农业肺健康研究中DNA甲基化与成人哮喘的表观基因组相关性研究
2020/09/18
摘要
全表观基因组相关性研究支持表观遗传学机制在哮喘中的作用;然而，对成人的研究很少，很少有对非特应性哮喘的研究。我们进行了规模最大的表观基因组相关性研究(EWAS)，研究成年人血液DNA甲基化与非特应性哮喘和特应性哮喘的关系。我们使用Illumina MethylationEPIC阵列测量了2286名参与者血液中的DNA甲基化，这些参与者参与了一项美国农业队列中当前成人哮喘的病例对照研究。采用血清特异性免疫球蛋白E (IgE)检测特异表型。参与者被分为特应性无哮喘组(185例)、非特应性哮喘(673例)、特应性哮喘(271例)和非特应性非哮喘的参照组(1157例)。分析采用logistic回归。在无哮喘的情况下，未观察到特异反应性。许多胞嘧啶-磷酸-鸟嘌呤(cytosine-phosphate-guanine, CpG)位点在非特应性哮喘中甲基化差异显著(8个家族错误率(FWER) p<9×10- 8,524个错误发现率(FDR)小于0.05)，涉及382个新基因。在特应性哮喘中发现了更多的CpG位点(FWER有181个，FDR有1086个)，涉及569个新基因。有104个FDR CpG位点重叠。35%的CpG位点在非特应性哮喘中，91%在特应性哮喘中，在全血、嗜酸性粒细胞、气道上皮细胞或鼻上皮细胞的研究中重复出现。牵连基因在与神经系统或炎症相关的通路中富集。我们在非特应性哮喘和特应性哮喘中鉴定了大量不同的甲基化CpG位点。来自于血液标本的许多CpG位点在其他哮喘相关组织中同样出现。这些循环生物标志物反映了疾病的风险和后遗症，同时也暗示了与非特应性和特应性哮喘相关的新基因。
Epigenome-wide association study of DNA methylation and adult asthma in the Agricultural Lung Health Study
Thanh T Hoang, Sinjini Sikdar, Cheng-Jian Xu, Mi Kyeong Lee, Jonathan Cardwell , Erick Forno , Medea Imboden , Ayoung Jeong, Anne-Marie Madore, Cancan Qi, Tianyuan Wang, Brian D Bennett, James M Ward, Christine G Parks, Laura E Beane-Freeman, Debra King, Alison Motsinger-Reif, David M Umbach, Annah B Wyss, David A Schwartz, Juan C Celedón, Catherine Laprise , Carole Ober, Nicole Probst-Hensch, Ivana V Yang, Gerard H Koppelman, Stephanie J London
Abstract
Epigenome-wide studies of methylation in children support a role for epigenetic mechanisms in asthma; however, studies in adults are rare and few have examined non-atopic asthma. We conducted the largest epigenome-wide association study (EWAS) of blood DNA methylation in adults in relation to non-atopic and atopic asthma.We measured DNA methylation in blood using the Illumina MethylationEPIC array among 2286 participants in a case-control study of current adult asthma nested within a United States agricultural cohort. Atopy was defined by serum specific immunoglobulin E (IgE). Participants were categorised as atopy without asthma (n=185), non-atopic asthma (n=673), atopic asthma (n=271), or a reference group of neither atopy nor asthma (n=1157). Analyses were conducted using logistic regression.No associations were observed with atopy without asthma. Numerous cytosine-phosphate-guanine (CpG) sites were differentially methylated in non-atopic asthma (eight at family-wise error rate (FWER) p<9×10-8, 524 at false discovery rate (FDR) less than 0.05) and implicated 382 novel genes. More CpG sites were identified in atopic asthma (181 at FWER, 1086 at FDR) and implicated 569 novel genes. 104 FDR CpG sites overlapped. 35% of CpG sites in non-atopic asthma and 91% in atopic asthma replicated in studies of whole blood, eosinophils, airway epithelium, or nasal epithelium. Implicated genes were enriched in pathways related to the nervous system or inflammation.We identified numerous, distinct differentially methylated CpG sites in non-atopic and atopic asthma. Many CpG sites from blood replicated in asthma-relevant tissues. These circulating biomarkers reflect risk and sequelae of disease, as well as implicate novel genes associated with non-atopic and atopic asthma.
