Genome-wide interaction study of early-life smoking exposure on time-to-asthma onset in childhood.

Abstract

BACKGROUND:

Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma.

OBJECTIVE:

Our aim was to identify new loci interacting with ELTS exposure on time-to-asthma onset (TAO) in childhood.

METHODS:

We conducted genome-wide interaction analyses of ELTS exposure on time-to-asthma onset in childhood in five European-ancestry studies (totalling 8273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analysed.

RESULTS:

The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P = 4.3 × 10-8 for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P < 5 × 10-6 ) were found at three other loci: 20p12 (rs13037508 within MACROD2; P = 4.9 × 10-7 ), 14q22 (rs7493885 near NIN; P = 2.9 × 10-6 ) and 2p22 (rs232542 near CYP1B1; P = 4.1 × 10-6 ). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings.

CONCLUSIONS AND CLINICAL RELEVANCE:

We identified novel candidate genes interacting with ELTS exposure on time-to-asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms.

• Authors: Pierre-Emmanuel Sugier, Chloé Sarnowski, Raquel Granell, Catherine Laprise, Markus J Ege, Patricia Margaritte-Jeannin, Marie-Hélène Dizier, Cosetta Minelli, Miriam F Moffatt, Mark Lathrop, William O C M Cookson, A John Henderson, Erika von Mutius, Manolis Kogevinas, Florence Demenais, Emmanuelle Bouzigon
• Journal: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology (Clin Exp Allergy) Vol. 49 Issue 10 Pg. 1342-1351 (10 2019) ISSN: 1365-2222 [Electronic] England
• PMID: 31379025 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 John Wiley & Sons Ltd.

Chemical References

• Cytoskeletal Proteins
• KLHL1 protein, human
• MACROD2 protein, human
• Microfilament Proteins
• NIN protein, human
• Nuclear Proteins
• Tobacco Smoke Pollution
• CYP1B1 protein, human
• Cytochrome P-450 CYP1B1
• Hydrolases
• DNA Repair Enzymes

Topics

• Asthma (genetics)
• Child
• Cytochrome P-450 CYP1B1 (genetics)
• Cytoskeletal Proteins (genetics)
• DNA Repair Enzymes (genetics)
• Female
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Hydrolases (genetics)
• Male
• Microfilament Proteins (genetics)
• Nuclear Proteins (genetics)
• Polymorphism, Single Nucleotide
• Tobacco Smoke Pollution (adverse effects)