新生儿 DNA 甲基化与青少年和成年早期哮喘发病的关系。
Newborn DNA methylation and asthma acquisition across adolescence and early adulthood.
机构信息
Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, Tennessee, USA.
Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
出版信息
Clin Exp Allergy. 2022 May;52(5):658-669. doi: 10.1111/cea.14091. Epub 2022 Jan 16.
BACKGROUND
Little is known about the association of newborn DNA methylation (DNAm) with asthma acquisition across adolescence and early adult life.
OBJECTIVE
We aim to identify epigenetic biomarkers in newborns for asthma acquisition during adolescence or young adulthood.
METHODS
The Isle of Wight Birth Cohort (IOWBC) (n = 1456) data at ages 10, 18 and 26 years were assessed. To screen cytosine-phosphate-guanine site (CpGs) potentially associated with asthma acquisition, at the genome scale, we examined differentially methylated regions (DMR) using dmrff R package and individual CpG sites using linear regression on such associations. For CpGs that passed screening, we examined their enrichment in biological pathways using their mapping genes and tested their associations with asthma acquisitions using logistic regressions. Findings in IOWBC were tested in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.
RESULTS
In total, 2636 unique CpGs passed screening, based on which we identified one biological pathway linked to asthma acquisition during adolescence in females (FDR adjusted p-value = .003 in IOWBC). Via logistic regressions, for females, four CpGs were shown to be associated with asthma acquisition during adolescence, and another four CpGs with asthma acquisition in young adulthood (FDR adjusted p-value < .05 in IOWBC) and these eight CpGs were replicated in ALSPAC (all p-values < .05). DNAm at all the identified CpGs was shown to be temporally consistent, and at six of the CpGs was associated with expressions of adjacent or mapping genes in females (all p-values < .05). For males, 622 CpGs were identified in IOWBC (FDR = 0.01), but these were not tested in ALSPAC due to small sample sizes.
CONCLUSION AND CLINICAL RELEVANCE
Eight CpGs on LHX5, IL22RA2, SOX11, CBX4, ACPT, CFAP46, MUC4, and ATP1B2 genes have the potential to serve as candidate epigenetic biomarkers in newborns for asthma acquisition in females during adolescence or young adulthood.
背景
对于新生儿 DNA 甲基化（DNAm）与青少年和成年早期哮喘发病的关联，我们知之甚少。
目的
我们旨在鉴定新生儿中与青少年或成年早期哮喘发病相关的表观遗传生物标志物。
方法
评估了 Isle of Wight Birth Cohort（IOWBC）（n=1456）在 10、18 和 26 岁时的数据。为了在全基因组范围内筛选与哮喘发病相关的潜在的胞嘧啶磷酸鸟嘌呤位点（CpG），我们使用 dmrff R 包检查差异甲基化区域（DMR），并使用线性回归检查这些关联的单个 CpG 位点。对于通过筛选的 CpG，我们使用其映射基因检查它们在生物途径中的富集情况，并使用逻辑回归测试它们与哮喘发病的关联。在 Isle of Wight Birth Cohort 中发现的结果在一个独立的队列，即 Avon Longitudinal Study of Parents and Children（ALSPAC）队列中进行了测试。
结果
总共 2636 个独特的 CpG 通过了筛选，基于此，我们确定了一个与女性青少年时期哮喘发病相关的生物学途径（在 IOWBC 中，经 FDR 调整的 p 值=0.003）。通过逻辑回归，对于女性，有四个 CpG 与青少年时期的哮喘发病相关，还有四个 CpG 与成年早期的哮喘发病相关（在 IOWBC 中，经 FDR 调整的 p 值均<.05），这八个 CpG 在 ALSPAC 中得到了复制（所有 p 值均<.05）。所有鉴定的 CpG 的 DNAm 表现出时间一致性，并且在六个 CpG 中与女性相邻或映射基因的表达相关（所有 p 值均<.05）。对于男性，在 IOWBC 中鉴定出 622 个 CpG（FDR=0.01），但由于样本量小，这些 CpG 未在 ALSPAC 中进行测试。
结论和临床意义
LHX5、IL22RA2、SOX11、CBX4、ACP、CFAP46、MUC4 和 ATP1B2 基因上的 8 个 CpG 有可能成为女性青少年或成年早期哮喘发病的新生儿候选表观遗传生物标志物。
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