Genetic and epigenetic regulation of YKL-40 in childhood

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• dc.contributor.author Guerra, Stefano
• dc.contributor.author Sunyer Deu, Jordi
• dc.contributor.author Lavi, Iris
• dc.contributor.author Benet, Marta
• dc.contributor.author Bustamante Pineda, Mariona
• dc.contributor.author Carsin, Anne-Elie
• dc.contributor.author Dobaño, Carlota
• dc.contributor.author Guxens Junyent, Mònica
• dc.contributor.author Tischer, Christina
• dc.contributor.author Vrijheid, Martine
• dc.contributor.author Antó i Boqué, Josep Maria
• dc.contributor.author Koppelman, Gerard H.
• dc.date.accessioned 2019-07-22T08:01:15Z
• dc.date.available 2019-07-22T08:01:15Z
• dc.date.issued 2018
• dc.description.abstract 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Guerra S, Melén E, Sunyer J, Xu CJ, Lavi I, Benet M et al. Genetic and epigenetic regulation of YKL-40 in childhood. J Allergy Clin Immunol. 2018;141(3):1105-14. DOI: 10.1016/j.jaci.2017.06.030
• dc.identifier.doi http://dx.doi.org/10.1016/j.jaci.2017.06.030
• dc.identifier.issn 0091-6749
• dc.identifier.uri http://hdl.handle.net/10230/42131
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Journal of Allergy and Clinical Immunology. 2018;141(3):1105-14
• dc.rights © Elsevier http://dx.doi.org/10.1016/j.jaci.2017.06.030
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword YKL-40
• dc.subject.keyword CHI3L1
• dc.subject.keyword Asthma
• dc.subject.keyword Epigenetics
• dc.subject.keyword DNA methylation
• dc.subject.keyword Genetics
• dc.title Genetic and epigenetic regulation of YKL-40 in childhood
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion