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Background: High cumulative tobacco consumption is associated with short telomeres and with increased all-cause mortality. We tested the hypothesis that high tobacco consumption is causally associated with short telomeres and with increased all-cause mortality.Methods: We studied 55 568 individuals including 32 823 ever smokers from the Danish general population, of whom 3430 died during 10 years of follow-up. All had telomere length measured, detailed information on smoking history, and CHRNA3 rs1051730 genotype, which is associated with tobacco consumption, determined. In a Mendelian randomization study, we conducted observational, genetic, and mediation analyses.Results: First, tobacco consumption was 21.1 pack-years in non-carriers, 22.8 in heterozygotes and 24.8 in homozygotes (P-trend <0.001). Second, the observational multivariable adjusted hazard ratio for all-cause mortality was 1.12 [95% confidence interval (CI): 1.09, 1.15] per doubling in tobacco consumption. In Mendelian randomization analysis, the hazard ratio was 1.08 (1.02, 1.14) per minor CHRNA3 allele in ever smokers. Third, in observational analysis telomeres shortened with −13 base pairs (−18, −8) per doubling in tobacco consumption. In Mendelian randomization analysis, the estimate was +3 base pairs (−10, +15) per minor CHRNA3 allele. Finally, individuals with the shortest vs longest telomeres had a multivariable adjusted hazard ratio of 1.30 (1.13, 1.50) for all-cause mortality; however, in mediation analysis short telomeres explained only +0.4% (−3.5%, +4.3%) of the association between high tobacco consumption and increased all-cause mortality.Conclusions: High tobacco consumption is causally associated with increased all-cause mortality. High cumulative tobacco consumption is associated with short telomeres observationally, but there is no clear genetic association. [ABSTRACT FROM AUTHOR]

Cross-sectional studies have associated short telomere length with smoking, body weight, physical activity, and possibly alcohol intake; however, whether these associations are due to confounding is unknown. We tested these hypotheses in 4,576 individuals from the general population cross-sectionally, and with repeat measurement of relative telomere length 10 years apart. We also tested whether change in telomere length is associated with mortality and morbidity in the general population. Relative telomere length was measured with quantitative polymerase chain reaction. Cross-sectionally at the first examination, short telomere length was associated with increased age (P for trend across quartiles = 3×10−77), current smoking (P = 8×10−3), increased body mass index (P = 7×10−14), physical inactivity (P = 4×10−17), but not with increased alcohol intake (P = 0.10). At the second examination 10 years later, 56% of participants had lost and 44% gained telomere length with a mean loss of 193 basepairs. Change in leukocyte telomere length during 10 years was associated inversely with baseline telomere length (P<1×10−300) and age at baseline (P = 1×10−27), but not with baseline or 10-year inter-observational tobacco consumption, body weight, physical activity, or alcohol intake. Prospectively during a further 10 years follow-up after the second examination, quartiles of telomere length change did not associate with risk of all-cause mortality, cancer, chronic obstructive pulmonary disease, diabetes mellitus, ischemic cerebrovascular disease, or ischemic heart disease. In conclusion, smoking, increased body weight, and physical inactivity were associated with short telomere length cross-sectionally, but not with telomere length change during 10 years observation, and alcohol intake was associated with neither. Also, change in telomere length did not associate prospectively with mortality or morbidity in the general population. [ABSTRACT FROM AUTHOR]

Background A previous case-control study of 100 individuals found that short telomere length was associated with a 28-fold increased risk of chronic obstructive pulmonary disease (COPD). Objectives To test the hypothesis that short telomere length is associated with reduced lung function and an increased risk of COPD. Methods Observational study of 46 396 individuals from the Danish general population. Measurements Leucocyte telomere length and spirometry were measured. COPD was defined using either fixed forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.70 as suggested by the Global initiative for chronic Obstructive Lung Disease (GOLD) or FEV1/FVC below the lower limit of normal (LLN). Results Telomere length decreased significantly with increasing age (p<10-300). FEV1, FVC and FEV1/FVC decreased with decreasing telomere length quartiles (p trend: 5×10-51, 5×10-35 and 6×10-137, respectively), but the associations attenuated after age and multivariable adjustment. The risk of COPD increased with decreasing telomere length quartile (p trend: p=7×10-92 for GOLD; p=8×10-44 for FEV1/FVC below LLN), but associations also attenuated after adjustment. Unadjusted and multivariable adjusted OR for shortest versus longest telomere length quartiles were 2.06 (95% CI 1.91 to 2.22) and 1.15 (95% CI 1.06 to 1.25) for GOLD and 1.73 (95% CI 1.60 to 1.88) and 1.19 (95% CI 1.09 to 1.30) for FEV1/ FVC below LLN, respectively. Per 1000 base pairs decrease in telomere length, the multivariable adjusted OR was 1.07 (95% CI 1.03 to 1.10) for GOLD and 1.07 (95% CI 1.03 to 1.11) for FEV1/FVC below LLN. Conclusions Short telomere length is associated with decreased lung function and with increased risk of COPD, but the associations are markedly attenuated after adjustment. Our data support a modest correlation between telomere length and the lung function indices examined. [ABSTRACT FROM AUTHOR]

Background Recent meta-analyses have suggested that short telomere length was associated with increased risk of cancer. We therefore tested the hypotheses that short telomere length was associated with increased risk of cancer and with increased risk of early death after cancer. Methods We measured leukocyte telomere length in a prospective study of 47 102 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 20 years for cancer diagnosis and death. Follow-up was 100% complete. All statistical tests were two-sided. Results Telomere length decreased linearly with increasing age (P <.001). During follow-up, we observed 3142 first cancers and, among these individuals, 1730 deaths. Decreasing quartiles of telomere length were associated with decreasing survival after cancer (log-rank P <.001). Multivariable-adjusted hazard ratios of early death were 1.31 (95% confidence interval [CI] = 1.14 to 1.52) in individuals in the quartile and 1.43 (95% CI = 1.13 to 1.80) in individuals in the decile with the shortest telomeres vs the longest. Unadjusted hazard ratios of cancer risk were 1.74 (95% CI = 1.58 to 1.93) and 2.00 (95% CI = 1.70 to 2.35) in individuals in the quartile and decile with the shortest vs longest telomeres; however, multivariable adjustment changed these hazard ratios to 0.98 (95% CI = 0.88 to 1.08) and 0.95 (95% CI = 0.80 to 1.11), mainly because of age adjustment. Conclusions Short telomere length is associated with reduced survival after cancer but not with cancer risk. The latter contrasts with findings from recent meta-analyses. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Short telomere length, cancer survival, and cancer risk in 47102 individuals" in the 2013 issue is presented.