Association of miR-126-3p, miR-1260b and miR-374a-5p with the incidence of heart failure in a population-based cohort: the Hortega Follow-Up Study

BACKGROUND: Circulating microRNAs (miRNAs) are emerging markers for cardiovascular prevention and control. miRNAs associated to vascular damage are candidates to play a causal role in the microvascular dysfunction of heart failure (HF). The aim was to evaluate the observational and causal (Mendelian randomization) association of miRNAs related with vascular alterations (miR-126-3p, miR-1260b and miR-374a-5p) with HF incidence in a sample from the general population. METHODS: Plasma miRNAs levels were measured in 985 Hortega Study participants using real time quantitative polymerase chain reaction (RT-qPCR). Single nucleotide polymorphisms (SNPs) were genotyped with the TOPMED imputable Illumina GSA array. We identified genetic instrumental variables for miR-126-3p (33 SNPs), miR-1260b (22 SNPs) and miR-374a-5p (35 SNPs) and run several Mendelian randomization approaches. RESULTS: The hazard ratio (95 % confidence interval) of HF by a 10-fold increase in miR-126-3p, miR-1260b and miR-374a-5p was 1.53 (1.09, 2.14), 1.38 (1.03, 1.86), and1.30 (1.09, 1.57), respectively. The corresponding rate differences were 9.7 (-0.1, 19.5), 12.0 (0.4, 23.6) and 9.1 (1.2, 17.1) per 10000 person-years. In flexible dose-response analysis, increased miRNAs levels were associated with higher HF risk, both in the relative and additive scale. In Mendelian randomization analysis, consistently suggestive positive causal associations were found with HF for increased miR-126-3p and miR-1260b levels, but not for miR-374a-5p. CONCLUSIONS: In observational analysis, miR-126-3p, miR-1260b and miR-374a-5p levels were positively associated with HF incidence. Mendelian randomization analysis supported a causal role for miR-126-3p and miR-1260b, thus suggesting a potential use as prognostic and therapeutic targets for HF prevention and control.