Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants

Autor: Erik Melén, Maties Torrent, Klaus Bønnelykke, Clare S. Murray, George Davey Smith, Oliver Fuchs, Beate St Pourcain, William O.C.M. Cookson, Gerard H. Koppelman, Johan C. de Jongste, John A. Curtin, Adnan Custovic, Carole Ober, W. James Gauderman, Albert Hofman, Marie Standl, Anna Gref, Emmanuelle Bouzigon, Hans Bisgaard, Angela Simpson, Karol Estrada, Muhammad T. Salam, Raquel Granell, Liesbeth Duijts, Miriam F. Moffatt, Rachel Nadif, Xia Li, Emma E. Thompson, Patrick M. A. Sleiman, Markus J. Ege, Hakon Hakonarson, Dirkje S. Postma, Jon Genuneit, Joachim Heinrich, John P. Kemp, Frank D. Gilliland, Ralf J. P. van der Valk, Carla M. T. Tiesler, Fernando Rivadeneira, Cornelia M. van Duijn, N J Timpson, David M. Evans, Martin K. Andersson, Wendy L. McArdle, Florence Demenais, Kiros Berhane, Vincent W. V. Jaddoe, A. J. Henderson, André G. Uitterlinden, Eskil Kreiner-Møller, Lavinia Paternoster, Alejandro Cáceres, Sandrah P. Eckel, Marjan Kerhof, H. Rob Taal, Liming Liang, Jordi Sunyer, Claudia Flexeder
Přispěvatelé: Pediatrics, Epidemiology, Internal Medicine, Public Health, Erasmus MC other, Groningen Research Institute for Asthma and COPD (GRIAC)
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Male
Linkage disequilibrium
Nitric Oxide Synthase Type II
Genome-wide association study
CHILDREN
Linkage Disequilibrium
0302 clinical medicine
Immunology and Allergy
genetics
Child
POPULATION
Genetics
0303 health sciences
education.field_of_study
HERITABILITY
respiratory system
3. Good health
Neoplasm Proteins
Breath Tests
Exhalation
Child
Preschool
biomarker
Female
Airway inflammation
Risk
GENES
Adolescent
Immunology
Population
Quantitative Trait Loci
asthma phenotypes
Single-nucleotide polymorphism
PHENOTYPES
Quantitative trait locus
Biology
Nitric Oxide
Polymorphism
Single Nucleotide
Article
03 medical and health sciences
INFLAMMATION
Humans
Airway Inflammation
Asthma Phenotypes
Biomarker
Genome-wide Association Study
GENOME-WIDE ASSOCIATION
education
Asma
030304 developmental biology
Genetic association
Tumors
Cromosomes humans
genome-wide association study
Xaperonines
COMPLEX TRAITS
GALECTIN-9
Òxid nítric
respiratory tract diseases
030228 respiratory system
Haplotypes
13. Climate action
Exhaled nitric oxide
Expression quantitative trait loci
ASTHMA
Proteïnes
Biomarkers
Chromosomes
Human
Pair 17
Molecular Chaperones
Zdroj: Journal of Allergy and Clinical Immunology
J. Allergy Clin. Immunol. 134, 46-55 (2014)
Recercat. Dipósit de la Recerca de Catalunya
instname
Journal of Allergy and Clinical Immunology, 134(1), 46-55. Mosby Inc.
Journal of Allergy and Clinical Immunology, 134(1), 46-55. MOSBY-ELSEVIER
ISSN: 0091-6749
Popis: BACKGROUND: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. OBJECTIVE: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). RESULTS: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. CONCLUSION: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma. C.O. is supported by a NIH grant that supported the Hutterite studies (R01 HL085197). D.E. is supported by UK Medical Research Council Centre (G0600705). G.S. is supported by UK Medical Research Council Centre (G0600705). J.K. is funded by a Wellcome Trust 4-year PhD studentship in molecular, genetic, and life course epidemiology (WT083431MA). L.D. is supported by a European Respiratory Society/Marie Curie Joint Research Fellowship of the European Respiratory Society and the European Community’s Seventh Framework Programme FP7/2007-2013–Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571 (no. MC 1226- 2009). N.T. is supported by UK Medical Research Council Centre (G0600705). R.V. was partly supported by an unrestricted personal grant from GlaxoSmithKline, NL. V.J. is supported by the Netherlands Organization for Health Research and Development (ZonMw 90700303, 916.10159). L. Duijts is supported by a European Respiratory Society/Marie Curie Joint Research Fellowship of the European Respiratory Society and the European Community’s Seventh Framework Programme (FP7/2007-2013-Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571 [no. MC 1226-2009]). M. T. Salam has received research support from the National Heart, Lung, and Blood Institute (NHLBI; 5R01HL61768 and 5R01HL76647); the Southern California Environmental Health Sciences Center funded by the National Institute of Environmental Health Sciences (5P30ES007048); and the Environmental Protection Agency (EPA; 5P01ES009581, R826708-01, and RD831861-01), the National Institute of Environmental Health Sciences (5P01ES011627), and the Hastings Foundation. J. Genuneit has received grant EuFP6 (018996 under IP LSH-2004-1.25- 1). Evans has received a grant in the form of the MRC New Investigator Award G0600705. B. St Pourcain has received research support with Autism Speaks (7132). O. Fuchs has received research support from the European Commission within Seventh Framework Programme (theme FP7-KBBE-2007- 1) as part of EFRAIM (Impact of exogenous factors in the development of Allergy, contract no. 211911), the European Respiratory Society for a long-term research fellowship (no. 675). F. D. Gilliand has received research support from the NHLBI (5R01HL61768 and 5R01HL76647), Southern California Environmental Health Sciences Center funded by the National Institute of Environmental Health Sciences (5P30ES007048), the Children’s Environmental Health Center funded by the National Institute of Environmental Health Sciences and the Environmental Protection Agency (5P01Es009581, R826708-01, and RD831861-01), the National Institute of Environmental Health Sciences (5P01ES011627)
Databáze: OpenAIRE
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