Exploring the Causal Pathway from Telomere Length to Coronary Heart Disease: A Network Mendelian Randomization Study.

Abstract

Rationale: Observational studies have found shorter leukocyte telomere length to be a risk factor for coronary heart disease (CHD), and more recently the association was suggested to be causal. However, the relationship between telomere length and common metabolic risk factors for CHD is not well understood. Whether these risk factors could explain pathways from telomere length to CHD warrants further attention. Objective: To examine if metabolic risk factors for CHD mediate the causal pathway from short telomere length to increased risk of CHD using a network Mendelian randomization (MR) design. Methods and Results: Summary statistics from several genome-wide association studies were used in a two-sample MR study design. Network MR 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 as well as metabolic risk factors. Summary statistics from the ENGAGE Telomere Consortium were used (n=37 684) as a telomere length (TL) genetic instrument, CARDIoGRAMplusC4D Consortium data were used (case=22 233, 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, HbA1c, body mass index, waist circumference, and waist to hip ratio). One unit increase of genetically determined TL was associated with -0.07 (95% confidence interval: -0.01, -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: Overall, our findings support a role of insulin as a mediator on the causal pathway from shorter telomeres to CHD pathogenesis.