Short Telomere Length and Ischemic Heart Disease: Observational and Genetic Studies in 290 022 Individuals

Abstract

BACKGROUND: Short telomeres are associated with aging and have been associated with a high risk of ischemic heart disease in observational studies; however, the latter association could be due to residual confounding and/or reverse causation. We wanted to test the hypothesis that short telomeres are associated with high risk of ischemic heart disease using a Mendelian randomization approach free of reverse causation and of most confounding.

Biological Age Predictors

“…Short telomeres were found to be risk factors for gastrointestinal, head and neck cancers only. Furthermore, short telomere length has been described as a risk factor for coronary heart disease as judged from a meta-analysis of 43,725 participants (8400 events) (Haycock et al, 2014), and from a large-scale observational study (Scheller Madrid et al, 2016). In fact, this relationship has been suggested to be causal by inferring genetic information (Scheller Madrid et al, 2016, Codd et al, 2013).…”

“…Furthermore, short telomere length has been described as a risk factor for coronary heart disease as judged from a meta-analysis of 43,725 participants (8400 events) (Haycock et al, 2014), and from a large-scale observational study (Scheller Madrid et al, 2016). In fact, this relationship has been suggested to be causal by inferring genetic information (Scheller Madrid et al, 2016, Codd et al, 2013). Likewise, in AD patients, telomere lengths have been shown to be shorter, both in observational (Forero et al, 2016a) and causal Mendelian Randomization (Zhan et al, 2015) studies.…”

Ancestry, Telomere Length, and Atherosclerosis Risk

“…In general, short LTL is associated with arterial aging, as expressed in arterial stiffness 35 , coronary artery calcifications 36,37 , and severity of atherosclerotic plaques in the coronary arteries 38,39 and the carotid arteries 40–43 .…”

Mendelian randomisation in cardiovascular research: an introduction for clinicians

“…When those biomarkers are on discrete pathways to the biomarker of interest, this is termed horizontal pleiotropy,28 and the use of the genetic variant in this circumstance may result in a confounded estimate from Mendelian randomisation. For example, use of genetic variants in loci that associate with telomere length29 but that also associates with cancers (and therefore, by extension, cancer therapy, some of which are deleterious to vascular health) could give a biassed estimate for the association of telomere length in the development of CHD as it is not clear whether telomere length itself is causing CHD or whether it is due to a pathway separate to it (red or blue arrows in figure 5A). Recent advances in methodology include Mendelian randomisation-Egger regression (based on the method used to assess small study bias in meta-analysis30), which can quantify the amount of bias due to horizontal pleiotropy and can provide a valid causal estimate even in the presence of horizontal pleiotropy 31…”