Monocyte miRNAs Are Associated With Type 2 Diabetes

Abstract

miRNAs are small noncoding RNAs that may contribute to common diseases through epigenetic regulation of gene expression. Little is known regarding the role of miRNAs in type 2 diabetes (T2D). We performed miRNA sequencing and transcriptomic profiling of peripheral monocytes from the longitudinal Multi-Ethnic Study of Atherosclerosis (MESA) (N = 1,154). We examined associations between miRNAs and prevalent impaired fasting glucose and T2D and evaluated the T2D-associated miRNA effect on incident T2D. Of 774 detected miRNAs, 6 (miR-22-3p, miR-33a-5p, miR-181c-5p, miR-92b-3p, miR-222-3p, and miR-944) were associated with prevalent T2D. For five of the six miRNAs (all but miR-222-3p), our findings suggest a dose-response relationship with impaired fasting glucose and T2D. Two of the six miRNAs were associated with incident T2D (miR-92b-3p: hazard ratio [HR] 1.64, P = 1.30E-03; miR-222-3p: HR 1.97, P = 9.10E-03) in the highest versus lowest tertile of expression. Most of the T2D-associated miRNAs were also associated with HDL cholesterol concentrations. The genes targeted by these miRNAs belong to key nodes of a cholesterol metabolism transcriptomic network. Higher levels of miRNA expression expected to increase intracellular cholesterol accumulation in monocytes are linked to an increase in T2D risk.

Figure 1

Cross-sectional associations of monocyte-derived miRNAs with impaired fasting glucose and T2D at examination visit 5. *Fold difference and 95% CI compared with MESA participants with normal fasting glucose. Raw and FDR-corrected P values are shown for the comparison of T2D with normal fasting glucose. Analyses were adjusted for age, sex, race/ethnicity, study site, and cell contamination (B cells, T cells, natural killer cells, neutrophils). Ref., reference.

Figure 2

Association of miR-92b-3p and miR-222-3p expression with T2D at examination visit 5 and incident T2D at examination visit 6. †For the cross-sectional analysis, MESA participants with impaired fasting glucose at visit 5 were excluded. ‡For the prospective analysis, MESA participants with a diagnosis of T2D at visit 5 were excluded. Analyses were adjusted for age, sex, race/ethnicity, study site, and cell contamination (B cells, T cells, natural killer cells, neutrophils). Ref., reference.

Figure 3

CMTN genes targeted by the T2D-associated miRNAs and their association with T2D. A: T2D miRNAs and their target CMTN genes, with a focus on genes related to cholesterol efflux, uptake, and synthesis. miRNAs and their target genes that were increased in T2D are colored pink, while miRNAs and their target genes that were decreased in T2D are colored blue. Greater miRNA expression is predicted to lead to decreased expression of its target genes, and lesser miRNA expression is predicted to lead to increased expression of its target genes. Therefore, the effects of miRNAs with decreased expression on their downstream gene targets are indicated with a short dashed line and an X. MYLIP encodes IDOL, which leads to degradation of the LDL receptor through its ubiquitin ligase activity. The activating effect of decreased MYLIP expression on the LDL receptor is indicated by the long dashed line and an X. B: Results of the differential gene expression analysis of the T2D-associated miRNA target genes by T2D status.