van der Valk, Ralf J P2; Duijts, Liesbeth2; Timpson, Nicolas J2; Salam, Muhammad T2; Standl, Marie2; Curtin, John A2; Genuneit, Jon2; Kerhof, Marjan2; Kreiner-Møller, Eskil2; Cáceres, Alejandro2; Gref, Anna2; Liang, Liming L2; Taal, H Rob2; Bouzigon, Emmanuelle2; Demenais, Florence2; Nadif, Rachel2; Ober, Carole2; Thompson, Emma E2; Estrada, Karol2; Hofman, Albert2; Uitterlinden, André G2; van Duijn, Cornélia2; Rivadeneira, Fernando2; Li, Xia2; Eckel, Sandrah P2; Berhane, Kiros2; Gauderman, W James2; Granell, Raquel2; Evans, David M2; St Pourcain, Beate2; McArdle, Wendy2; Kemp, John P2; Smith, George Davey2; Tiesler, Carla M T2; Flexeder, Claudia2; Simpson, Angela2; Murray, Clare S2; Fuchs, Oliver2; Postma, Dirkje S2; Bønnelykke, Klaus2; Torrent, Maties2; Andersson, Martin2; Sleiman, Patrick2; Hakonarson, Hakon2; Cookson, William O2; Moffatt, Miriam F2; Paternoster, Lavinia2; Melén, Erik2; Sunyer, Jordi2; Bisgaard, Hans3; Koppelman, Gerard H2; Ege, Markus2; Custovic, Adnan2; Heinrich, Joachim2; Gilliland, Frank D2; Henderson, Alexander J2; Jaddoe, Vincent W V2; de Jongste, Johan C2
1 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 unknown3 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
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.
Journal of Allergy and Clinical Immunology, 2014, Vol 134, Issue 1, p. 46-55