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

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.

• Authors: 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
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 139 Issue 2 Pg. 533-540 (02 2017) ISSN: 1097-6825 [Electronic] United States
• PMID: 27612410 (Publication Type: Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• 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