Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea.
Division of Biomedical Convergence, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, Republic of Korea.
Sci Rep. 2021 Aug 17;11(1):16692. doi: 10.1038/s41598-021-95887-7.
Emphysema is an important feature of chronic obstructive pulmonary disease (COPD). Genetic factors likely affect emphysema pathogenesis, but this question has predominantly been studied in those of European ancestry. In this study, we sought to determine genetic components of emphysema severity and characterize the potential function of the associated loci in Korean population. We performed a genome-wide association study (GWAS) on quantitative emphysema in subjects with or without COPD from two Korean COPD cohorts. We investigated the functional consequences of the loci using epigenetic annotation and gene expression data. We also compared our GWAS results with an epigenome-wide association study and previous differential gene expression analysis. In total, 548 subjects (476 [86.9%] male) including 514 COPD patients were evaluated. We identified one genome-wide significant SNP (P < 5.0 × 10), rs117084279, near PIBF1. We identified an additional 57 SNPs (P < 5.0 × 10) associated with emphysema in all subjects, and 106 SNPs (P < 5.0 × 10) in COPD patients. Of these candidate SNPs, 2 (rs12459249, rs11667314) near CYP2A6 were expression quantitative trait loci in lung tissue and a SNP (rs11214944) near NNMT was an expression quantitative trait locus in whole blood. Of note, rs11214944 was in linkage disequilibrium with variants in enhancer histone marks in lung tissue. Several genes near additional SNPs were identified in our previous EWAS study with nominal level of significance. We identified a novel SNP associated with quantitative emphysema on CT. Including the novel SNP, several candidate SNPs in our study may provide clues to the genetic etiology of emphysema in Asian populations. Further research and validation of the loci will help determine the genetic factors for the development of emphysema.
肺气肿是慢性阻塞性肺疾病（COPD）的一个重要特征。遗传因素可能影响肺气肿的发病机制，但这个问题主要在欧洲血统的人群中进行了研究。在这项研究中，我们试图确定韩国人群中肺气肿严重程度的遗传成分，并描述相关基因座的潜在功能。我们对来自两个韩国 COPD 队列的 COPD 患者或无 COPD 的患者进行了定量肺气肿的全基因组关联研究（GWAS）。我们使用表观遗传注释和基因表达数据研究了基因座的功能后果。我们还将我们的 GWAS 结果与全基因组关联研究和以前的差异基因表达分析进行了比较。总共评估了 548 名受试者（514 名男性[86.9%]），包括 514 名 COPD 患者。我们确定了一个全基因组显著的 SNP（P < 5.0 × 10，rs117084279），位于 PIBF1 附近。我们在所有受试者中发现了另外 57 个与肺气肿相关的 SNP（P < 5.0 × 10，rs12459249，rs11667314），在 COPD 患者中发现了 106 个 SNP（P < 5.0 × 10）。在这些候选 SNP 中，2 个（rs12459249，rs11667314）位于 CYP2A6 附近是肺组织中的表达数量性状基因座，1 个 SNP（rs11214944）位于 NNMT 附近是全血中的表达数量性状基因座。值得注意的是，rs11214944 与肺组织中增强子组蛋白标记的变体呈连锁不平衡。在我们之前的 EWAS 研究中，在名义水平上发现了几个靠近其他 SNP 的基因。我们确定了一个与 CT 定量肺气肿相关的新 SNP。包括新 SNP，我们研究中的几个候选 SNP 可能为亚洲人群肺气肿的遗传病因提供线索。对基因座的进一步研究和验证将有助于确定肺气肿发生的遗传因素。
