To identify circulating serum microRNAs (miRNAs) in healthy humans which predict future onset of both diabetes mellitus and cardiovascular disease.Design and method:
In serum of 12 test subjects, we identified 48 miRNAs consistently detectable in all subjects out of a panel of 786 miRNAs well-conserved in mammals. The population-based Malmö Diet and Cancer Cardiovascular Cohort (n = 5400) (MDC-CC), underwent a baseline examination 1991–1994, where fasted blood was stored after which the population was followed for incidence of diabetes mellitus (DM) and cardiovascular disease (fatal and non-fatal myocardial infarction and stroke) (CVD). We measured the 48 miRNAs using a TaqMan quantitative real-time PCR Low Density Array (TLDA) based method in fasting serum of 553 healthy subjects from MDC-CC, including 155 incident cases of DM and 171 incident cases of CVD and used multivariate logistic regression to test individual miRNAs for association with incident DM and CVD.Results:
After Bonferroni correction and adjustment for age and sex, each SD increment of log-transformed miR483-5p was significantly associated with both incident DM (OR = 1.48; 95% CI 1.18–1.84, P = 0.001) and CVD (OR = 1.40; 95% CI 1.15, 1.72, P = 0.001). In cross sectional analysis, MIR 483_5p was positively correlated with BMI (r = 0.162, P = 0.0001), fasting insulin (r = 0.156, P = 0.0002), HDL (r = -0.099, P = 0.02) and triglycerides (r = 0.11, P = 0.10). Adjustment for these metabolic risk factors, as well as traditional risk factors attenuated the miR-483-5p association with incident DM (OR = 1.28 95% CI 1.00–1.64, P = 0.049) whereas its association with incident CVD remained virtually unchanged (OR = 1.46 95% CI, 1.18-1.81, P = 0.0005).Conclusions:
miR483–5p predicts development of both DM and CVD. The association with DM seems partly mediated by obesity and insulin resistance whereas the association with incident CVD is independent of these metabolic factors and traditional CVD risk factors. Previous studies (Ma et al. 2011, Mol Cell Endocrinol) suggest an underlying mechanism of our findings as miR-483-5p, which is co-expressed with its host gene Igf2, downregulates the expression of socs3 and thereby could mediate development of obesity and a state of high cardiometabolic risk.