Revealing their findings in Aging Cell, researchers have found a new biochemical target for chronic obstructive pulmonary disease (COPD).
Smoking is only one cause
COPD, which is characterized by bouts of lung problems, has only limited treatments, is progressive and currently incurable, and often occurs in people over 60 [1]. While smoking is its most widely known risk factor, aging and environmental pollutants also contribute to the disease, and its incidence is on the rise [2]. While it has similarities to idiopathic pulmonary fibrosis (IPF), which these researchers also included in this study, the physical causes of COPD are well documented but in IPF are less clear.
However, understanding the physical causes is not the same as understanding the biochemical ones. To better grasp those, these researchers employed genome-wide association studies (GWAS), a technology that is constantly improving. They looked across the map of gene transcription and proteins for potential mechanisms and targets.
One key metric they examined was leukocyte telomere length (LTL), a biomarker of telomere attrition, one of the hallmarks of aging. Previous work has found that LTL is causally associated with IPF but not COPD [3].
Bringing together large databases
These researchers employed multiple databases containing extensive biological data. including the gene expression databases eQTLGen and GTEx, two separate proteomics databases with thousands of proteins and tens of thousands of participants, and the well-known UK Biobank along with the similar FinnGen.
Comparing their genomics databases to patient data, the researchers found a total of 16 proteins that were associated in some way with IPF, 6 proteins associated with COPD, and 17 proteins associated with LTL. While the researchers found other promising targets, only one of these proteins, SCARF2, was negatively associated with both COPD and IPF, completely independently of LTL, and these researchers’ algorithms found this to be causal: that is, higher SCARF2 is likely to protect against these lung diseases.
Other data supported this view. SCARF2 was found to be associated with gene variants that have effects on the lungs. Similarly, as expected, epithelial cells in the lungs of people with COPD had less SCARF2 than in people without it.
These results were also bolstered by similar gene expression data and multivariable analysis. Similar to the protein data, gene expression databases found that cells that expressed more SCARF2 in their mRNA were less likely to be from people with IPF or COPD. Even after adjusting for LTL, SCARF2 was still found to have a significant effect.
This protein has not been heavily investigated. Previous work has found that it is a scavenger protein that binds to acetylated low-density lipoprotein (LDL) [4]; this is widely known as the harmful form of cholesterol, although it is unclear if that relationship plays any role in COPD or IPF. Being that this is a novel and unexplored target, there are as of yet no prospective drugs for increasing SCARF2 in lung cells. If one can be found and successfully tested, this discovery might offer new hope to older people whose lungs are deteiorating from these crippling and dangerous diseases.
Literature
[1] Bhatt, S. P., Agusti, A., Bafadhel, M., Christenson, S. A., Bon, J., Donaldson, G. C., … & Martinez, F. J. (2023). Phenotypes, Etiotypes, and Endotypes of Exacerbations of Chronic Obstructive Pulmonary Disease. American Journal of Respiratory and Critical Care Medicine, 208(10), 1026-1041.
[2] Singla, A., Reuter, S., Taube, C., Peters, M., & Peters, K. (2023). The molecular mechanisms of remodeling in asthma, COPD and IPF with a special emphasis on the complex role of Wnt5A. Inflammation Research, 72(3), 577-588.
[3] Duckworth, A., Gibbons, M. A., Allen, R. J., Almond, H., Beaumont, R. N., Wood, A. R., … & Scotton, C. J. (2021). Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study. The Lancet Respiratory Medicine, 9(3), 285-294.
[4] Ishii, J., Adachi, H., Aoki, J., Koizumi, H., Tomita, S., Suzuki, T., … & Arai, H. (2002). SREC-II, a new member of the scavenger receptor type F family, trans-interacts with SREC-I through its extracellular domain. Journal of Biological Chemistry, 277(42), 39696-39702.
View the article at lifespan.io
