Abstract
MicroRNAs (miRNAs) are non-coding RNA molecules that regulate gene expression. Extensive research has explored the role of miRNAs in the risk for type 2 diabetes (T2D) and coronary heart disease (CHD) using single-omics data, but much less by leveraging population-based omics data. Here we aimed to conduct a multi-omics analysis to identify miRNAs associated with cardiometabolic risk factors and diseases. First, we used publicly available summary statistics from large-scale genome-wide association studies to find genetic variants in miRNA-related sequences associated with various cardiometabolic traits, including lipid and obesity-related traits, glycemic indices, blood pressure, and disease prevalence of T2D and CHD. Then, we used DNA methylation and miRNA expression data from participants of the Rotterdam Study to further investigate the link between associated miRNAs and cardiometabolic traits. After correcting for multiple testing, 180 genetic variants annotated to 67 independent miRNAs were associated with the studied traits. Alterations in DNA methylation levels of CpG sites annotated to 38 of these miRNAs were associated with the same trait(s). Moreover, we found that plasma expression levels of 8 of the 67 identified miRNAs were also associated with the same trait. Integrating the results of different omics data showed miR-10b-5p, miR-148a-3p, miR-125b-5p, and miR-100-5p to be strongly linked to lipid traits. Collectively, our multi-omics analysis revealed multiple miRNAs that could be considered as potential biomarkers for early diagnosis and progression of cardiometabolic diseases.
Highlights
Type 2 diabetes mellitus (T2D) is a complex metabolic disease that is characterized by insulin resistance and impairment of insulin secretion, which leads to hyperglycemia
Out of 23,990 miRNA-related Singlenucleotide polymorphisms (SNPs), 2,358 independent SNPs were present in the genome-wide association studies (GWAS) data based on HapMap and 8,652 independent SNPs were present in the 1000G project
180 SNPs annotated to 67 miRNAs passed the significance threshold to be associated with at least one cardiometabolic trait (Table 1)
Summary
Type 2 diabetes mellitus (T2D) is a complex metabolic disease that is characterized by insulin resistance and impairment of insulin secretion, which leads to hyperglycemia. The presence of T2D leads to a two- to four-fold increase risk of developing coronary heart disease (CHD) (Kannel and Mcgee, 1979), which is among the leading causes of morbidity and mortality worldwide MicroRNAs Associated With Cardiometabolic Traits et al, 2018). Many risk factors are identified as mediators of these diseases, including hypertension, dyslipidemia, central adiposity and elevated blood glucose, which are together known as cardiometabolic traits (Wilson et al, 2005). Despite substantial advances in diagnosis and widely prescribed drugs for these diseases, their rate continue to increase worldwide, emphasizing the need for deeper insights into underlying mechanisms and innovative therapeutic strategies. Cardiometabolic traits and diseases have underlying genetic components and many loci have been discovered through large-scale genome- and epigenome-wide association studies (Peloso et al, 2014; De Rosa et al, 2018). One of the potential regulatory mechanisms involved might be microRNAs (miRNAs)
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