Association of Telomere Length With Risk of Disease and Mortality

Abstract

Importance: Telomeres protect DNA from damage. Because they shorten with each mitotic cycle, leukocyte telomere length (LTL) serves as a mitotic clock. Reduced LTL has been associated with multiple human disorders.

Objective: To determine the association between LTL and overall as well as disease-specific mortality and morbidity.

Design, setting, and participants: This multicenter, community-based cohort study conducted from March 2006 to December 2010 included longitudinal follow-up (mean [SD], 12 [2] years) for 472 432 English participants from the United Kingdom Biobank (UK Biobank) and analyzed morbidity and mortality. The data were analyzed in 2021.

Main outcomes and measures: Hazard ratios (HRs) and odds ratios for mortality and morbidity associated with a standard deviation change in LTL, adjusted for age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared), and ethnicity.

Results: This study included a total of 472 432 English participants, of whom 54% were women (mean age, 57 years). Reduced LTL was associated with increased overall (HR, 1.08; 95% CI, 1.07-1.09), cardiovascular (HR, 1.09; 95% CI, 1.06-1.12), respiratory (HR, 1.40; 95% CI, 1.34-1.45), digestive (HR, 1.26; 95% CI, 1.19-1.33), musculoskeletal (HR, 1.51; 95% CI, 1.35-1.92), and COVID-19 (HR, 1.15; 95% CI, 1.07-1.23) mortality, but not cancer-related mortality. A total of 214 disorders were significantly overrepresented and 37 underrepresented in participants with shorter LTL. Respiratory (11%), digestive/liver-related (14%), circulatory (18%), and musculoskeletal conditions (6%), together with infections (5%), accounted for most positive associations, whereas (benign) neoplasms and endocrinologic/metabolic disorders were the most underrepresented entities. Malignant tumors, esophageal cancer, and lymphoid and myeloid leukemia were significantly more common in participants with shorter LTL, whereas brain cancer and melanoma were less prevalent. While smoking and alcohol consumption were associated with shorter LTL, additional adjustment for both factors, as well as cognitive function/major comorbid conditions, did not significantly alter the results.

Conclusions and relevance: This cohort study found that shorter LTL was associated with a small risk increase of overall mortality, but a higher risk of mortality was associated with specific organs and diseases.

Figure 1.. Association of Overall and Cause-Specific Mortality With Leukocyte Telomere Shortening Adjusted for Age, Sex, Body Mass Index (BMI), and Ethnicity

All major International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) categories, as well as selected cause-specific mortalities, were analyzed. Hazard ratios (HRs) per ICD-10 codes were generated from competing risk regression models, accounting for the risk of death through other causes; HRs (95% CI) per SD decrease of telomere length are shown. COPD indicates chronic obstructive pulmonary disease. BMI was calculated as weight in kilograms divided by height in meters squared.

Figure 2.. Multivariable Phenomewide Association Study Corrected for Age, Sex, Body Mass Index (BMI), and Ethnicity

Manhattan plot of adjusted log10 (P values) for all phecodes comparing their occurrence per SD telomere shortening. Highlighted are associations results with −log10 P values between 10 and 120. A and B, Upwards/downwards pointing triangles refer to phecodes that are over and/or underrepresented. NOS indicates not otherwise specified; SIRS, systemic inflammatory response syndrome. BMI was calculated as weight in kilograms divided by height in meters squared.

Figure 3.. Most Overrepresented Phecodes in Patients With Shorter Telomeres

Adjusted for age, sex, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and ethnicity. Odds ratios (ORs) and 95% CIs per SD decrease of telomere length are given. Only phecodes that remained significant after adjustment for multiple testing are displayed. NOS indicates not otherwise specified.

Figure 4.. Association Between Telomere Length and the Top 25 Cancers That Lead to Death, Sorted by Descending Hazard Ratio (HR), and Adjusted for Age, Sex, Body Mass Index (BMI), and Ethnicity

Hazard ratios per International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) code were generated from competing risk regression models, accounting for the risk of death through other causes. The HRs (95% CI) per SD decrease of telomere length are shown. BMI is calculated as weight in kilograms divided by height in meters squared.

Figure 5.. Association of Overall and Cause-Specific Mortality for the First Percentile of Telomere Length Corrected for Age, Sex, Body Mass Index (BMI), and Ethnicity

All major International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) categories, as well as selected cause-specific mortalities, were analyzed. Hazard ratios (HRs) per ICD-10 code were generated from competing risk regression models, accounting for the risk of death of other causes. The HRs (95% CI) per SD decrease of telomere length are shown. COPD indicates chronic obstructive pulmonary disease; NA, not applicable.