Circulatory MicroRNAs as Potential Biomarkers for Stroke Risk: The Rotterdam Study

Abstract

Background and Purpose: MicroRNAs (miRNAs) are post-transcriptionally regulators of gene expression that can be released extracellularly upon pathophysiological processes. By complementary binding of target transcripts, miRNAs can modulate the expression of an abundance of genes. Increasing evidence recognize miRNAs as promising biomarkers for complex traits, including cardiovascular disease and stroke. We conducted a longitudinal study to determine the association between circulatory miRNAs and incident stroke in a population-based setting. Methods: Next-generation sequencing was used to measure expression levels of 2083 miRNAs in plasma samples, collected between 2002 and 2005, from 1914 stroke-free participants of the Rotterdam Study. Participants were assessed for incident stroke through continuous monitoring of medical records until January 1, 2016. Cox proportional hazards regression models adjusted for age, sex, and vascular risk factors were used to investigate the association between the levels of 591 miRNAs well-expressed in plasma and incident stroke. Furthermore, stroke subtype analysis was performed to assess the link between identified miRNAs and ischemic, hemorrhagic, and unspecified stroke. Subsequently, post hoc analyses were conducted to gain insight into the association between putative target genes of miRNAs and stroke. Results: Of 1914 participants (mean age 71.5 years ±7.6; 57.7% women), 138 were diagnosed with incident stroke during a mean follow-up of 9.7±3.2 years. After adjusting for potential confounders, we found plasma levels of 3 miRNAs to be associated with incident stroke (false discovery rate-adjusted P<0.05). These include miR-6124 (hazard ratio, 1.66 [95% CI, 1.31-2.09]), miR-5196-5p (hazard ratio, 1.90 [95% CI, 1.39-2.61]), and miR-4292 (hazard ratio, 2.65 [95% CI, 1.62-4.34]). In silico analysis of the putative target genes of these miRNAs showed associations of variants in several target genes with stroke. Conclusions: This study indicates that plasma levels of 3 miRNAs are associated with the risk of stroke, proposing them as potential biomarkers for early detection of the disease.