Genetic regulation of gene expression in the lung identifies CST3 and CD22 as potential causal genes for airflow obstruction
Genetic regulation of gene expression in the lung identifies CST3 and CD22 as potential causal genes for airflow obstruction
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DOI：
10.1136/thoraxjnl-2014-205630
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发表时间：
2014-11-01
期刊：
影响因子：
10
通讯作者：
Postma, Dirkje S.
中科院分区：
文献类型：
--
作者：
Lamontagne, Maxime;Timens, Wim;Postma, Dirkje S.
COPD是一种复杂的慢性疾病，其发病机制尚不清楚。整合基因组方法有可能阐明COPD和肺功能的生物学网络。我们最近结合全基因组基因分型和1111例人类肺标本的基因表达来绘制表达数量性状基因座（eQTL）。目的在我们的肺eQTL数据集中确定COPD与肺功能相关的单核苷酸多态性（SNP）和肺组织基因表达变化之间的因果关系。方法我们评估了三种COPD表型的SNP和基因表达之间的因果关系：FEV1%预测值、FEV1/FVC和COPD作为分类变量。在三个队列中独立评估不同的模型，并进行荟萃分析。对与COPD表型和基因表达相关的SNP进行因果途径建模和人工处理。计算机模拟分析评价了新鉴定的致病基因中生物途径的功能富集。结果SNP-mRNA-表型三联体与FEV1%predicted（n = 169）和FEV1/FVC（n = 80）之间存在高度可靠的因果关系。揭示了与COPD潜在生物学相关的几个基因。上调半胱氨酸蛋白酶抑制剂C（CST3）和CD22的eQTL-SNP与更差的肺功能相关。富含致病基因的信号通路包括外源性物质代谢、细胞凋亡、蛋白酶-抗蛋白酶和氧化-抗氧化balances.Conclusions通过使用整合基因组学和分析COPD表型与肺组织中SNP和基因表达的关系，我们确定CST3和CD22为气流阻塞的潜在致病基因。这项研究还增强了对先前描述的COPD途径的理解。
Background COPD is a complex chronic disease with poorly understood pathogenesis. Integrative genomic approaches have the potential to elucidate the biological networks underlying COPD and lung function. We recently combined genome-wide genotyping and gene expression in 1111 human lung specimens to map expression quantitative trait loci (eQTL).Objective To determine causal associations between COPD and lung function-associated single nucleotide polymorphisms (SNPs) and lung tissue gene expression changes in our lung eQTL dataset.Methods We evaluated causality between SNPs and gene expression for three COPD phenotypes: FEV1% predicted, FEV1/FVC and COPD as a categorical variable. Different models were assessed in the three cohorts independently and in a meta-analysis. SNPs associated with a COPD phenotype and gene expression were subjected to causal pathway modelling and manual curation. In silico analyses evaluated functional enrichment of biological pathways among newly identified causal genes. Biologically relevant causal genes were validated in two separate gene expression datasets of lung tissues and bronchial airway brushings.Results High reliability causal relations were found in SNP-mRNA-phenotype triplets for FEV1% predicted (n=169) and FEV1/FVC (n=80). Several genes of potential biological relevance for COPD were revealed. eQTL-SNPs upregulating cystatin C (CST3) and CD22 were associated with worse lung function. Signalling pathways enriched with causal genes included xenobiotic metabolism, apoptosis, protease-antiprotease and oxidant-antioxidant balance.Conclusions By using integrative genomics and analysing the relationships of COPD phenotypes with SNPs and gene expression in lung tissue, we identified CST3 and CD22 as potential causal genes for airflow obstruction. This study also augmented the understanding of previously described COPD pathways.