Genetic and epigenetic regulation of YKL-40 in childhood - 07/03/18
, Erik Melén, MD, PhD e, Jordi Sunyer, MD, PhD a, b, c, f, Cheng-Jian Xu, PhD g, h, i, Iris Lavi, PhD a, b, c, Marta Benet, BStat a, b, c, Mariona Bustamante, PhD a, b, c, j, Anne-Elie Carsin, MS a, b, c, f, Carlota Dobaño, PhD k, Mònica Guxens, MD, PhD a, b, c, l, Christina Tischer, PhD a, b, c, Martine Vrijheid, PhD a, b, c, Inger Kull, RN, PhD m, Anna Bergström, PhD e, Ashish Kumar, MSc e, n, o, Cilla Söderhäll, PhD p, Ulrike Gehring, PhD q, Dorieke J. Dijkstra, MSc r, Pieter van der Vlies, BSc i, Magnus Wickman, MD, PhD e, Jean Bousquet, MD, PhD s, Dirkje S. Postma, MD, PhD g, h, Josep M. Anto, MD, PhD a, b, c, f, Gerard H. Koppelman, MD, PhD h, tAbstract |
Background |
Circulating levels of the chitinase-like protein YKL-40 are influenced by genetic variation in its encoding gene (chitinase 3–like 1 [CHI3L1]) and are increased in patients with several diseases, including asthma. Epigenetic regulation of circulating YKL-40 early in life is unknown.
Objective |
We sought to determine (1) whether methylation levels at CHI3L1 CpG sites mediate the association of CHI3L1 single nucleotide polymorphisms (SNPs) with YKL-40 levels in the blood and (2) whether these biomarkers (CHI3L1 SNPs, methylation profiles, and YKL-40 levels) are associated with asthma in early childhood.
Methods |
We used data from up to 2405 participants from the Spanish Infancia y Medio Ambiente; the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey; and the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohorts. Associations between 68 CHI3L1 SNPs, methylation levels at 14 CHI3L1 CpG sites in whole-blood DNA, and circulating YKL-40 levels at 4 years of age were tested by using correlation analysis, multivariable regression, and mediation analysis. Each of these biomarkers was also tested for association with asthma at 4 years of age by using multivariable logistic regression.
Results |
YKL-40 levels were significantly associated with 7 SNPs and with methylation at 5 CpG sites. Consistent associations between these 7 SNPs (particularly rs10399931 and rs4950928) and 5 CpG sites were observed. Alleles linked to lower YKL-40 levels were associated with higher methylation levels. Participants with high YKL-40 levels (defined as the highest YKL-40 tertile) had increased odds for asthma compared with subjects with low YKL-40 levels (meta-analyzed adjusted odds ratio, 1.90 [95% CI, 1.08-3.36]). In contrast, neither SNPs nor methylation levels at CpG sites in CHI3L1 were associated with asthma.
Conclusions |
The effects of CHI3L1 genetic variation on circulating YKL-40 levels are partly mediated by methylation profiles. In our study YKL-40 levels, but not CHI3L1 SNPs or methylation levels, were associated with childhood asthma.
Le texte complet de cet article est disponible en PDF.Key words : YKL-40, CHI3L1, asthma, epigenetics, DNA methylation, genetics
Abbreviations used : adjOR, BAMSE, CHI3L1, GWAS, INMA, LD, MeDALL, PCA, PIAMA, SNP
Plan
| Disclosure of potential conflict of interest: U. Gehring receives grant support from EU FP7 grant no. 261357. J. Bousquet serves on the board for Almirall, Meda, Merck, MSD, Novartis, Sanofi-Aventis, Takeda, Teva, and Uriach and receives payment for lectures from Almirall, AstraZeneca, Chiesi, GlaxoSmithKline, Meda, Menarini, Merck, MSD, Novartis, Sanofi-Aventis, Takeda, Teva, and Uriach. D. S. Postma serves as a consultant for Takeda, TEVA, Chiesi, GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim and receives grant support from Astra Zeneca, Chiesi, Genentech, GlaxoSmithKline, and Roche. G. H. Koppelman receives grant support from the Lung Foundation of the Netherlands, TEVA, Ubbo Emmius Foundation, and TETRI Foundation and receives travel support from GlaxoSmithKline. The rest of the authors declare that they have no relevant conflicts of interest. |
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| Supported by grant agreement no. 261357 (Mechanisms of the Development of Allergy [MeDALL]) from the EU Seventh Framework Programme. Additional funding for individual cohorts was provided as follows: INMA (Instituto de Salud Carlos III [Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; MS13/00054], Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 [090430]); BAMSE (the Swedish Heart-Lung Foundation, Swedish Research Council, Freemason Child House Foundation in Stockholm, Stockholm County Council [ALF], Swedish Foundation for Strategic Research [SSF, RBc08-0027, EpiGene project] and the Strategic Research Programme [SFO] in Epidemiology at Karolinska Institute); and PIAMA (The Netherlands Organization for Health Research and Development; The Netherlands Organization for Scientific Research; The Netherlands Lung Foundation (AF 4.1.14.001); The Netherlands Ministry of Spatial Planning, Housing, and the Environment; and The Netherlands Ministry of Health, Welfare, and Sport). |
Vol 141 - N° 3
P. 1105-1114 - mars 2018 Retour au numéro
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