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.
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
J Allergy Clin Immunol. 2018 Mar;141(3):1105-1114. doi: 10.1016/j.jaci.2017.06.030. Epub 2017 Jul 21.
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.
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.
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.
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.
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.
壳聚糖酶样蛋白 YKL-40 的循环水平受其编码基因（几丁质酶 3 样 1 [CHI3L1]）中遗传变异的影响，并在包括哮喘在内的多种疾病患者中升高。生命早期循环 YKL-40 的表观遗传调控尚不清楚。
我们旨在确定（1）CHI3L1 CpG 位点的甲基化水平是否介导 CHI3L1 单核苷酸多态性（SNP）与血液中 YKL-40 水平之间的关联，以及（2）这些生物标志物（CHI3L1 SNPs、甲基化谱和 YKL-40 水平）是否与儿童早期的哮喘有关。
我们使用了来自西班牙 Infancia y Medio Ambiente、瑞典 Barn/Children、Allergy、Milieu、Stockholm、Epidemiological survey 和荷兰 Prevention and Incidence of Asthma and Mite Allergy 出生队列的多达 2405 名参与者的数据。通过相关分析、多变量回归和中介分析来检验 68 个 CHI3L1 SNP、全血 DNA 中 14 个 CHI3L1 CpG 位点的甲基化水平以及 4 岁时循环 YKL-40 水平之间的关联。通过多变量逻辑回归检验了这些生物标志物与 4 岁时哮喘的关联。
YKL-40 水平与 7 个 SNP 和 5 个 CpG 位点的甲基化显著相关。观察到这 7 个 SNP（特别是 rs10399931 和 rs4950928）和 5 个 CpG 位点之间一致的关联。与较低 YKL-40 水平相关的等位基因与较高的甲基化水平相关。与 YKL-40 水平较低的受试者相比，YKL-40 水平较高（定义为 YKL-40 三分位最高）的参与者患哮喘的几率增加（meta 分析调整比值比，1.90 [95%CI，1.08-3.36]）。相比之下，CHI3L1 中的 SNP 或 CpG 位点的甲基化水平均与哮喘无关。
CHI3L1 遗传变异对循环 YKL-40 水平的影响部分由甲基化谱介导。在我们的研究中，YKL-40 水平，但不是 CHI3L1 SNP 或甲基化水平，与儿童哮喘有关。
