Genome-Wide Association Identifies Regulatory Loci Associated with Distinct Local Histogram Emphysema Patterns
Genome-Wide Association Identifies Regulatory Loci Associated with Distinct Local Histogram Emphysema Patterns
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DOI：
10.1164/rccm.201403-0569oc
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发表时间：
2014-08-15
影响因子：
24.7
通讯作者：
Silverman, Edwin K.
中科院分区：
文献类型：
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作者：
Castaldi, Peter J.;Cho, Michael H.;Silverman, Edwin K.
依据：肺气肿是一种遗传特征，发生在吸烟者伴或不伴慢性阻塞性肺疾病的人群中。肺气肿发生在不同的病理模式，但这些模式的遗传决定因素是unknow.Objectives：识别与吸烟者肺气肿的不同模式相关的遗传基因座，并调查这些基因座的调节功能。方法：不同肺气肿模式的定量措施产生的计算机断层扫描从吸烟者在COPD基因研究使用局部直方图肺气肿量化方法。全基因组关联研究（GWAS）在9,614名受试者中进行了五种肺气肿模式，结果参考了ENCODE和Roadmap表观基因组学细胞系的增强子和DNA酶I超敏感区域。两个是位于细胞间信号传导和细胞迁移基因内的新关联（MYO 1D中的最高单核苷酸多态性rs379123和VMA 8中的rs 9590614），五个是先前与慢性阻塞性肺疾病易感性相关的基因座（HHIP，IREB 2/CHRNA 3，CYP 2A 6/ADCK，TGFB 2和MMP 12）。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DNA酶I超敏反应区域内。对最高GWAS相关性的增强子富集分析（P < 5 x 10（-6）的单核苷酸多态性相关）确定了在最高GWAS基因座中具有显著增强子富集的多个细胞系，包括肺成纤维细胞。结论：本研究首次证实了通过计算机断层扫描定量的肺气肿的不同模式的遗传相关性。增强子区域在这些GWAS结果中显著富集，其中肺成纤维细胞在显示最强富集的细胞类型中。
Rationale: 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.Objectives: To identify genetic loci associated with distinct patterns of emphysema in smokers and investigate the regulatory function of these loci.Methods: 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.Measurements and Main Results: 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 x 10(-6)) identified multiple cell lines with significant enhancer enrichment among top GWAS loci, including lung fibroblasts.Conclusions: 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.