Identification of an emphysema-associated genetic variant near <i>TGFB2</i> with regulatory effects in lung fibroblasts.

Abstract

Murine studies have linked TGF-β 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-β superfamily. However, the functional regulatory mechanisms at these loci have not been identified. We performed the largest GWAS of emphysema patterns to date, identifying 10 GWAS loci including an association peak spanning a 200 kb region downstream from <i>TGFB2</i>. Integrative analysis of publicly available eQTL, DNaseI, and chromatin conformation data identified a putative functional variant, rs1690789, that may regulate <i>TGFB2</i> expression in human fibroblasts. Using chromatin conformation capture, we confirmed that the region containing rs1690789 contacts the <i>TGFB2</i> promoter in fibroblasts, and CRISPR/Cas-9 targeted deletion of a ~ 100 bp region containing rs1690789 resulted in decreased <i>TGFB2</i> expression in primary human lung fibroblasts. These data provide novel mechanistic evidence linking genetic variation affecting the TGF-β pathway to emphysema in humans.