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 |
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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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