Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants
Van Der Valk RJP., Duijts L., Timpson NJ., Salam MT., Standl M., Curtin JA., Genuneit J., Kerhof M., Kreiner-Møller E., Cáceres A., Gref A., Liang LL., Taal HR., Bouzigon E., Demenais F., Nadif R., Ober C., Thompson EE., Estrada K., Hofman A., Uitterlinden AG., Van Duijn C., Rivadeneira F., Li X., Eckel SP., Berhane K., Gauderman WJ., Granell R., Evans DM., St Pourcain B., McArdle W., Kemp JP., Smith GD., Tiesler CMT., Flexeder C., Simpson A., Murray CS., Fuchs O., Postma DS., Bønnelykke K., Torrent M., Andersson M., Sleiman P., Hakonarson H., Cookson WO., Moffatt MF., Paternoster L., Melén E., Sunyer J., Bisgaard H., Koppelman GH., Ege M., Custovic A., Heinrich J., Gilliland FD., Henderson AJ., Jaddoe VWV., De Jongste JC.
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. © 2014 American Academy of Allergy, Asthma and Immunology.