Mild catalytic defects of tert rs61748181 polymorphism affect the clinical presentation of chronic obstructive pulmonary disease

Scientific Reports, Vol. 11 (2021)

Mots clés
Authors
  • Jialin Xu
  • Faculty of Pharmaceutical Sciences, University of British Columbia
  • Diego Madureira de Oliveira
  • Faculty of Pharmaceutical Sciences, University of British Columbia
  • Matthew A. Trudeau
  • Faculty of Pharmaceutical Sciences, University of British Columbia
  • Yang Yang
  • Division of Epidemiology and Biostatistics, School of Public Health, Hong Kong University
  • Jessica J. Y. Chin
  • Centre for Heart Lung Innovation, University of British Columbia and St Paul’s Hospital
  • Don D. Sin
  • Centre for Heart Lung Innovation, University of British Columbia and St Paul’s Hospital
  • Andrew J. Sandford
  • Centre for Heart Lung Innovation, University of British Columbia and St Paul’s Hospital
  • Judy M. Y. Wong
  • Faculty of Pharmaceutical Sciences, University of British Columbia

Résumé

Abstract Chronic obstructive pulmonary disease (COPD) is a disorder of accelerated lung aging. Multiple pieces of evidence support that the aging biomarker short telomeres, which can be caused by mutations in telomerase reverse transcriptase (TERT), contribute to COPD pathogenesis. We hypothesized that short telomere risk-associated single nucleotide polymorphisms (SNPs) in TERT, while not able to drive COPD development, nonetheless modify the disease presentation. We set out to test the SNP carrying status in a longitudinal study of smokers with COPD and found that rapid decline of FEV1 in lung function was associated with the minor allele of rs61748181 (adjusted odds ratio 2.49, p = 0.038). Biochemical evaluation of ex vivo engineered human cell models revealed that primary cells expressing the minor allele of rs61748181 had suboptimal telomere length maintenance due to reduced telomerase catalytic activity, despite having comparable cell growth kinetics as WT-TERT expressing cells. This ex vivo observation translated clinically in that shorter telomeres were found in minor allele carriers in a sub-population of COPD patients with non-declining lung function, over the 5-year period of the longitudinal study. Collectively, our data suggest that functional TERT SNPs with mild catalytic defects are nonetheless implicated in the clinical presentation of COPD.

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