BACKGROUND: Circulating levels of the chitinase-like protein YKL-40 are influenced by genetic variation in its encoding gene (CHI3L1) and are increased in several diseases, including asthma. Epigenetic regulation of circulating YKL-40 early in life is unknown.
OBJECTIVE: 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 INMA, BAMSE, and PIAMA 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 using correlation analysis, multivariable regression, and mediation analysis. Each of these biomarkers was also tested for association with asthma at 4 years of age using multivariable logistic regression.
RESULTS: YKL-40 levels were significantly associated with seven SNPs and with methylation at five CpG sites. Consistent associations between these seven SNPs (particularly rs10399931 and rs4950928) and five 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 as compared with subjects with low YKL-40 levels [meta-analyzed adjusted odds ratio (adjOR): 1.90, 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 are partly mediated by methylation profiles. In our study, YKL-40 levels, but not CHI3L1 SNPs or methylation levels, were associated with childhood asthma.