Identification of an emphysema-associated genetic variant nearwith regulatory effects in lung fibroblasts

Murine studies have linked TGF-b signaling to emphysema, and human genome-wide association studies (GWAS) studies of lung function and COPD have identified associated regions near genes in the TGF-b superfamily. However, the functional regulatory mechanisms at these loci have not been identified. We performed the largest GWAS of emphysema patterns to date, identifying ten GWAS loci including an association peak spanning a 200kb region downstream from . Integrative analysis of publicly available eQTL, DNaseI, and chromatin conformation data identified a putative functional variant, rs1690789, that may regulate expression in human fibroblasts. Using chromatin conformation capture, we confirmed that the region containing rs1690789 contacts the promoter in fibroblasts, and CRISPR/Cas-9 targeted deletion of a  100bp region containing rs1690789 resulted in decreased expression in primary human lung fibroblasts. These data provide novel mechanistic evidence linking genetic variation affecting the TGF-b pathway to emphysema in humans.