TY - JOUR
T1 - Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants
AU - Van Der Valk, Ralf J.P.
AU - Duijts, Liesbeth
AU - Timpson, Nicolas J.
AU - Salam, Muhammad T.
AU - Standl, Marie
AU - Curtin, John A.
AU - Genuneit, Jon
AU - Kerhof, Marjan
AU - Kreiner-Møller, Eskil
AU - Cáceres, Alejandro
AU - Gref, Anna
AU - Liang, Liming L.
AU - Taal, H. Rob
AU - Bouzigon, Emmanuelle
AU - Demenais, Florence
AU - Nadif, Rachel
AU - Ober, Carole
AU - Thompson, Emma E.
AU - Estrada, Karol
AU - Hofman, Albert
AU - Uitterlinden, André G.
AU - Van Duijn, Cornélia
AU - Rivadeneira, Fernando
AU - Li, Xia
AU - Eckel, Sandrah P.
AU - Berhane, Kiros
AU - Gauderman, W. James
AU - Granell, Raquel
AU - Evans, David M.
AU - St Pourcain, Beate
AU - McArdle, Wendy
AU - Kemp, John P.
AU - Smith, George Davey
AU - Tiesler, Carla M.T.
AU - Flexeder, Claudia
AU - Simpson, Angela
AU - Murray, Clare S.
AU - Fuchs, Oliver
AU - Postma, Dirkje S.
AU - Bønnelykke, Klaus
AU - Torrent, Maties
AU - Andersson, Martin
AU - Sleiman, Patrick
AU - Hakonarson, Hakon
AU - Cookson, William O.
AU - Moffatt, Miriam F.
AU - Paternoster, Lavinia
AU - Melén, Erik
AU - Sunyer, Jordi
AU - Bisgaard, Hans
AU - Koppelman, Gerard H.
AU - Ege, Markus
AU - Custovic, Adnan
AU - Heinrich, Joachim
AU - Gilliland, Frank D.
AU - Henderson, Alexander J.
AU - Jaddoe, Vincent W.V.
AU - De Jongste, Johan C.
N1 - Funding Information:
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).
Funding Information:
Disclosure of potential conflict of interest: R. J. P. van der Valk has received an unrestricted personal grant from GlaxoSmithKline for partial salary payment. 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 ); the Children's Environmental Health Center funded by the National Institute of Environmental Health Sciences ; 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. A. Curtin receives royalties from UCSF irrelevant to this work for a patent related to Cancer. J. Genuneit has received grant EuFP6 (018996 under IP LSH-2004-1.25-1 ). S. P. Eckel has received research support from the National Institutes of Health (NIH) . D. M. Evans has received a grant in the form of the MRC New Investigator Award G0600705 . K. Berhane has received research support from the NIH . W. J. Gauderman has received research support from the NHLBI . B. St Pourcain has received research support with Autism Speaks (7132). A. Simpson has received grants from the Medical Research Council and Microsoft Research ; is employed by the University of Manchester; has grants/grants pending from the MRC and EUFP7 ; receives payment for lectures, including service on speakers' bureaus from Chiesi and GlaxoSmithKline; and has received travel support from GlaxoSmithKline and Phadia for the EAACI and BSACI meetings . 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 ), and the Austrian, German and Swiss Pediatric Respiratory Society for a training scholarship . D. S. Postma has consultant arrangements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Takeda, and TEVA; has received research support from AstraZeneca and Chiesi ; and has received lecture fees from Chiesi. H. Bisgaard has received consultancy fees from Chiesi; has received travel support from the American Academy of Allergy, Asthma & Immunology (AAAAI) and the American Thoracic Society ; and is a board member for Boehringer Ingelheim and Chiesi. G. H. Koppelman has received support from the Dutch Lung Foundation and BBMRI-NL . M. Ege has received research support from the European Commission and European Research Council . A. Custovic has grants/grants pending from the MRC Moulton Charitable Foundation ; and has received lecture fees from GlaxoSmithKline, Thermo Fisher Scientific, Airsonet, Novartis, MSD, and ALK-Abelló . 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 ), and the Hastings Foundation . A. J. Henderson has received research support from MRC (UK) and the Wellcome Trust . The rest of the authors declare that they have no relevant conflicts of interest.
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2014/7
Y1 - 2014/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84903700139&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2013.08.053
DO - 10.1016/j.jaci.2013.08.053
M3 - Journal articles
C2 - 24315451
AN - SCOPUS:84903700139
SN - 0091-6749
VL - 134
SP - 46
EP - 55
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 1
ER -
