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



The aim of this study was to identify common genetic variants associated with FEV1and its ratio to forced vital capacity (FVC) in never-smokers.



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.



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 FEV1identification analysis were not replicated.



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.
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.
Diana A
DA
van der Plaat
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.
Kim
K
de Jong
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
Lies
L
Lahousse
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.
Alen
A
Faiz
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.
Judith M
JM
Vonk
Department of Genetics, University of Groningen, University Medical Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Cleo C
CC
van Diemen
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Ivana
I
Nedeljkovic
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Najaf
N
Amin
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.
Guy G
GG
Brusselle
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Albert
A
Hofman
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.
Corry-Anke
CA
Brandsma
Department of Molecular, Medicine, Laval University, Institut universitaire de cardiologie et de pneumologie de Québec, Quebec City, Quebec, Canada.
Yohan
Y
Bossé
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.
Don D
DD
Sin
Merck & Co, MRL, Seattle, Wash.
David C
DC
Nickle
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Cornelia M
CM
van Duijn
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.
Dirkje S
DS
Postma
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.
H Marike
HM
Boezen
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005541:Forced Expiratory Volume; D020690:GTPase-Activating Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008168:Lung / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D012306:Risk; D012907:Smoking / Q000009:adverse effects; D013147:Spirometry; D014797:Vital Capacity; D055815:Young Adult
D002352:Carrier Proteins; C570078:FAM13A protein, human; D020690:GTPase-Activating Proteins; C117596:HHIP protein, human; D008562:Membrane Glycoproteins
Genome-wide association study; chronic obstructive pulmonary disease; genetics; never-smokers; pulmonary function