Telomere length and metabolic syndrome traits: A Mendelian randomisation study

Abstract

Observational studies have revealed associations between short leucocyte telomere length (LTL), a TL marker in somatic tissues and multiple Metabolic Syndrome (MetS) traits. Animal studies have supported these findings by showing that increased telomere attrition leads to adipose tissue dysfunction and insulin resistance. We investigated the associations between genetically instrumented LTL and MetS traits using Mendelian Randomisation (MR). Fifty‐two independent variants identified at FDR<0.05 from a genome‐wide association study (GWAS) including 78,592 Europeans and collectively accounting for 2.93% of LTL variance were selected as genetic instruments for LTL. Summary‐level data for MetS traits and for the MetS as a binary phenotype were obtained from the largest publicly available GWAS and two‐sample MR analyses were used to estimate the associations of LTL with these traits. The combined effect of the genetic instruments was modelled using inverse variance weighted regression and sensitivity analyses with MR‐Egger, weighted‐median and MR‐PRESSO were performed to test for and correct horizonal pleiotropy. Genetically instrumented longer LTL was associated with higher waist‐to‐hip ratio adjusted for body mass index (β = 0.045 SD, SE = 0.018, p = 0.01), raised systolic (β = 1.529 mmHg, SE = 0.332, p = 4x10−6) and diastolic (β = 0.633 mmHg, SE = 0.222, p = 0.004) blood pressure, and increased MetS risk (OR = 1.133, 95% CI 1.057–1.215). Consistent results were obtained in sensitivity analyses, which provided no evidence of unbalanced horizontal pleiotropy. Telomere shortening might not be a major driver of cellular senescence and dysfunction in human adipose tissue. Future experimental studies should examine the mechanistic bases for the links between longer LTL and increased upper‐body fat distribution and raised blood pressure.

Investigating the impact of metabolic syndrome traits on telomere length: a Mendelian randomization study

“…Mendelian randomization (MR) is an epidemiological tool using data from genetic studies to estimate the nonconfounded associations between exposures and outcomes. We and others have recently explored the relationships between LTL and MetS traits using MR but failed to detect any causal associations between short telomeres and higher risk of MetS or its constituent traits [11, 20]. On the contrary, longer LTL was associated with higher blood pressure (BP), higher waist‐hip ratio adjusted for body mass index (WHRadjBMI), and increased MetS risk [20].…”

Telomere Length and Hearing Loss: A Two-Sample Mendelian Randomization

“…Previously reported meta-analysis of GWAS data from participants of European ancestry identified 52 potential SNPs for this evaluation. Our data validation reduced this to 16 SNPs related to TL, which were also independent of any potential confounding factors and then applied as instrumental variables in our MR evaluations to identify any causal relationships between TL and HL [ 29 , 34 , 35 ]. The proportion of variance in average TL explained by individual SNPs ranged from 0.08% to 0.36% [ 35 ], and the F statistic of these SNPs was much greater than 10, indicating that the possibility of weak instrumental variable deviation was low.…”

“…A recent report indicated that telomere shortening is not believed to be directly involved in other signs of aging but only a regulator of the genetic changes in human gene expression associated with cellular aging, with the majority of the genes affected by TL involved in apoptosis and cell death [ 12 ]. Similarly, there have been several observational studies that have suggested a potential link between TL and various cancers and non-neoplastic diseases, but none of these reported any causality when evaluated by MR, with these outcomes likely the result of the sensitivity of observational studies to confounding effects and reverse causality [ 29 , 34 , 42 , 43 ]. At present, there is insufficient evidence to suggest that TL is the driving etiological factor in many diseases, and the pathogenic link between TL and HL needs to be evaluated in greater detail.…”

“…MR uses instrumental variables to assess the causal relationship between a given exposure and a specific outcome [ 20 , 26 , 27 ]. MR can prevent confounding and reverse causation biases in conventional observational studies, and it relies on three assumptions [ 28 , 29 ]: (1) The instrumental variables need to be significantly associated with TL, (2) the instrumental variables must not be associated with any other factors associated with both TL and HL risk, and (3) the instrumental variables must only affect HL risk via TL ( Figure 1 ).…”

Telomere length, Metabolic Traits, and Myocardial Infarction: A Mediation Mendelian Randomization Analysis

“…Unexceptionally, another MR study including 78 592 Europeans suggested that genetically instrumented longer LTL was associated with raised SBP and DBP, while no unbalanced horizontal pleiotropy was detected 51 . A possible explanation for this stems from an epidemiological study in the Framingham Offspring Cohort that longer LTL was associated with increased aldosterone-to-renin ratio and eventually causes hypertension 52 .…”