细胞因子诱导的气道平滑肌细胞分子反应为哮喘的全基因组关联研究提供了信息
2020/08/20
摘要
背景：后GWAS时代的一个挑战是赋予疾病相关变异位点以功能。然而，可用的资源并不包括所有组织或与所有疾病相关的环境暴露。例如，气道平滑肌细胞（ASMCs）的过度收缩定义为气道高反应性（AHR），这是哮喘的一个主要特征。然而，ASMC在遗传和基因组研究中的作用却被忽视了。我们的研究旨在解决哮喘基因组研究中关键组织的数据可用性缺口。
方法：我们建立了一个AHR的细胞模型，用来寻找与转录、表观遗传及对两种促进AHR的细胞因子（IL-13和IL-17A）的细胞反应相关的变异位点，并且对人类支气管反应性（BRI）进行了GWAS分析。
结果：我们的研究显示哮喘患者和对照组的ASMCs的反应存在显著差异，包括与哮喘易感性有关的基因。我们界定了不同的分子定量位点（QTLs），包括关于表达（eQTLs）、甲基化（meQTLs）、细胞收缩性（coQTLs）及人类受试者BRI的GWAS的位点。哮喘GWAS中ASM QTL和BRI相关SNP的变异位点显著增多，在近ASM功能基因处较多，许多P值小，在GWAS中没有达到严格的显著阈值。
结论：我们的研究发现哮喘患者和对照组的ASMC之间存在显著差异，可能反映了这些细胞的耐受性，及一组在以前的GWAS中被忽略、反映哮喘AHR成分的变异位点。
Cytokine-induced molecular responses in airway smooth muscle cells inform genome-wide association studies of asthma.
Emma E Thompson, Quynh Dang, Blair Mitchell-Handley, Kavitha Rajendran, Sumati Ram-Mohan, Julian Solway, Carole Ober, Ramaswamy Krishnan
.
Abstract
BACKGROUND:A challenge in the post-GWAS era is to assign function to disease-associated variants. However, available resources do not include all tissues or environmental exposures that are relevant to all diseases. For example, exaggerated bronchoconstriction of airway smooth muscle cells (ASMCs) defines airway hyperresponsiveness (AHR), a cardinal feature of asthma. However, the contribution of ASMC to genetic and genomic studies has largely been overlooked. Our study aimed to address the gap in data availability from a critical tissue in genomic studies of asthma
METHODS:We developed a cell model of AHR to discover variants associated with transcriptional, epigenetic, and cellular responses to two AHR promoting cytokines, IL-13 and IL-17A, and performed a GWAS of bronchial responsiveness (BRI) in humans.
RESULTS:Our study revealed significant response differences between ASMCs from asthma cases and controls, including genes implicated in asthma susceptibility. We defined molecular quantitative trait loci (QTLs) for expression (eQTLs) and methylation (meQTLs), and cellular QTLs for contractility (coQTLs) and performed a GWAS of BRI in human subjects. Variants in asthma GWAS were significantly enriched for ASM QTLs and BRI-associated SNPs, and near genes enriched for ASM function, many with small P values that did not reach stringent thresholds of significance in GWAS.
CONCLUSIONS:Our study identified significant differences between ASMCs from asthma cases and controls, potentially reflecting trained tolerance in these cells, as well as a set of variants, overlooked in previous GWAS, which reflect the AHR component of asthma.
背景：后GWAS时代的一个挑战是赋予疾病相关变异位点以功能。然而，可用的资源并不包括所有组织或与所有疾病相关的环境暴露。例如，气道平滑肌细胞（ASMCs）的过度收缩定义为气道高反应性（AHR），这是哮喘的一个主要特征。然而，ASMC在遗传和基因组研究中的作用却被忽视了。我们的研究旨在解决哮喘基因组研究中关键组织的数据可用性缺口。
方法：我们建立了一个AHR的细胞模型，用来寻找与转录、表观遗传及对两种促进AHR的细胞因子（IL-13和IL-17A）的细胞反应相关的变异位点，并且对人类支气管反应性（BRI）进行了GWAS分析。
结果：我们的研究显示哮喘患者和对照组的ASMCs的反应存在显著差异，包括与哮喘易感性有关的基因。我们界定了不同的分子定量位点（QTLs），包括关于表达（eQTLs）、甲基化（meQTLs）、细胞收缩性（coQTLs）及人类受试者BRI的GWAS的位点。哮喘GWAS中ASM QTL和BRI相关SNP的变异位点显著增多，在近ASM功能基因处较多，许多P值小，在GWAS中没有达到严格的显著阈值。
结论：我们的研究发现哮喘患者和对照组的ASMC之间存在显著差异，可能反映了这些细胞的耐受性，及一组在以前的GWAS中被忽略、反映哮喘AHR成分的变异位点。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Genome Med. 2020 Jul 20;12(1):64. doi: 10.1186/s13073-020-00759-w.)
(Genome Med. 2020 Jul 20;12(1):64. doi: 10.1186/s13073-020-00759-w.)
Cytokine-induced molecular responses in airway smooth muscle cells inform genome-wide association studies of asthma.
Emma E Thompson, Quynh Dang, Blair Mitchell-Handley, Kavitha Rajendran, Sumati Ram-Mohan, Julian Solway, Carole Ober, Ramaswamy Krishnan
.
Abstract
BACKGROUND:A challenge in the post-GWAS era is to assign function to disease-associated variants. However, available resources do not include all tissues or environmental exposures that are relevant to all diseases. For example, exaggerated bronchoconstriction of airway smooth muscle cells (ASMCs) defines airway hyperresponsiveness (AHR), a cardinal feature of asthma. However, the contribution of ASMC to genetic and genomic studies has largely been overlooked. Our study aimed to address the gap in data availability from a critical tissue in genomic studies of asthma
METHODS:We developed a cell model of AHR to discover variants associated with transcriptional, epigenetic, and cellular responses to two AHR promoting cytokines, IL-13 and IL-17A, and performed a GWAS of bronchial responsiveness (BRI) in humans.
RESULTS:Our study revealed significant response differences between ASMCs from asthma cases and controls, including genes implicated in asthma susceptibility. We defined molecular quantitative trait loci (QTLs) for expression (eQTLs) and methylation (meQTLs), and cellular QTLs for contractility (coQTLs) and performed a GWAS of BRI in human subjects. Variants in asthma GWAS were significantly enriched for ASM QTLs and BRI-associated SNPs, and near genes enriched for ASM function, many with small P values that did not reach stringent thresholds of significance in GWAS.
CONCLUSIONS:Our study identified significant differences between ASMCs from asthma cases and controls, potentially reflecting trained tolerance in these cells, as well as a set of variants, overlooked in previous GWAS, which reflect the AHR component of asthma.
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Mcl-1保护嗜酸性粒细胞免于凋亡并加剧过敏性气道炎症
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气道肌成纤维细胞在哮喘中的作用
