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Shorter telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survival.

ABSTRACT: Patients with short telomeres and interstitial lung disease may have decreased chronic lung allograft dysfunction (CLAD)-free survival following lung transplantation. The relationship between post-transplant telomere length and outcomes following lung transplantation has not been characterised among all recipients, regardless of native lung disease. This was a single-centre prospective cohort study. Consenting transplant recipients had their telomere length measured using quantitative real-time PCR assays on peripheral blood collected at the time of surveillance bronchoscopy. We assessed the association between early post-transplant telomere length (as measured in the first 100 days) and CLAD-free survival, time to clinically significant leukopenia, cytomegalovirus (CMV) viraemia, chronic kidney disease, and acute cellular rejection. We also assessed the association between rate of telomere shortening and CLAD-free survival. Telomere lengths were available for 98 out of 215 (45.6%) recipients who underwent lung transplant during the study period (median measurement per patient=2 (interquartile range, 1-3)). Shorter telomere length was associated with decreased CLAD-free survival (hazard ratio (HR)=1.24; 95% CI=1.03-1.48; p=0.02), leukopenia requiring granulocyte colony-stimulating factor (HR=1.17, 95% CI=1.01-1.35, p=0.03), and CMV viraemia among CMV-mismatch recipients (HR=4.04, 95% CI=1.05-15.5, p=0.04). Telomere length was not associated with acute cellular rejection or chronic kidney disease. Recipients with more rapid loss in telomere length (defined as the highest tertile of telomere shortening) did not have worse subsequent CLAD-free survival than those without rapid loss (HR=1.38, 95% CI=0.27-7.01, p=0.70). Shorter early post-transplant telomere length is associated with decreased CLAD-free survival and clinically significant leukopenia in lung transplant recipients, regardless of native lung disease.

SUBMITTER: Courtwright AM

PROVIDER: S-EPMC7293991 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFrailty is a multidimensional syndrome of decline that affects multiple systems and predisposes to adverse health outcomes. Although chronological age is the major risk factor, inter-individual variation in risk is not fully understood. Leucocyte telomere length (LTL), a proposed marker of biological age, has been associated with risk of many diseases. We sought to determine whether LTL is associated with risk of frailty.MethodsWe utilized cross-sectional data from 441 781 UK Biobank participants (aged 40-69 years), with complete data on frailty indicators and LTL. Frailty was defined as the presence of at least three of five indicators: weaker grip strength, slower walking pace, weight loss in the past year, lower physical activity, and exhaustion in the past 2 weeks. LTL was measured using a validated qPCR method and reported as a ratio of the telomere repeat number (T) to a single-copy gene (S) (T/S ratio). Association of LTL with frailty was evaluated using adjusted (chronological age, sex, deprivation, smoking, alcohol intake, body mass index, and multimorbidity) multinomial and ordinal regression models, and results are presented as relative risk (RRR) or odds ratios (OR), respectively, alongside the 95% confidence interval (CI). Mendelian randomization (MR), using 131 genetic variants associated with LTL, was used to assess if the association of LTL with frailty was causal.ResultsFrail participants (4.6%) were older (median age difference (95% CI): 3 (2.5; 3.5) years, P = 2.73 × 10-33 ), more likely to be female (61%, P = 1.97 × 10-129 ), and had shorter LTL (-0.13SD vs. 0.03SD, P = 5.43 × 10-111 ) than non-frail. In adjusted analyses, both age and LTL were associated with frailty (RRR = 1.03 (95% CI: 1.02; 1.04) per year of older chronological age, P = 3.99 × 10-12 ; 1.10 (1.08; 1.11) per SD shorter LTL, P = 1.46 × 10-30 ). Within each age group (40-49, 50-59, 60-69 years), the prevalence of frailty was about 33% higher in participants with shorter (-2SD) versus longer telomeres (+2SD). MR analysis showed an association of LTL with frailty that was directionally consistent with the observational association, but not statistically significant (MR-Median: OR (95% CI): 1.08 (0.98; 1.19) per SD shorter LTL, P = 0.13).ConclusionsInter-individual variation in LTL is associated with the risk of frailty independently of chronological age and other risk factors. Our findings provide evidence for an additional biological determinant of frailty.

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Shorter telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survival.

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