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

van der Valk, Ralf J. P., Duijts, Liesbeth, Timpson, Nicolas J., Salam, Muhammad T., Standl, Marie, Curtin, John A., Genuneit, Jon, Kerhof, Marjan, Kreiner-Møller, Eskil, Cáceres, Alejandro, Gref, Anna, Liang, Liming L., Taal, H. Rob, Bouzigon, Emmanuelle, Demenais, Florence, Nadif, Rachel, Ober, Carole, Thompson, Emma E., Estrada, Karol, Hofman, Albert, Uitterlinden, André G., van Duijn, Cornélia, Rivadeneira, Fernando, Li, Xia, Eckel, Sandrah P., Berhane, Kiros, Gauderman, W. James, Granell, Raquel, Evans, David M., St Pourcain, Beate, McArdle, Wendy, Kemp, John P., Smith, George Davey, Tiesler, Carla M. T., Flexeder, Claudia, Simpson, Angela, Murray, Clare S., Fuchs, Oliver, Postma, Dirkje S., Bønnelykke, Klaus, Torrent, Maties, Andersson, Martin, Sleiman, Patrick, Hakonarson, Hakon, Cookson, William O., Moffatt, Miriam F., Paternoster, Lavinia, Melén, Erik, Sunyer, Jordi, Bisgaard, Hans, Koppelman, Gerard H., Ege, Markus, Custovic, Adnan, Heinrich, Joachim, Gilliland, Frank D., Henderson, Alexander J., Jaddoe, Vincent W. V. and de Jongste, Johan C. (2013) Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants. Journal of Allergy and Clinical Immunology, 134 1: 46-55. doi:10.1016/j.jaci.2013.08.053

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Author van der Valk, Ralf J. P.
Duijts, Liesbeth
Timpson, Nicolas J.
Salam, Muhammad T.
Standl, Marie
Curtin, John A.
Genuneit, Jon
Kerhof, Marjan
Kreiner-Møller, Eskil
Cáceres, Alejandro
Gref, Anna
Liang, Liming L.
Taal, H. Rob
Bouzigon, Emmanuelle
Demenais, Florence
Nadif, Rachel
Ober, Carole
Thompson, Emma E.
Estrada, Karol
Hofman, Albert
Uitterlinden, André G.
van Duijn, Cornélia
Rivadeneira, Fernando
Li, Xia
Eckel, Sandrah P.
Berhane, Kiros
Gauderman, W. James
Granell, Raquel
Evans, David M.
St Pourcain, Beate
McArdle, Wendy
Kemp, John P.
Smith, George Davey
Tiesler, Carla M. T.
Flexeder, Claudia
Simpson, Angela
Murray, Clare S.
Fuchs, Oliver
Postma, Dirkje S.
Bønnelykke, Klaus
Torrent, Maties
Andersson, Martin
Sleiman, Patrick
Hakonarson, Hakon
Cookson, William O.
Moffatt, Miriam F.
Paternoster, Lavinia
Melén, Erik
Sunyer, Jordi
Bisgaard, Hans
Koppelman, Gerard H.
Ege, Markus
Custovic, Adnan
Heinrich, Joachim
Gilliland, Frank D.
Henderson, Alexander J.
Jaddoe, Vincent W. V.
de Jongste, Johan C.
Title Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants
Journal name Journal of Allergy and Clinical Immunology   Check publisher's open access policy
ISSN 0091-6749
Publication date 2013-12-06
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.jaci.2013.08.053
Open Access Status
Volume 134
Issue 1
Start page 46
End page 55
Total pages 10
Place of publication Philadelphia, PA, United States
Publisher Mosby
Collection year 2014
Language eng
Formatted abstract
Background The fraction of exhaled nitric oxide (Fᴇɴᴏ) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Fᴇɴᴏ 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 Fᴇɴᴏ 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 Fᴇɴᴏ 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 Fᴇɴᴏ 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 Fᴇɴᴏ values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Fᴇɴᴏ values. This study highlights that both shared and distinct genetic factors affect Fᴇɴᴏ values and childhood asthma.
Keyword Airway inflammation
Asthma phenotypes
Genome-wide association study
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ
Additional Notes Available online 6 December 2013

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
UQ Diamantina Institute - Open Access Collection
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Citation counts: TR Web of Science Citation Count  Cited 9 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 9 times in Scopus Article | Citations
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Created: Wed, 19 Mar 2014, 12:08:23 EST by Kylie Hengst on behalf of UQ Diamantina Institute