MicroRNA 146a is associated with diabetic complications in type 1 diabetic patients from the EURODIAB PCS

Abstract

Background MicroRNA-146a-5p (miR-146a-5p) is a key regulator of inflammatory processes. Expression of miR-146a-5p is altered in target organs of diabetic complications and deficiency of miR-146a-5p has been implicated in their pathogenesis. We investigated if serum miR-146a-5p levels were independently associated with micro/macrovascular complications of type 1 diabetes (DM1). Methods A nested case–control study from the EURODIAB PCS of 447 DM1 patients was performed. Cases (n = 294) had one or more complications of diabetes, whereas controls (n = 153) did not have any complication. Total RNA was isolated from all subjects and miR-146a-5p levels measured by qPCR. Both the endogenous controls U6 snRNA and the spike (Cel-miR-39) were used to normalize the results. Logistic regression analysis was carried out to investigate the association of miR-146a-5p with diabetes complications. Results MiR-146a-5p levels were significantly lower in cases [1.15 (0.32–3.34)] compared to controls [1.74 (0.44–6.74) P = 0.039]. Logistic regression analysis showed that levels of miR-146a-5p in the upper quartile were inversely associated with reduced odds ratio (OR) of all complications (OR 0.34 [95% CI 0.14–0.76]) and particularly with cardiovascular diseases (CVD) (OR 0.31 [95% CI 0.11–0.84]) and diabetic retinopathy (OR 0.40 [95% CI 0.16–0.99]), independently of age, sex, diabetes duration, A1c, hypertension, AER, eGFR, NT-proBNP, and TNF-α. Conclusions In this large cohort of DM1 patients, we reported an inverse and independent association of miR-146a-5p with diabetes chronic complications and in particular with CVD and retinopathy, suggesting that miR-146a-5p may be a novel candidate biomarker of DM1 complications.

Association of serum MicroRNA-145-5p levels with microvascular complications of type 1 Diabetes: The EURODIAB prospective complications study

“…Levels of miR-145-5p in the lower tertile were associated with an increased OR for all complications that was predominantly driven by a significantly enhanced risk of both retinopathy and nephropathy. Similarly, we have previously reported that both miR-126 and miR-146-5p were associated with retinopathy and CVD in T1DM patients of the EURODIAB nested case-control study [36,46].…”

Association of MicroRNA-146a with Type 1 and 2 Diabetes and their Related Complications

“…miR-146a is a key regulator of inflammatory processes. Expression of miR-146a is altered in target organs of diabetic complications, and deficiency of miR-146a has been implicated in their pathogenesis [26]. In human monocytes, miR-146a, which is encoded by the locus of the LOC285628 gene located on chromosome 5, reacts to lipopolysaccharide (LPS) stimulation, and its activation is reliant on nuclear factor kappa B (NF-κB) [27].…”

Podocyte-specific deletion of miR-146a increases podocyte injury and diabetic kidney disease

“…Conversely, we previously found that the glomerular miR-146a levels were dramatically reduced in the kidney sections of diabetic patients (18), and that the level of miR-146a expression in the kidneys inversely correlated with proteinuria in the patients, suggesting that podocytic miR-146a plays a protective role in DN. A recent study with 460 subjects (300 cases and 160 controls) also confirmed that there exits an inverse association of blood miR-146a levels with diabetes and its complications (19). Furthermore, miR-146a levels were found to be down-modulated in the kidneys of diabetic rats and mice, suggesting that it plays a reno-protective role (20).…”

“…A number of studies, including ours ( 18 ), show that reduced miR-146a levels are associated with injury. For example, serum miR-146a levels inversely and independently correlate with chronic complications of diabetes, including cardiovascular disease (CVD) and diabetic retinopathy, in a cohort of patients with type 1 diabetes ( 19 ). Similarly, serum miR-146a levels show significant age-related decline in type 2 diabetics and show inverse correlation with creatinine ( 40 ).…”