Functional Studies of Single-Nucleotide Polymorphisms Suggest Heterogeneity in Chronic Obstructive Pulmonary Disease due to Susceptibility of Different Cell Types
Year: 2018
Type: conference-abstract
Abstract: Chronic obstructive pulmonary disease (COPD) is a syndrome that comprises several lung pathologies, but subphenotyping the various disease subtypes has not been successful. We found that a single-nucleotide polymorphism (SNP) within the proline-rich domain of transformation-related protein 53 (TP53) that modifies Pro72 to Arg is associated with twofold increased risk for chronic bronchitis in the Lovelace Smokers and COPDGene cohorts. This association is pronounced for those who report either wood smoke, dust, or fumes exposure. The p53Pro compared with p53Arg variant reduces bcl-2 mRNA half-life, increases transcription of SAM-pointed domain-containing Ets-like factor (SPDEF), and thereby promotes mucous cell hyperplasia in primary human airway epithelial cell cultures (1). These findings were confirmed when targeted replacement of prolines in the proline-rich domain of murine TP53 of 129J and C57Bl/6J mice also increased SPDEF, Bcl-2 expression, and mucous cell hyperplasia. In a separate study, we found that both patients with COPD and cigarette smoke–exposed mice exhibit chronic renal injury, increased urinary albumin/creatinine ratios, and oxidative stress–advanced glycation end products in endothelial cells (2). Because SNPs in vascular endothelial growth factor are associated with reduced airway function (3), we propose that susceptibility of endothelial cells to cigarette smoke and other pollutants leads to pulmonary and renal/endothelial injury in small vessels, ultimately leading to COPD. Other studies have shown that in patients with COPD macrophages are localized to sites of alveolar destruction and that a SNP in the gene encoding macrophage elastase, MMP-12, is associated with COPD in smokers (4). Collectively, functional studies of these polymorphisms suggest that susceptible airway, endothelial cells, or macrophages initially may generate COPD endotypes that are characterized by distinct pathobiological mechanisms and ultimately manifest themselves as emphysema (Figure 1). Other SNPs that render other cell types susceptible, including fibroblasts or hematopoietic cells, remain to be identified and could represent yet other endotypes of COPD. Figure 1.Proposed model of how different cell types with susceptibilities in different genes can initiate chronic obstructive pulmonary disease pathogenesis. COPD = chronic obstructive pulmonary disease; MMP-12 = matrix metalloproteinase 12; SNPs = single nucleotide polymorphisms; TGF-β = transforming growth factor-β; TP53 = transformation-related protein 53; VEGF = vascular endothelial growth factor.
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2905442952