TY - JOUR
T1 - Genetic regulation of IL1RL1 methylation and IL1RL1 - A protein levels in asthma
AU - Dijk, F. Nicole
AU - Xu, Chengjian
AU - Melén, Erik
AU - Carsin, Anne Elie
AU - Kumar, Asish
AU - Nolte, Ilja M.
AU - Gruzieva, Olena
AU - Pershagen, Goran
AU - Grotenboer, Neomi S.
AU - Savenije, Olga E.M.
AU - Antó, Josep Maria
AU - Lavi, Iris
AU - Dobaño, Carlota
AU - Bousquet, Jean
AU - Van Der Vlies, Pieter
AU - Van Der Valk, Ralf J.P.
AU - De Jongste, Johan C.
AU - Nawijn, Martijn C.
AU - Guerra, Stefano
AU - Postma, Dirkje S.
AU - Koppelman, Gerard H.
N1 - Funding Information:
Conflict of interest: J. Bousquet has received personal fees for acting on scientific and advisory boards from Almirall, Meda, Merck, MSD, Novartis, Sanofi-Aventis, Takeda, Teva and Uriach; and personal fees for lecturing from Almirall, AstraZeneca, Chiesi, GSK, Meda, Menarini, Merck, MSD, Novartis, Sanofi-Aventis, Takeda, Teva and Uriach, outside the submitted work. R.J.P. van der Valk received a grant from the Dutch Lung Foundation during the conduct of the study; and is a Dutch Medical Affairs employee of GlaxoSmithKline (since June 2015), but does not hold stocks and is not involved in conducting any R&D activities for GlaxoSmithKline. M.C. Nawijn received a supporting grant to his institution for the submitted work from the Lung Foundation Netherlands during the conduct of the study. S. Guerra received a grant from European Commission’s Seventh Framework Programme during the conduct of the study. D.S. Postma: The University of Groningen received grants for research from AstraZeneca, Chiesi, Genentec, GSK and Roche. Fees for consultancies were given to the University of Groningen by AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. G.H. Koppelman has received institutional grants from the Netherlands Lung Foundation, Ubbo Emmius Foundation and the European Commission during the conduct of the study; and grants from the Netherlands Lung Foundation, TEVA (the Netherlands) and Stichting Astma Bestrijding outside the submitted work.
Funding Information:
Support Statement: For the funding of this research we thank the Dutch Lung Foundation (grant numbers AF 95.05, AF 98.48 and AF3.2.09.081JU); University Medical Center Groningen; Ubbo Emmius fund; European Commission’s Seventh Framework Programme (grant number 261357); Netherlands Organization for Health Research and Development; Netherlands Organization for Scientific Research; Netherlands Ministry of Spatial Planning, Housing, and the Environment; Netherlands Ministry of Health, Welfare, and Sport; Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041); Spanish Ministry of Health (FIS-PI041436, FIS-PI081151); Generalitat de Catalunya-CIRIT (1999SGR 00241); Fundació La marató de TV3 (090430); Swedish Research Council; Swedish Heart-Lung Foundation; Stockholm County Council (ALF); Strategic Research Programme (SFO) in Epidemiology; The Swedish Research Council Formas and the Swedish Environment Protection Agency. Funding information for this article has been deposited with the Crossref Funder Registry.
Publisher Copyright:
© ERS 2018.
PY - 2018
Y1 - 2018
N2 - Interleukin-1 receptor-like 1 (IL1RL1) is an important asthma gene. (Epi)genetic regulation of IL1RL1 protein expression has not been established. We assessed the association between IL1RL1 single nucleotide polymorphisms (SNPs), IL1RL1 methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma. Associations of IL1RL1 SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNA IL1RL1 methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genomewide protein QTL analysis on serum IL1RL1-a levels (n=1462). We investigated the association of IL1RL1 CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101). IL1RL1 asthma-risk SNPs strongly associated with IL1RL1 methylation (rs1420101; p=3.7×10-16) and serum IL1RL1-a levels (p=2.8×10-56). IL1RL1 methylation was not associated with asthma or IL1RL1-a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma. In conclusion, asthma-associated IL1RL1 SNPs strongly regulate IL1RL1 methylation and serum IL1RL1-a levels, yet neither these IL1RL1-methylation CpG sites nor IL1RL1-a levels are associated with asthma.
AB - Interleukin-1 receptor-like 1 (IL1RL1) is an important asthma gene. (Epi)genetic regulation of IL1RL1 protein expression has not been established. We assessed the association between IL1RL1 single nucleotide polymorphisms (SNPs), IL1RL1 methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma. Associations of IL1RL1 SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNA IL1RL1 methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genomewide protein QTL analysis on serum IL1RL1-a levels (n=1462). We investigated the association of IL1RL1 CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101). IL1RL1 asthma-risk SNPs strongly associated with IL1RL1 methylation (rs1420101; p=3.7×10-16) and serum IL1RL1-a levels (p=2.8×10-56). IL1RL1 methylation was not associated with asthma or IL1RL1-a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma. In conclusion, asthma-associated IL1RL1 SNPs strongly regulate IL1RL1 methylation and serum IL1RL1-a levels, yet neither these IL1RL1-methylation CpG sites nor IL1RL1-a levels are associated with asthma.
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U2 - 10.1183/13993003.01377-2017
DO - 10.1183/13993003.01377-2017
M3 - Article
C2 - 29519908
AN - SCOPUS:85059292447
SN - 0903-1936
VL - 51
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 3
M1 - 1701377
ER -