BACKGROUND Underlying biological mechanisms involved in sex differences in asthma status changes from pre- to post-adolescence are unclear. DNA methylation (DNAm) has been shown to be associated with the risk of asthma. OBJECTIVE We hypothesized that asthma acquisition from pre- to post-adolescence was associated with changes in DNAm during this period at asthma-associated cytosine-phosphate-guanine (CpG) sites and such an association was sex-specific. METHODS Subjects from the Isle of Wight birth cohort (IOWBC) with DNAm in blood at ages 10 and 18 years (n=124 females, 151 males) were studied. Using a training-testing approach, epigenome-wide CpGs associated with asthma were identified. Logistic regression was used to examine sex-specific associations of DNAm changes with asthma acquisition between ages 10 and 18 at asthma-associated CpGs. The ALSPAC birth cohort was used for independent replication. To assess functional relevance of identified CpGs, association of DNAm with gene expression in blood was assessed. RESULTS We identified 535 CpGs potentially associated with asthma. Significant interaction effects of DNAm changes and sex on asthma acquisition in adolescence were found at 13 of the 535 CpGs in IOWBC (p-values<1.0×10-3 ). In the replication cohort, consistent interaction effects were observed at 10 of the 13 CpGs. At 7 of these 10 CpGs, opposite DNAm changes across adolescence were observed between sexes in both cohorts. In both cohorts, cg20891917, located on IFRD1 linked to asthma, shows strong sex-specific effects on asthma transition (p-values<0.01 in both cohorts). CONCLUSION Gender-reversal in asthma acquisition is associated with opposite changes in DNAm (males vs females) from pre- to post-adolescence at asthma-associated CpGs. These CpGs are potential biomarkers of sex-specific asthma acquisition in adolescence.

中文翻译：

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哮喘获得与青春期 DNA 甲基化变化的性别特异性关联

背景 涉及从青春期前到青春期后哮喘状态变化的性别差异的潜在生物学机制尚不清楚。DNA甲基化（DNAm）已被证明与哮喘风险相关。目的 我们假设从青春期前到青春期后的哮喘获得与此期间哮喘相关胞嘧啶 - 磷酸 - 鸟嘌呤 (CpG) 位点的 DNAm 变化相关，并且这种关联具有性别特异性。方法 研究了来自怀特岛出生队列 (IOWBC) 的 10 岁和 18 岁血液中有 DNAm 的受试者（n = 124 名女性，151 名男性）。使用训练测试方法，确定了与哮喘相关的表观基因组范围的 CpG。逻辑回归用于检查 10 至 18 岁哮喘相关 CpG 中 DNAm 变化与哮喘获得的性别特异性关联。ALSPAC 出生队列用于独立复制。为了评估已鉴定 CpG 的功能相关性，评估了 DNAm 与血液中基因表达的关联。结果 我们确定了 535 个可能与哮喘相关的 CpG。在 IOWBC 的 535 个 CpG 中有 13 个发现 DNAm 变化和性别对青春期哮喘获得的显着交互作用（p 值<1.0×10-3）。在复制队列中，在 13 个 CpG 中的 10 个处观察到一致的相互作用效应。在这 10 个 CpG 中的 7 个中，在两个队列的性别之间观察到了青春期相反的 DNAm 变化。在这两个队列中，位于与哮喘相关的 IFRD1 上的 cg20891917 对哮喘转变显示出强烈的性别特异性影响（两个队列中的 p 值<0.01）。结论 哮喘获得中的性别逆转与哮喘相关 CpG 从青春期前到青春期后 DNAm（男性与女性）的相反变化相关。这些 CpG 是青春期获得性别特异性哮喘的潜在生物标志物。