Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts.
Margaret M ParkerYuan HaoFeng GuoBetty PhamRobert ChaseJohn PlatigMichael H ChoCraig P HershVictor J ThannickalJames CrapoGeorge WashkoScott H RandellEdwin K SilvermanRaúl San José EstéparXiaobo ZhouPeter J CastaldiPublished in: eLife (2019)
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 TGFB2. Integrative analysis of publicly available eQTL, DNaseI, and chromatin conformation data identified a putative functional variant, rs1690789, that may regulate TGFB2 expression in human fibroblasts. Using chromatin conformation capture, we confirmed that the region containing rs1690789 contacts the TGFB2 promoter in fibroblasts, and CRISPR/Cas-9 targeted deletion of a ~ 100 bp region containing rs1690789 resulted in decreased TGFB2 expression in primary human lung fibroblasts. These data provide novel mechanistic evidence linking genetic variation affecting the TGF-β pathway to emphysema in humans.
Keyphrases
- lung function
- genome wide
- chronic obstructive pulmonary disease
- genome wide association
- transcription factor
- cystic fibrosis
- air pollution
- dna methylation
- endothelial cells
- transforming growth factor
- extracellular matrix
- crispr cas
- poor prognosis
- gene expression
- genome wide association study
- case control
- electronic health record
- induced pluripotent stem cells
- dna damage
- genome wide identification
- big data
- genome editing
- pulmonary fibrosis
- pluripotent stem cells
- molecular dynamics simulations
- epithelial mesenchymal transition
- bioinformatics analysis
- idiopathic pulmonary fibrosis
- artificial intelligence
- long non coding rna
- crystal structure