Castaldi Peter J, Cho Michael H, San José Estépar Raúl, McDonald Merry-Lynn N, Laird Nan, Beaty Terri H, Washko George, Crapo James D, Silverman Edwin K
1 Channing Division of Network Medicine and.
Am J Respir Crit Care Med. 2014 Aug 15;190(4):399-409. doi: 10.1164/rccm.201403-0569OC.
Emphysema is a heritable trait that occurs in smokers with and without chronic obstructive pulmonary disease. Emphysema occurs in distinct pathologic patterns, but the genetic determinants of these patterns are unknown.
To identify genetic loci associated with distinct patterns of emphysema in smokers and investigate the regulatory function of these loci.
Quantitative measures of distinct emphysema patterns were generated from computed tomography scans from smokers in the COPDGene Study using the local histogram emphysema quantification method. Genome-wide association studies (GWAS) were performed in 9,614 subjects for five emphysema patterns, and the results were referenced against enhancer and DNase I hypersensitive regions from ENCODE and Roadmap Epigenomics cell lines.
Genome-wide significant associations were identified for seven loci. Two are novel associations (top single-nucleotide polymorphism rs379123 in MYO1D and rs9590614 in VMA8) located within genes that function in cell-cell signaling and cell migration, and five are in loci previously associated with chronic obstructive pulmonary disease susceptibility (HHIP, IREB2/CHRNA3, CYP2A6/ADCK, TGFB2, and MMP12). Five of these seven loci lay within enhancer or DNase I hypersensitivity regions in lung fibroblasts or small airway epithelial cells, respectively. Enhancer enrichment analysis for top GWAS associations (single-nucleotide polymorphisms associated at P < 5 × 10(-6)) identified multiple cell lines with significant enhancer enrichment among top GWAS loci, including lung fibroblasts.
This study demonstrates for the first time genetic associations with distinct patterns of pulmonary emphysema quantified by computed tomography scan. Enhancer regions are significantly enriched among these GWAS results, with pulmonary fibroblasts among the cell types showing the strongest enrichment.
肺气肿是一种可遗传的性状，在有或没有慢性阻塞性肺疾病的吸烟者中均会出现。肺气肿以不同的病理模式出现，但其模式的遗传决定因素尚不清楚。
确定与吸烟者肺气肿不同模式相关的基因座，并研究这些基因座的调控功能。
使用局部直方图肺气肿量化方法，从慢性阻塞性肺疾病基因研究中吸烟者的计算机断层扫描生成不同肺气肿模式的定量测量值。对9614名受试者进行了全基因组关联研究（GWAS），以研究五种肺气肿模式，并将结果与来自ENCODE和表观基因组路线图细胞系的增强子和DNase I超敏区域进行比对。
确定了七个基因座与全基因组显著相关。两个是新的关联（MYO1D中的顶级单核苷酸多态性rs379123和VMA8中的rs9590614），位于在细胞间信号传导和细胞迁移中起作用的基因内，另外五个位于先前与慢性阻塞性肺疾病易感性相关的基因座（HHIP、IREB2/CHRNA3、CYP2A6/ADCK、TGFB2和MMP12）中。这七个基因座中的五个分别位于肺成纤维细胞或小气道上皮细胞的增强子或DNase I超敏区域内。对顶级GWAS关联（P < 5 × 10(-6) 时相关的单核苷酸多态性）进行增强子富集分析，确定了多个在顶级GWAS基因座中具有显著增强子富集的细胞系，包括肺成纤维细胞。
本研究首次证明了通过计算机断层扫描量化的肺气肿不同模式的遗传关联。在这些GWAS结果中，增强子区域显著富集，肺成纤维细胞是显示最强富集的细胞类型之一。
