儿童鼻上皮，特应性和特应性哮喘中的DNA甲基化：一项全基因组研究
2019/01/09
摘要
背景：表观遗传机制可以改变气道上皮屏障并最终导致特应性疾病，如哮喘。我们的目的是确定与学龄儿童相关的DNA甲基化谱，并且可以准确地分类特应性和特应性哮喘。
方法：我们对483名年龄在9-20岁的波多黎各儿童的鼻上皮和特应性或特应性哮喘进行了DNA甲基化的全基因组研究，采用多阶段概率抽样进行招募。特应性定义为至少有一种对常见的空气过敏原呈阳性的IgE（≥0.35IU / mL），哮喘被定义为内科医生的诊断加一年喘息。甲基化信号与基因表达呈显著相关（假发现率p <0.01），并通过焦磷酸测序验证了最高CPGs。然后，我们在一个由72名非洲裔美国儿童组成的队列中，以及来自欧洲出生队列的432名儿童中复制了我们的甲基化研究结果。接下来，我们在所有的队列中测试了基于鼻部甲基化的分类模型来区分特应性或特应性哮喘。
结果：2014年2月12日至2017年5月8日期间招募的波多黎各发现队列中，有（n = 312）和无（n = 171）特应性的儿童的DNA甲基化谱显著不同。调整协变量和多次测试后，我们通过特应性发现了8664个差异甲基化的CpGs，对于前30个CpGs，假发现率调整的p值范围从9.58×1017到2.18×1022。这些CpGs位于或接近与上皮屏障功能相关的基因，包括CDHR3和CDH26，以及与气道上皮完整性和免疫调节相关的其他基因，例如FBXL7，NTRK1和SLC9A3。此外，前30个CpGs中有28个在两个独立队列中以相同方向复制。基于鼻甲基化的特应性分类模型在波多黎各队列（曲线下面积[AUC] 0.93-0.94，准确率85-88％）和两个复制队列中均表现良好（AUC 0.74-0. 92，准确率68-82％）。该模型对于波多黎各队列中的特应性哮喘（AUC 0.95-1.00，准确度88％）和复制组（AUC 0.82-0.88，准确度86％）也表现良好。
结论：我们在气道上皮中鉴定了与儿童特应性和特应性哮喘相关的特异性甲基化谱，以及可以区分特应性或特应性哮喘儿童的鼻甲基化组。我们的研究结果支持使用鼻甲基化组用于未来临床应用的可行性，例如预测喘息婴儿哮喘的发展。
DNA methylation in nasal epithelium, atopy, and atopic asthma in children: a genome-wide study.
Forno E, Wang T, Qi C, Yan Q, Xu CJ, Boutaoui N, Han YY, Weeks DE, Jiang Y, Rosser F, Vonk JM, Brouwer S, Acosta-Perez E, Colón-Semidey A, Alvarez M, Canino G, Koppelman GH, Chen W, Celedón JC.
Abstract
BACKGROUND:Epigenetic mechanisms could alter the airway epithelial barrier and ultimately lead to atopic diseases such as asthma. We aimed to identify DNA methylation profiles that are associated with-and could accurately classify-atopy and atopic asthma in school-aged children.
METHODS:We did a genome-wide study of DNA methylation in nasal epithelium and atopy or atopic asthma in 483 Puerto Rican children aged 9-20 years, recruited using multistage probability sampling. Atopy was defined as at least one positive IgE (≥0·35 IU/mL) to common aeroallergens, and asthma was defined as a physician's diagnosis plus wheeze in the previous year. Significant (false discovery rate p<0·01) methylation signals were correlated with gene expression, and top CpGs were validated by pyrosequencing. We then replicated our top methylation findings in a cohort of 72 predominantly African American children, and in 432 children from a European birth cohort. Next, we tested classification models based on nasal methylation for atopy or atopic asthma in all cohorts.
RESULTS:DNA methylation profiles were markedly different between children with (n=312) and without (n=171) atopy in the Puerto Rico discovery cohort, recruited from Feb 12, 2014, until May 8, 2017. After adjustment for covariates and multiple testing, we found 8664 differentially methylated CpGs by atopy, with false discovery rate-adjusted p values ranging from 9·58 × 10-17 to 2·18 × 10-22 for the top 30 CpGs. These CpGs were in or near genes relevant to epithelial barrier function, including CDHR3 and CDH26, and in other genes related to airway epithelial integrity and immune regulation, such as FBXL7, NTRK1, and SLC9A3. Moreover, 28 of the top 30 CpGs replicated in the same direction in both independent cohorts. Classification models of atopy based on nasal methylation performed well in the Puerto Rico cohort (area under the curve [AUC] 0·93-0·94 and accuracy 85-88%) and in both replication cohorts (AUC 0·74-0·92, accuracy 68-82%). The models also performed well for atopic asthma in the Puerto Rico cohort (AUC 0·95-1·00, accuracy 88%) and the replication cohorts (AUC 0·82-0·88, accuracy 86%).
CONCLUSIONS:We identified specific methylation profiles in airway epithelium that are associated with atopy and atopic asthma in children, and a nasal methylation panel that could classify children by atopy or atopic asthma. Our findings support the feasibility of using the nasal methylome for future clinical applications, such as predicting the development of asthma among wheezing infants.
