Genome-Wide Association Identifies Regulatory Loci Associated with Distinct Local Histogram Emphysema Patterns

被引：74

作者：

Castaldi, Peter J. ^{[1
,2
,3
]}

Cho, Michael H. ^{[1
,4
]}

Estepar, Raul San Jose ^{[5
]}

McDonald, Merry-Lynn N. ^{[1
]}

Laird, Nan ^{[6
]}

Beaty, Terri H. ^{[7
]}

Washko, George ^{[4
]}

Crapo, James D. ^{[8
]}

Silverman, Edwin K. ^{[1
,4
]}

机构：

[1] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Boston, MA USA

[4] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Surg Planning Lab, Boston, MA 02115 USA

[6] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA

[7] Johns Hopkins Univ Bloomberg, Sch Publ Hlth, Baltimore, MD USA

[8] Natl Jewish Hlth, Denver, CO USA

来源：

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE | 2014年 / 190卷 / 04期

基金：

美国国家卫生研究院;

关键词：

emphysema; COPD; genetics; gene regulation; spiral computed tomography; OBSTRUCTIVE PULMONARY-DISEASE; SUSCEPTIBILITY LOCUS; COMPUTED-TOMOGRAPHY; LUNG-CANCER; COPD; POPULATION; PHENOTYPES; GENES; SCAN;

D O I：

10.1164/rccm.201403-0569OC

中图分类号：

R4 [临床医学];

学科分类号：

100218 [急诊医学];

摘要：

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.

引用

页码：399 / 409

页数：11

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