Genetic and epigenetic regulation of YKL-40 in childhood

Stefano Guerra, Erik Melén, Jordi Sunyer, Cheng Jian Xu, Iris Lavi, Marta Benet, Mariona Bustamante, Anne Elie Carsin, Carlota Dobaño, Mònica Guxens, Christina Tischer, Martine Vrijheid, Inger Kull, Anna Bergström, Ashish Kumar, Cilla Söderhäll, Ulrike Gehring, Dorieke J. Dijkstra, Pieter van der Vlies, Magnus WickmanJean Bousquet, Dirkje S. Postma, Josep M. Anto, Gerard H. Koppelman

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1105-1114
Number of pages10
JournalJournal of Allergy and Clinical Immunology
Volume141
Issue number3
DOIs
StatePublished - Mar 2018

Keywords

  • CHI3L1
  • DNA methylation
  • YKL-40
  • asthma
  • epigenetics
  • genetics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Guerra, S., Melén, E., Sunyer, J., Xu, C. J., Lavi, I., Benet, M., Bustamante, M., Carsin, A. E., Dobaño, C., Guxens, M., Tischer, C., Vrijheid, M., Kull, I., Bergström, A., Kumar, A., Söderhäll, C., Gehring, U., Dijkstra, D. J., van der Vlies, P., ... Koppelman, G. H. (2018). Genetic and epigenetic regulation of YKL-40 in childhood. Journal of Allergy and Clinical Immunology, 141(3), 1105-1114. https://doi.org/10.1016/j.jaci.2017.06.030