Leucocyte telomere length and risk of type 2 diabetes mellitus: new prospective cohort study and literature-based meta-analysis.
BACKGROUND
Short telomeres have been linked to various age-related diseases. We aimed to assess the association of telomere length with incident type 2 diabetes mellitus (T2DM) in prospective cohort studies.


METHODS
Leucocyte relative telomere length (RTL) was measured using quantitative polymerase chain reaction in 684 participants of the prospective population-based Bruneck Study (1995 baseline), with repeat RTL measurements performed in 2005 (n = 558) and 2010 (n = 479). Hazard ratios for T2DM were calculated across quartiles of baseline RTL using Cox regression models adjusted for age, sex, body-mass index, smoking, socio-economic status, physical activity, alcohol consumption, high-density lipoprotein cholesterol, log high-sensitivity C-reactive protein, and waist-hip ratio. Separate analyses corrected hazard ratios for within-person variability using multivariate regression calibration of repeated measurements. To contextualise findings, we systematically sought PubMed, Web of Science and EMBASE for relevant articles and pooled results using random-effects meta-analysis.


RESULTS
Over 15 years of follow-up, 44 out of 606 participants free of diabetes at baseline developed incident T2DM. The adjusted hazard ratio for T2DM comparing the bottom vs. the top quartile of baseline RTL (i.e. shortest vs. longest) was 2.00 (95% confidence interval: 0.90 to 4.49; P = 0.091), and 2.31 comparing the bottom quartile vs. the remainder (1.21 to 4.41; P = 0.011). The corresponding hazard ratios corrected for within-person RTL variability were 3.22 (1.27 to 8.14; P = 0.014) and 2.86 (1.45 to 5.65; P = 0.003). In a random-effects meta-analysis of three prospective cohort studies involving 6,991 participants and 2,011 incident T2DM events, the pooled relative risk was 1.31 (1.07 to 1.60; P = 0.010; I2 = 69%).


CONCLUSIONS
Low RTL is independently associated with the risk of incident T2DM. To avoid regression dilution biases in observed associations of RTL with disease risk, future studies should implement methods correcting for within-person variability in RTL. The causal role of short telomeres in T2DM development remains to be determined.
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Peter
P
Willeit
Division of Genetic Epidemiology, Innsbruck Medical University, Innsbruck, Austria.
Julia
J
Raschenberger
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Emma E
EE
Heydon
Department of Medicine, University of California San Diego, La Jolla, United States of America.
Sotirios
S
Tsimikas
Division of Genetic Epidemiology, Innsbruck Medical University, Innsbruck, Austria.
Margot
M
Haun
Department of Laboratory Medicine, Bruneck Hospital, Bruneck, Italy.
Agnes
A
Mayr
Department of Internal Medicine, Bruneck Hospital, Bruneck, Italy.
Siegfried
S
Weger
Department of Medicine, University of California San Diego, La Jolla, United States of America.
Joseph L
JL
Witztum
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Adam S
AS
Butterworth
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
Johann
J
Willeit
Division of Genetic Epidemiology, Innsbruck Medical University, Innsbruck, Austria.
Florian
F
Kronenberg
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
Stefan
S
Kiechl
D000328:Adult; D000367:Age Factors; D000368:Aged; D000428:Alcohol Drinking / Q000503:physiopathology; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009043:Motor Activity; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D012737:Sex Factors; D012923:Social Class; D016615:Telomere / Q000737:chemistry* / Q000378:metabolism; D059506:Telomere Shortening; D049629:Waist-Hip Ratio
D008076:Cholesterol, HDL; D002097:C-Reactive Protein