Abstract

Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD). Mendelian randomisation studies, using single nucleotide polymorphisms (SNPs) associated with short LTL, infer a causal role of LTL in ASCVD. Recent results, using the blood-and-muscle model, indicate that higher early life LTL attrition, as estimated by the ratio between LTL and skeletal muscle telomere length (MTL), rather than short LTL at conception, as estimated by MTL, should be responsible of the ASCVD-LTL connection. We combined LTL and MTL measurements and SNPs profiling in 402 individuals to determine if 15 SNPs classically described as associated with short LTL at adult age were rather responsible for higher LTL attrition during early life than for shorter LTL at birth. Two of these SNPs (rs12696304 and rs10936599) were associated with LTL in our cohort (p = 0.027 and p = 0.025, respectively). These SNPs, both located on the TERC gene, were associated with the LTL/MTL ratio (p = 0.007 and p = 0.037, respectively), but not with MTL (p = 0.78 and p = 0.32 respectively). These results suggest that SNPs located on genes coding for telomere maintenance proteins may contribute to a higher LTL attrition during the highly replicative first years of life and have an impact later on the development of ASCVD.

Highlights

  • Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD) and its complications [1,2]

  • In our cohort of patients, single nucleotide polymorphisms (SNPs) that were found to be associated with short LTL are associated with a lower LTL/muscle telomere length (MTL) ratio but are not associated with MTL

  • The present results indicate that rs12696304 and rs10936599, two TERC SNPs previously described as associated with short LTL, do not influence TL at conception as reflected by MTL, but rather higher LTL attrition from conception onwards as expressed in the LTL/MTL ratio

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Summary

Introduction

Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD) and its complications [1,2]. The hypothesis is that inherited short LTL is associated with ASCVD. We recently showed, using the blood and muscle model, that the association between short LTL and ASCVD was not related to shorter telomere length (TL) at the beginning of life—as estimated by minimally proliferative skeletal muscle telomere length (MTL)—but. In this genetic study, we tested this hypothesis by combining SNPs profiling of 15 variants associated with short LTL and telomere length measurements in leukocytes and skeletal muscles. We found that SNPs associated with short LTL in our cohort, TERC variants rs12696304 and rs10936599, are linked with higher estimated early life LTL attrition rather than with shorter estimated

The Cohort
Telomere Length Measurements
Statistical Analyses
Telomere Length Dynamics
Single Nucleotide Polymorphisms Association with Telomere Length
Discussion
Full Text
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