No Causal Effect of Telomere Length on Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study

Abstract

Background: Epidemiological studies observing inconsistent associations of telomere length (TL) with ischemic stroke (IS) are susceptible to bias according to reverse causation and residual confounding. We aimed to assess the causal association between TL, IS, and the subtypes of IS, including large artery stroke (LAS), small vessel stroke (SVS), and cardioembolic stroke (CES) by performing a series of two-sample Mendelian randomization (MR) approaches. Methods: Seven single nucleotide polymorphisms (SNPs) were involved as candidate instrumental variables (IVs), summarized from a genome-wide meta-analysis including 37,684 participants of European descent. We analyzed the largest ever genome-wide association studies of stroke in Europe from the MEGASTROKE collaboration with 40,585 stroke cases and 406,111 controls. The weighted median (WM), the penalized weighted median (PWM), the inverse variance weighted (IVW), the penalized inverse variance weighted (PIVW), the robust inverse variance weighted (RIVW), and the Mendelian randomization-Egger (MR-Egger) methods were conducted for the MR analysis to estimate a causal effect and detect the directional pleiotropy. Results: No significant association between genetically determined TL with overall IS, LAS, or CES were found (all p > 0.05). SVS was associated with TL by the RIVW method (odds ratio (OR) = 0.72, 95% confidence interval (CI): 0.54–0.97, p = 0.028), after excluding rs9420907, rs10936599, and rs2736100. Conclusions: By a series of causal inference approaches using SNPs as IVs, no strong evidence to support the causal effect of shorter TL on IS and its subtypes were found.

Association between telomere length in peripheral blood leukocytes and risk of ischemic stroke in a Han Chinese population: a linear and non-linear Mendelian randomization analysis

“…One MR analysis showed conflicting results which shorter TL was marginally statistically significantly associated with the decreased risk of stroke [ 21 ]. Another two linear MR analysis provided no evidence of the linear association between genetically predicted short TL and IS as well as its subtypes [ 22 , 23 ]. Similarly, we also found null linear relationship between genetically predicted TL and IS risk in a Han Chinese population.…”

“…First, a MR study showed that shorter telomeres lead to a marginally significantly decreased odds of stroke in individual-level data [ 21 ]. Another two MR studies suggested that TL may be a marker of IS and its subtypes rather than a cause [ 22 , 23 ]. Two-sample MR typically assume that the exposure-outcome association is linear or log-linear [ 24 ].…”

Type 2 Diabetes Mellitus is Associated with the Immunoglobulin G N-Glycome through Putative Proinflammatory Mechanisms in an Australian Population

“…Therefore, whether the association of IgG N-glycans with T2DM is the cause or consequence of the disease remains unconfirmed. Further cohort studies with longitudinal data (Cao et al, 2019a) or Mendelian randomization studies (Cao et al, 2019b) are warranted to monitor the changes in N-glycome through the whole course of T2DM, and so as to provide a more definitive explanation regarding the causal relationship between N-glycan profiles and T2DM.…”

Telomere Length: A Potential Biomarker for the Risk and Prognosis of Stroke

“…The high heterogeneity, particularly age difference, and reduced sample size might contribute the equivocal results of the subgroup analysis. Another meta-analysis based on causal inference approaches using TL-related SNPs as instrumental variables did not support the causal effect of shorter TL on ischemic stroke (36). It has to be noted that age, one of the most important covariates, was not considered in this study.…”