Mild catalytic defects of tert rs61748181 polymorphism affect the clinical presentation of chronic obstructive pulmonary disease
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
|---|---|
| Enthalten in: |
Scientific reports - 11(2021), 1 vom: 22. Feb., Seite 4333 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Xu, Jialin [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
EC 2.7.7.49 |
|---|
| Anmerkungen: |
Date Completed 03.12.2021 Date Revised 23.08.2022 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41598-021-83686-z |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM32177793X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM32177793X | ||
| 003 | DE-627 | ||
| 005 | 20231226202629.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41598-021-83686-z |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1072.xml |
| 035 | |a (DE-627)NLM32177793X | ||
| 035 | |a (NLM)33619289 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Xu, Jialin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Mild catalytic defects of tert rs61748181 polymorphism affect the clinical presentation of chronic obstructive pulmonary disease |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 03.12.2021 | ||
| 500 | |a Date Revised 23.08.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a TERT protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.7.49 |2 NLM | |
| 650 | 7 | |a Telomerase |2 NLM | |
| 650 | 7 | |a EC 2.7.7.49 |2 NLM | |
| 700 | 1 | |a de Oliveira, Diego Madureira |e verfasserin |4 aut | |
| 700 | 1 | |a Trudeau, Matthew A |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Chin, Jessica J Y |e verfasserin |4 aut | |
| 700 | 1 | |a Sin, Don D |e verfasserin |4 aut | |
| 700 | 1 | |a Sandford, Andrew J |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Judy M Y |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Scientific reports |d 2011 |g 11(2021), 1 vom: 22. Feb., Seite 4333 |w (DE-627)NLM215703936 |x 2045-2322 |7 nnns |
| 773 | 1 | 8 | |g volume:11 |g year:2021 |g number:1 |g day:22 |g month:02 |g pages:4333 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41598-021-83686-z |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 11 |j 2021 |e 1 |b 22 |c 02 |h 4333 | ||