• Ralf Jp van der Valk, Liesbeth Duijts, Nicolas J Timpson, Muhammad T Salam, Marie Standl, John A Curtin, Jon Genuneit, Marjan Kerhof, Eskil Kreiner-Møller, Alejandro Cáceres, Anna Gref, Liming L Liang, H Rob Taal, Emmanuelle Bouzigon, Florence Demenais, Rachel Nadif, Carole Ober, Emma E Thompson, Karol Estrada, Albert Hofman, André G Uitterlinden, Cornélia van Duijn, Fernando Rivadeneira, Xia Li, Sandrah P Eckel, Kiros Berhane, W James Gauderman, Raquel Granell, David M Evans, Beate St Pourcain, Wendy McArdle, John P Kemp, George Davey Smith, Carla Mt Tiesler, Claudia Flexeder, Angela Simpson, Clare S Murray, Oliver Fuchs, Dirkje S Postma, Klaus Bønnelykke, Maties Torrent, Martin Andersson, Patrick Sleiman, Hakon Hakonarson, William O Cookson, Miriam F Moffatt, Lavinia Paternoster, Erik Melén, Jordi Sunyer, Hans Bisgaard, Gerard H Koppelman, Markus Ege, Adnan Custovic, Joachim Heinrich, Frank D Gilliland, Alexander J Henderson, Vincent Wv Jaddoe, Johan C de Jongste, and EArly Genetics & Lifecourse Epidemiology (EAGLE) Consortium.
• The Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.
• J. Allergy Clin. Immunol. 2014 Jul 1; 134 (1): 46-55.

BackgroundThe 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.ObjectiveWe sought to identify the genetic variants associated with childhood Feno values and their relation with asthma.MethodsFeno 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).ResultsWe 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.ConclusionThis 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.Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

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