Differential DNA methylation marks and gene comethylation of COPD in African-Americans with COPD exacerbations.
Differential DNA methylation marks and gene comethylation of COPD in African-Americans with COPD exacerbations.
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DOI：
10.1186/s12931-016-0459-8
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发表时间：
2016-11-05
影响因子：
5.8
通讯作者：
DeMeo D
中科院分区：
文献类型：
--
作者：
Busch R;Qiu W;Lasky-Su J;Morrow J;Criner G;DeMeo D
慢性阻塞性肺疾病（COPD）是全球第三大死因。识别非裔美国人中与 COPD 相关的 DNA 甲基化标记可能有助于我们了解 COPD 易感性的种族差异。我们确定了与慢性阻塞性肺病相关的差异甲基化基因和共甲基化网络模块，这些基因和共甲基化网络模块是从宾夕法尼亚州慢性阻塞性肺急性加重研究（PA-SCOPE）队列中招募的慢性阻塞性肺病恶化期间和吸烟控制期间招募的非裔美国人。我们使用 Illumina Infinium HumanMmethylation27 BeadChip Array 评估了 PA-SCOPE 队列中 362 名非裔美国吸烟者全血样本的 DNA 甲基化。最终分析包括 19302 个 CpG 探针，在质量控制后注释到最近的基因转录本。我们使用混合线性模型测试了甲基化与 COPD 病例对照状态的关联。使用加权基因共表达网络分析（WGCNA）构建加权基因共甲基化网络，并分析网络模块与 COPD 的关联。有 5 个差异甲基化 CpG 探针与非裔美国人中的 COPD 显着相关（FDR 小于 5%），还有 7 个探针在 FDR 小于 10% 时接近显着性。排名最高的基因关联是 MAML1，它已被证明会影响小鼠肺部的 NOTCH 依赖性血管生成。网络建模产生了与 COPD 显着相关的“黄色”和“蓝色”共甲基化模块（p 值分别为 4 × 10-10 和 4 × 10-9）。黄色模块富含与已知与慢性阻塞性肺病相关的炎症途径相关的基因集。蓝色模块包含同步差异甲基化分析中排名靠前的基因（FXYD1/LGI4，基因显着性 p 值 1.2 × 10-26；MAML1，p 值 2.0 × 10-26；CD72，p 值 2.1 × 10-25；LPO，p 值7.2 × 10-25），并且在Gene Ontology基因集富集分析中与肺发育过程显着相关。我们鉴定了 12 个与 COPD 相关的差异甲基化 CpG 位点，这些位点映射到生物学上合理的基因。网络模块共甲基化模式已经确定了可能导致 COPD 易感性和严重程度种族差异的候选基因。 COPD 相关的共甲基化模块包含先前与肺部疾病和炎症相关的基因，并概括了已知的 COPD 相关基因。差异甲基化和 WGCNA 分析涉及的基因可能提供促进非裔美国人 COPD 易感性、恶化和结果的机制目标。试验注册：NCT00774176，注册处：ClinicalTrials.gov，URL：www.clinicaltrials.gov，第一位参与者注册日期：2004 年 6 月，注册日期：2008 年 1 月 4 日（追溯注册）。本文的在线版本 (doi:10.1186/s12931-016-0459-8) 包含补充材料，可供授权用户使用。
Chronic obstructive pulmonary disease (COPD) is the third-leading cause of death worldwide. Identifying COPD-associated DNA methylation marks in African-Americans may contribute to our understanding of racial disparities in COPD susceptibility. We determined differentially methylated genes and co-methylation network modules associated with COPD in African-Americans recruited during exacerbations of COPD and smoking controls from the Pennsylvania Study of Chronic Obstructive Pulmonary Exacerbations (PA-SCOPE) cohort. We assessed DNA methylation from whole blood samples in 362 African-American smokers in the PA-SCOPE cohort using the Illumina Infinium HumanMethylation27 BeadChip Array. Final analysis included 19302 CpG probes annotated to the nearest gene transcript after quality control. We tested methylation associations with COPD case-control status using mixed linear models. Weighted gene comethylation networks were constructed using weighted gene coexpression network analysis (WGCNA) and network modules were analyzed for association with COPD. There were five differentially methylated CpG probes significantly associated with COPD among African-Americans at an FDR less than 5 %, and seven additional probes that approached significance at an FDR less than 10 %. The top ranked gene association was MAML1, which has been shown to affect NOTCH-dependent angiogenesis in murine lung. Network modeling yielded the “yellow” and “blue” comethylation modules which were significantly associated with COPD (p-value 4 × 10-10 and 4 × 10-9, respectively). The yellow module was enriched for gene sets related to inflammatory pathways known to be relevant to COPD. The blue module contained the top ranked genes in the concurrent differential methylation analysis (FXYD1/LGI4, gene significance p-value 1.2 × 10-26; MAML1, p-value 2.0 × 10-26; CD72, p-value 2.1 × 10-25; and LPO, p-value 7.2 × 10-25), and was significantly associated with lung development processes in Gene Ontology gene-set enrichment analysis. We identified 12 differentially methylated CpG sites associated with COPD that mapped to biologically plausible genes. Network module comethylation patterns have identified candidate genes that may be contributing to racial differences in COPD susceptibility and severity. COPD-associated comethylation modules contained genes previously associated with lung disease and inflammation and recapitulated known COPD-associated genes. The genes implicated by differential methylation and WGCNA analysis may provide mechanistic targets contributing to COPD susceptibility, exacerbations, and outcomes among African-Americans. Trial Registration: NCT00774176, Registry: ClinicalTrials.gov, URL: www.clinicaltrials.gov, Date of Enrollment of First Participant: June 2004, Date Registered: 04 January 2008 (retrospectively registered). The online version of this article (doi:10.1186/s12931-016-0459-8) contains supplementary material, which is available to authorized users.
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影响因子：
3.5
作者：
Cho, Michael H.;Castaldi, Peter J.;Silverman, Edwin K.
通讯作者：
Silverman, Edwin K.
影响因子：
168.9
作者：
Brightling, CE;Monteiro, W;Pavord, ID
通讯作者：
Pavord, ID
影响因子：
46.9
作者：
通讯作者：
--
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
影响因子：
9.6
作者：
Han, MeiLan K.;Curran-Everett, Douglas;Foreman, Marilyn G.
通讯作者：
Foreman, Marilyn G.