Genome-Wide Association Study Identifies New Genetic Determinants of Emphysema Distribution

Abstract

Rationale: Emphysema has considerable variability in the severity and distribution of parenchymal destruction throughout the lungs. Upper lobe predominant emphysema has emerged as an important predictor of response to lung volume reduction surgery. Yet, aside from alpha-1 antitrypsin deficiency, the genetic determinants of emphysema distribution remain largely unknown. Objectives: To identify the genetic influences of emphysema distribution in non-alpha-1 antitrypsin deficient smokers. Methods: 11,532 subjects with complete genotype and CT densitometry data were analyzed. Two CT scan emphysema distribution measures (difference between upper third and lower third emphysema; ratio of upper third to lower third emphysema) were tested for genetic associations in the COPDGene (non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), and GenKOLS (Genetics of COPD, Norway) studies. Separate analyses in each study population were followed by a fixed effect meta-analysis. Single nucleotide polymorphism (SNP)-, gene-, and pathway-based approaches were used. In silico functional evaluation was also performed. Results: We identified 5 loci associated with emphysema distribution at genome-wide significance. These loci included two previously reported associations with COPD susceptibility (4q31 near HHIP and 15q25 near CHRNA5) as well as three new associations near SOWAHB, TRAPPC9, and KIAA1462. Gene set analysis and in silico functional evaluation revealed pathways and cell types that may potentially contribute to the pathogenesis of emphysema distribution. Conclusion: This multi-cohort GWAS identified new genomic loci associated with differential emphysematous destruction throughout the lungs. These findings may point to new biological pathways upon which to expand our diagnostic and therapeutic approaches in COPD.