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

doi:10.1016/j.jaci.2017.06.030

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

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, SE-171 77 Stockholm, Sweden; Centre for Occupational and Environmental Medicine, Stockholm County Council, 104 22 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
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 Paediatric Pulmonology and Paediatric Allergology, Beatrix Children's Hospital, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), 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.

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	1105-1114
Number of pages	10
Journal	Journal of Allergy and Clinical Immunology
Volume	141
Issue number	3
DOIs	https://doi.org/10.1016/j.jaci.2017.06.030
Publication status	Published - Mar 2018

Keywords

YKL-40
CHI3L1
asthma
epigenetics
DNA methylation
genetics

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10.1016/j.jaci.2017.06.030

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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

@article{e28ee8c166b5447cb286f73e41cb101e,

title = "Genetic and epigenetic regulation of YKL-40 in childhood",

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.",

keywords = "YKL-40, CHI3L1, asthma, epigenetics, DNA methylation, genetics",

author = "Stefano Guerra and Erik Mel{\'e}n and Jordi Sunyer and Cheng-Jian Xu and Iris Lavi and Marta Benet and Mariona Bustamante and Anne-Elie Carsin and Carlota Doba{\~n}o and M{\`o}nica Guxens and Christina Tischer and Martine Vrijheid and Inger Kull and Anna Bergstr{\"o}m and Ashish Kumar and Cilla S{\"o}derh{\"a}ll and Ulrike Gehring and Dijkstra, {Dorieke J} and {van der Vlies}, Pieter and Magnus Wickman and Jean Bousquet and Postma, {Dirkje S} and Anto, {Josep M} and Koppelman, {Gerard H}",

year = "2018",

month = mar,

doi = "10.1016/j.jaci.2017.06.030",

language = "English",

volume = "141",

pages = "1105--1114",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "3",

}

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, DJ, van der Vlies, P, Wickman, M, Bousquet, J, Postma, DS, Anto, JM & Koppelman, GH 2018, 'Genetic and epigenetic regulation of YKL-40 in childhood', Journal of Allergy and Clinical Immunology, vol. 141, no. 3, pp. 1105-1114. https://doi.org/10.1016/j.jaci.2017.06.030

TY - JOUR

T1 - Genetic and epigenetic regulation of YKL-40 in childhood

AU - Guerra, Stefano

AU - Melén, Erik

AU - Sunyer, Jordi

AU - Xu, Cheng-Jian

AU - Lavi, Iris

AU - Benet, Marta

AU - Bustamante, Mariona

AU - Carsin, Anne-Elie

AU - Dobaño, Carlota

AU - Guxens, Mònica

AU - Tischer, Christina

AU - Vrijheid, Martine

AU - Kull, Inger

AU - Bergström, Anna

AU - Kumar, Ashish

AU - Söderhäll, Cilla

AU - Gehring, Ulrike

AU - Dijkstra, Dorieke J

AU - van der Vlies, Pieter

AU - Wickman, Magnus

AU - Bousquet, Jean

AU - Postma, Dirkje S

AU - Anto, Josep M

AU - Koppelman, Gerard H

PY - 2018/3

Y1 - 2018/3

N2 - 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.

AB - 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.

KW - YKL-40

KW - CHI3L1

KW - asthma

KW - epigenetics

KW - DNA methylation

KW - genetics

U2 - 10.1016/j.jaci.2017.06.030

DO - 10.1016/j.jaci.2017.06.030

M3 - Article

C2 - 28739286

SN - 0091-6749

VL - 141

SP - 1105

EP - 1114

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 3

ER -

Genetic and epigenetic regulation of YKL-40 in childhood

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Keywords

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