Exploring the Causal Pathway From Telomere Length to Coronary Heart Disease

Abstract

In this study, we aim to examine metabolic risk factors as possible mediators in the causal relationship between genetically determined TL and CHD using a network MR method 12 from summarized genome-wide association study (GWAS) data. The rationale for focusing on metabolic risk factors is based on the following: (1) these metabolic risk factors explain a large proportion Molecular Medicine© 2017 American Heart Association, Inc. Rationale: Observational studies have found shorter leukocyte telomere length (TL) to be a risk factor for coronary heart disease (CHD), and recently the association was suggested to be causal. However, the relationship between TL and common metabolic risk factors for CHD is not well understood. Whether these risk factors could explain pathways from TL to CHD warrants further attention.Objective: To examine whether metabolic risk factors for CHD mediate the causal pathway from short TL to increased risk of CHD using a network Mendelian randomization design. Methods and Results:Summary statistics from several genome-wide association studies were used in a 2-sample Mendelian randomization study design. Network Mendelian randomization analysis-an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality-was performed to examine the causal association between telomeres and CHD and metabolic risk factors. Summary statistics from the ENGAGE Telomere Consortium were used (n=37 684) as a TL genetic instrument, CARDIoGRAMplusC4D Consortium data were used (case=22 233 and control=64 762) for CHD, and other consortia data were used for metabolic traits (fasting insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, fasting glucose, diabetes mellitus, glycohemoglobin, body mass index, waist circumference, and waist:hip ratio). One-unit increase of genetically determined TL was associated with −0.07 (95% confidence interval, −0.01 to −0.12; P=0.01) lower log-transformed fasting insulin (pmol/L) and 21% lower odds (95% confidence interval, 3-35; P=0.02) of CHD. Higher genetically determined log-transformed fasting insulin level was associated with higher CHD risk (odds ratio, 1.86; 95% confidence interval, 1.01-3.41; P=0.04). Conclusions:

Telomere Length Dynamics and Atherosclerotic Disease

“…The result ties back to the genetic studies where a higher genetic risk for shorter telomeres indicated heritable risks for cardiovascular diseases. 7,8 Another fact that goes well in line with…”

“…6 These findings have subsequently been backed-up by causal evidence from genetic studies using single nucleotide polymorphisms associated with LTL, which have shown that individuals with inherited risk alleles for shorter telomeres pose higher risks of developing cardiovascular diseases. 7,8 The latter studies, termed Mendelian randomization studies described in more detail here, 9 have been suggesting that part of the link between short telomeres and increased risk of cardiovascular diseases may be mediated by insulin pathways. 8 Other explanations have been oxidative stress and inflammation that could enhance telomere shortening and lead to detrimental effects on atherogenesis and repair mechanisms in the cardiovascular system.…”

“…7,8 The latter studies, termed Mendelian randomization studies described in more detail here, 9 have been suggesting that part of the link between short telomeres and increased risk of cardiovascular diseases may be mediated by insulin pathways. 8 Other explanations have been oxidative stress and inflammation that could enhance telomere shortening and lead to detrimental effects on atherogenesis and repair mechanisms in the cardiovascular system.…”

Developments in molecular epidemiology of aging

“…Another type of study using recent GWAS findings within genetic and molecular epidemiology is the application of Mendelian randomizations to assess causal associations in aging. Several papers have used this design to provide evidence for causality using genetically predicted telomere length on disease outcomes [66][67][68]. The benefit of conducting studies using genotype information is that biases such as reverse causation and confounding, which are problematic for other biomarkers or observational associations, are avoided.…”

Stress reactivity elicits a tissue-specific reduction in telomere length in ageing zebrafish (Danio rerio)

“…Shorter telomeres have been identified in both Alzheimer's (14) and Parkinson's disease (15) patients and have been found to accelerate both the onset and underlying pathology of neurodegeneration in mice models (16). Shorter telomere length is also associated with a higher risk of coronary heart disease (17), an association that is thought to be causal (18). Interestingly, the likelihood of onset and progression of age-related diseases is associated with an anxious personality (19)(20)(21) and HPA axis dysfunction (22,23).…”