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 Wickman, Jean Bousquet, Dirkje S Postma, Josep M Anto, Gerard H Koppelman

Journal: The Journal of allergy and clinical immunology 2019;141(3):1105-1114

PMID: 28739286

Full Text on Elsevier Science View on PubMed

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.

Address: ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz. Electronic address: [email protected].; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.; ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.; University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.; ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.; ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Centre for Genomic Regulation (CRG), the Barcelona Institute of Science and Technology, Barcelona, Spain.; ISGlobal, Barcelona Center for International Health Research (CRESIB), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.; ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands.; Sachs' Children's Hospital, Södersjukhuset, Stockholm, and the Department of Clinical Science and Education, Karolinska Institutet at Södersjukhuset, Stockholm, Sweden.; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, and Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.; Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.; Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.; University Hospital Montpellier, and the Respiratory and Environmental Epidemiology Team, INSERM 1018, CESP Centre, Villejuif, France.; University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.; Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, Groningen, The Netherlands.

DOI: 10.1016/j.jaci.2017.06.030

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MeSH Terms: Asthma, Biomarkers, Child, Preschool, Chitinase-3-Like Protein 1, DNA Methylation, Epigenesis, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide