine, Laval University, Institut universitaire de cardiologie et de pneumologie de Québec, Quebec City, Quebec, Canada.
⁸ Department of Medicine, Division of Respiratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada.
⁹ Merck & Co, MRL, Seattle, Wash.
¹⁰ Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: h.m.boezen@umcg.nl.

PMID: 27612410
DOI: 10.1016/j.jaci.2016.06.062

Abstract

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.

Keywords: Genome-wide association study; chronic obstructive pulmonary disease; genetics; never-smokers; pulmonary function.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Carrier Proteins / genetics*
Cohort Studies
Female
Forced Expiratory Volume
GTPase-Activating Proteins / genetics*
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Lung / physiology*
Male
Membrane Glycoproteins / genetics*
Middle Aged
Polymorphism, Single Nucleotide
Pulmonary Disease, Chronic Obstructive / genetics*
Quantitative Trait Loci / genetics
Risk
Smoking / adverse effects
Spirometry
Vital Capacity
Young Adult

Substances

Carrier Proteins
FAM13A protein, human
GTPase-Activating Proteins
HHIP protein, human
Membrane Glycoproteins