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Clinical Trial
. 2014 Aug 15;190(4):399-409.
doi: 10.1164/rccm.201403-0569OC.

Genome-wide Association Identifies Regulatory Loci Associated With Distinct Local Histogram Emphysema Patterns

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Free PMC article
Clinical Trial

Genome-wide Association Identifies Regulatory Loci Associated With Distinct Local Histogram Emphysema Patterns

Peter J Castaldi et al. Am J Respir Crit Care Med. .
Free PMC article

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.

Trial registration: ClinicalTrials.gov NCT00608764.

Keywords: COPD; emphysema; gene regulation; genetics; spiral computed tomography.

Figures

Figure 1.
Figure 1.
Normal local histogram-based emphysema pattern local association plots near rs17486278 in the 15q25 locus from (A) metaanalysis of non-Hispanic white and African American subjects, (B) non-Hispanic whites (n = 6,456), and (C) African Americans (n = 3,158).
Figure 2.
Figure 2.
Moderate centrilobular local histogram-based emphysema pattern genome-wide association studies local association plots near rs56113850 in the 19q13 locus in (A) metaanalysis of non-Hispanic white and African American subjects, (B) non-Hispanic whites (n = 6,456), and (C) African Americans (n = 3,158). Conditional association in non-Hispanic whites conditioning on rs56113850 is shown in D.
Figure 3.
Figure 3.
Panlobular local histogram-based emphysema pattern genome-wide association studies local association plots near rs9590614 in the 13q14 locus in (A) metaanalysis of non-Hispanic white and African American subjects, (B) non-Hispanic whites (n = 6,456), and (C) African Americans (n = 3,158).
Figure 4.
Figure 4.
Severe centrilobular local histogram-based emphysema pattern genome-wide association studies local association plots near rs379123 in the 17q11 locus in (A) metaanalysis of non-Hispanic white and African American subjects, (B) non-Hispanic whites (n = 6,456), and (C) African Americans (n = 3,158).
Figure 5.
Figure 5.
Enhancer and DNase I hypersensitive regions in selected ENCODE and Roadmap cell lines at the 17q11 locus. Red box indicates the lead genome-wide association studies single-nucleotide polymorphism, rs379123, and overlapping enhancer (orange bars) and DNase I hypersensitive regions in multiple cell lines, including small airway epithelial cells (SAEC). There are multiple transcriptionally active candidate regions in the 5′ end of the MYO1D. Image generated with UCSC Genome Browser.

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