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

Abstract

The associations between leukocyte telomere length (LTL) and common metabolic traits for myocardial infarction (MI) are unclear. We aimed to evaluate the causal effect of LTL on MI and the mediating role of metabolic traits in the pathway from LTL to MI. Summary statistics for LTL, twelve metabolic traits and MI were obtained from large consortia of genome-wide association studies. A two-sample two-step MR was used to determine 1) the causal effect of LTL on MI and twelve metabolic traits; 2) causal effects of metabolic traits on MI after adjusting for LTL; and 3) mediation effects of these metabolic traits. We observed genetically predicted longer LTL was strongly associated with lower risk of MI (OR[95% CI]:0.832[0.750,0.924]; P<0.001), lower FI (β[95% CI]:-0.041[-0.062,-0.020]; P<0.001), higher SBP (1.558[0.778,2.338]; P<0.001), and higher DBP (0.785[0.223,1.347]; P<0.001)but not associated with other metabolic traits. SBP, DBP and FI were positively associated with MI after adjusting for LTL. Mediation analysis showed evidence of positively indirect effect of LTL on MI through SBP and DBP, while an inversely indirect effect through FI. The direct effect of LTL on MI (OR[95% CI]:0.778[0.666,0.909]; P=0.002) was observed after adjusting for SBP, DBP and FI. Our study identified the independent causal role of LTL on MI and the mediating effects of SBP, DBP and FI in the causal pathway from LTL to MI.