背景：表观遗传机制可以改变气道上皮屏障并最终导致特应性疾病，如哮喘。我们的目的是确定与学龄儿童相关的DNA甲基化谱，并且可以准确地分类特应性和特应性哮喘。
方法：我们对483名年龄在9-20岁的波多黎各儿童的鼻上皮和特应性或特应性哮喘进行了DNA甲基化的全基因组研究，采用多阶段概率抽样进行招募。特应性定义为至少有一种对常见的空气过敏原呈阳性的IgE（≥0.35IU / mL），哮喘被定义为内科医生的诊断加一年喘息。甲基化信号与基因表达呈显著相关（假发现率p <0.01），并通过焦磷酸测序验证了最高CPGs。然后，我们在一个由72名非洲裔美国儿童组成的队列中，以及来自欧洲出生队列的432名儿童中复制了我们的甲基化研究结果。接下来，我们在所有的队列中测试了基于鼻部甲基化的分类模型来区分特应性或特应性哮喘。
结果：2014年2月12日至2017年5月8日期间招募的波多黎各发现队列中，有（n = 312）和无（n = 171）特应性的儿童的DNA甲基化谱显著不同。调整协变量和多次测试后，我们通过特应性发现了8664个差异甲基化的CpGs，对于前30个CpGs，假发现率调整的p值范围从9.58×1017到2.18×1022。这些CpGs位于或接近与上皮屏障功能相关的基因，包括CDHR3和CDH26，以及与气道上皮完整性和免疫调节相关的其他基因，例如FBXL7，NTRK1和SLC9A3。此外，前30个CpGs中有28个在两个独立队列中以相同方向复制。基于鼻甲基化的特应性分类模型在波多黎各队列（曲线下面积[AUC] 0.93-0.94，准确率85-88％）和两个复制队列中均表现良好（AUC 0.74-0. 92，准确率68-82％）。该模型对于波多黎各队列中的特应性哮喘（AUC 0.95-1.00，准确度88％）和复制组（AUC 0.82-0.88，准确度86％）也表现良好。
结论：我们在气道上皮中鉴定了与儿童特应性和特应性哮喘相关的特异性甲基化谱，以及可以区分特应性或特应性哮喘儿童的鼻甲基化组。我们的研究结果支持使用鼻甲基化组用于未来临床应用的可行性，例如预测喘息婴儿哮喘的发展。
(中日友好医院呼吸与危重症医学科 王瑞茵 摘译 林江涛 审校)
(Lancet Respir Med. 2018 Dec 21. pii: S2213-2600(18)30466-1. doi: 10.1016/S2213-2600(18)30466-1. [Epub ahead of print])
(Lancet Respir Med. 2018 Dec 21. pii: S2213-2600(18)30466-1. doi: 10.1016/S2213-2600(18)30466-1. [Epub ahead of print])
DNA methylation in nasal epithelium, atopy, and atopic asthma in children: a genome-wide study.
Forno E, Wang T, Qi C, Yan Q, Xu CJ, Boutaoui N, Han YY, Weeks DE, Jiang Y, Rosser F, Vonk JM, Brouwer S, Acosta-Perez E, Colón-Semidey A, Alvarez M, Canino G, Koppelman GH, Chen W, Celedón JC.
Abstract
BACKGROUND:Epigenetic mechanisms could alter the airway epithelial barrier and ultimately lead to atopic diseases such as asthma. We aimed to identify DNA methylation profiles that are associated with-and could accurately classify-atopy and atopic asthma in school-aged children.
METHODS:We did a genome-wide study of DNA methylation in nasal epithelium and atopy or atopic asthma in 483 Puerto Rican children aged 9-20 years, recruited using multistage probability sampling. Atopy was defined as at least one positive IgE (≥0·35 IU/mL) to common aeroallergens, and asthma was defined as a physician's diagnosis plus wheeze in the previous year. Significant (false discovery rate p<0·01) methylation signals were correlated with gene expression, and top CpGs were validated by pyrosequencing. We then replicated our top methylation findings in a cohort of 72 predominantly African American children, and in 432 children from a European birth cohort. Next, we tested classification models based on nasal methylation for atopy or atopic asthma in all cohorts.
RESULTS:DNA methylation profiles were markedly different between children with (n=312) and without (n=171) atopy in the Puerto Rico discovery cohort, recruited from Feb 12, 2014, until May 8, 2017. After adjustment for covariates and multiple testing, we found 8664 differentially methylated CpGs by atopy, with false discovery rate-adjusted p values ranging from 9·58 × 10-17 to 2·18 × 10-22 for the top 30 CpGs. These CpGs were in or near genes relevant to epithelial barrier function, including CDHR3 and CDH26, and in other genes related to airway epithelial integrity and immune regulation, such as FBXL7, NTRK1, and SLC9A3. Moreover, 28 of the top 30 CpGs replicated in the same direction in both independent cohorts. Classification models of atopy based on nasal methylation performed well in the Puerto Rico cohort (area under the curve [AUC] 0·93-0·94 and accuracy 85-88%) and in both replication cohorts (AUC 0·74-0·92, accuracy 68-82%). The models also performed well for atopic asthma in the Puerto Rico cohort (AUC 0·95-1·00, accuracy 88%) and the replication cohorts (AUC 0·82-0·88, accuracy 86%).
CONCLUSIONS:We identified specific methylation profiles in airway epithelium that are associated with atopy and atopic asthma in children, and a nasal methylation panel that could classify children by atopy or atopic asthma. Our findings support the feasibility of using the nasal methylome for future clinical applications, such as predicting the development of asthma among wheezing infants.
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