全表观基因组相关性研究支持表观遗传学机制在哮喘中的作用;然而，对成人的研究很少，很少有对非特应性哮喘的研究。我们进行了规模最大的表观基因组相关性研究(EWAS)，研究成年人血液DNA甲基化与非特应性哮喘和特应性哮喘的关系。我们使用Illumina MethylationEPIC阵列测量了2286名参与者血液中的DNA甲基化，这些参与者参与了一项美国农业队列中当前成人哮喘的病例对照研究。采用血清特异性免疫球蛋白E (IgE)检测特异表型。参与者被分为特应性无哮喘组(185例)、非特应性哮喘(673例)、特应性哮喘(271例)和非特应性非哮喘的参照组(1157例)。分析采用logistic回归。在无哮喘的情况下，未观察到特异反应性。许多胞嘧啶-磷酸-鸟嘌呤(cytosine-phosphate-guanine, CpG)位点在非特应性哮喘中甲基化差异显著(8个家族错误率(FWER) p<9×10- 8,524个错误发现率(FDR)小于0.05)，涉及382个新基因。在特应性哮喘中发现了更多的CpG位点(FWER有181个，FDR有1086个)，涉及569个新基因。有104个FDR CpG位点重叠。35%的CpG位点在非特应性哮喘中，91%在特应性哮喘中，在全血、嗜酸性粒细胞、气道上皮细胞或鼻上皮细胞的研究中重复出现。牵连基因在与神经系统或炎症相关的通路中富集。我们在非特应性哮喘和特应性哮喘中鉴定了大量不同的甲基化CpG位点。来自于血液标本的许多CpG位点在其他哮喘相关组织中同样出现。这些循环生物标志物反映了疾病的风险和后遗症，同时也暗示了与非特应性和特应性哮喘相关的新基因。
(中日友好医院呼吸与危重症医学科 张清 摘译 林江涛 审校)
(Eur Respir J. 2020 Sep 3;56(3):2000217. doi: 10.1183/13993003.00217-2020.)
(Eur Respir J. 2020 Sep 3;56(3):2000217. doi: 10.1183/13993003.00217-2020.)
Epigenome-wide association study of DNA methylation and adult asthma in the Agricultural Lung Health Study
Thanh T Hoang, Sinjini Sikdar, Cheng-Jian Xu, Mi Kyeong Lee, Jonathan Cardwell , Erick Forno , Medea Imboden , Ayoung Jeong, Anne-Marie Madore, Cancan Qi, Tianyuan Wang, Brian D Bennett, James M Ward, Christine G Parks, Laura E Beane-Freeman, Debra King, Alison Motsinger-Reif, David M Umbach, Annah B Wyss, David A Schwartz, Juan C Celedón, Catherine Laprise , Carole Ober, Nicole Probst-Hensch, Ivana V Yang, Gerard H Koppelman, Stephanie J London
Abstract
Epigenome-wide studies of methylation in children support a role for epigenetic mechanisms in asthma; however, studies in adults are rare and few have examined non-atopic asthma. We conducted the largest epigenome-wide association study (EWAS) of blood DNA methylation in adults in relation to non-atopic and atopic asthma.We measured DNA methylation in blood using the Illumina MethylationEPIC array among 2286 participants in a case-control study of current adult asthma nested within a United States agricultural cohort. Atopy was defined by serum specific immunoglobulin E (IgE). Participants were categorised as atopy without asthma (n=185), non-atopic asthma (n=673), atopic asthma (n=271), or a reference group of neither atopy nor asthma (n=1157). Analyses were conducted using logistic regression.No associations were observed with atopy without asthma. Numerous cytosine-phosphate-guanine (CpG) sites were differentially methylated in non-atopic asthma (eight at family-wise error rate (FWER) p<9×10-8, 524 at false discovery rate (FDR) less than 0.05) and implicated 382 novel genes. More CpG sites were identified in atopic asthma (181 at FWER, 1086 at FDR) and implicated 569 novel genes. 104 FDR CpG sites overlapped. 35% of CpG sites in non-atopic asthma and 91% in atopic asthma replicated in studies of whole blood, eosinophils, airway epithelium, or nasal epithelium. Implicated genes were enriched in pathways related to the nervous system or inflammation.We identified numerous, distinct differentially methylated CpG sites in non-atopic and atopic asthma. Many CpG sites from blood replicated in asthma-relevant tissues. These circulating biomarkers reflect risk and sequelae of disease, as well as implicate novel genes associated with non-atopic and atopic asthma.
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肺炎相关重症哮喘表型的新疗法
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