Genome-wide association identifies regulatory loci associated with distinct local histogram emphysema patterns

Peter J. Castaldi; Michael H. Cho; Raúl San José Estépar; Merry Lynn N. McDonald; Nan Laird; Terri H. Beaty; George Washko; James D. Crapo; Edwin K. Silverman

doi:10.1164/rccm.201403-0569OC

Genome-wide association identifies regulatory loci associated with distinct local histogram emphysema patterns

Peter J. Castaldi, Michael H. Cho, Raúl San José Estépar, Merry Lynn N. McDonald, Nan Laird, Terri H. Beaty, George Washko, James D. Crapo, Edwin K. Silverman

School of Medicine

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

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 × 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.

Original language	English (US)
Pages (from-to)	399-409
Number of pages	11
Journal	American journal of respiratory and critical care medicine
Volume	190
Issue number	4
DOIs	https://doi.org/10.1164/rccm.201403-0569OC
State	Published - Aug 15 2014

Keywords

COPD
Emphysema
Gene regulation
Genetics
Spiral computed tomography

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine
Critical Care and Intensive Care Medicine

Access to Document

10.1164/rccm.201403-0569OC

Cite this

Castaldi, P. J., Cho, M. H., Estépar, R. S. J., McDonald, M. L. N., Laird, N., Beaty, T. H., Washko, G., Crapo, J. D., & Silverman, E. K. (2014). Genome-wide association identifies regulatory loci associated with distinct local histogram emphysema patterns. American journal of respiratory and critical care medicine, 190(4), 399-409. https://doi.org/10.1164/rccm.201403-0569OC

@article{be8b9fc137d94bbb98dfc1065d89303f,

title = "Genome-wide association identifies regulatory loci associated with distinct local histogram emphysema patterns",

abstract = "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 × 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.",

keywords = "COPD, Emphysema, Gene regulation, Genetics, Spiral computed tomography",

author = "Castaldi, {Peter J.} and Cho, {Michael H.} and Est{\'e}par, {Ra{\'u}l San Jos{\'e}} and McDonald, {Merry Lynn N.} and Nan Laird and Beaty, {Terri H.} and George Washko and Crapo, {James D.} and Silverman, {Edwin K.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2014 by the American Thoracic Society.",

year = "2014",

month = aug,

day = "15",

doi = "10.1164/rccm.201403-0569OC",

language = "English (US)",

volume = "190",

pages = "399--409",

journal = "American journal of respiratory and critical care medicine",

issn = "1073-449X",

publisher = "American Thoracic Society",

number = "4",

}

TY - JOUR

T1 - Genome-wide association identifies regulatory loci associated with distinct local histogram emphysema patterns

AU - Castaldi, Peter J.

AU - Cho, Michael H.

AU - Estépar, Raúl San José

AU - McDonald, Merry Lynn N.

AU - Laird, Nan

AU - Beaty, Terri H.

AU - Washko, George

AU - Crapo, James D.

AU - Silverman, Edwin K.

PY - 2014/8/15

Y1 - 2014/8/15

N2 - 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 × 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.

AB - 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 × 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.

KW - COPD

KW - Emphysema

KW - Gene regulation

KW - Genetics

KW - Spiral computed tomography

UR - http://www.scopus.com/inward/record.url?scp=84907820687&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907820687&partnerID=8YFLogxK

U2 - 10.1164/rccm.201403-0569OC

DO - 10.1164/rccm.201403-0569OC

M3 - Article

C2 - 25006744

AN - SCOPUS:84907820687

SN - 1073-449X

VL - 190

SP - 399

EP - 409

JO - American journal of respiratory and critical care medicine

JF - American journal of respiratory and critical care medicine

IS - 4

ER -

Genome-wide association identifies regulatory loci associated with distinct local histogram emphysema patterns

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this