Circulating MicroRNA-21 And Cardiovascular Risk Reduction In Response To Weight-loss Diets: The Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) Trial

Introduction: MicroRNA-21 (MiR-21) is one of the most highly expressed microRNAs in the cardiovascular system and plays a pivotal role in the pathogenesis of cardiovascular diseases (CVD). Hypothesis: We assessed the hypothesis that circulating miR-21 is associated with the change in overall CVD risk and individual cardiovascular risk factors in response to weight-loss diet interventions. Methods: Circulating miR-21 was measured at baseline and 6 months in 511 participants with overweight or obesity from the 2-year weight-loss diet intervention study, the POUNDS LOST trial. MiR-21-5p is a mature sequence derived from the 5' end of the miR-21 stem-loop precursor and another mature sequence, miR-21-3p, is derived from the 3' end of miR-21. The primary outcome was the change in the global Framingham Risk Score (FRS), which estimates the 10-year probability of a CVD event. Secondary outcomes were the change in the FRS components including systolic blood pressure, diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, insulin, homeostatic model assessment of insulin resistance, gut microbiota metabolites, and adiposity measures. Results: Circulating miR-21-3p levels were positively associated with fasting insulin ( P =0.011), insulin resistance ( P =0.008), and triglycerides ( P =0.003) at baseline. We found that lower pre-intervention expression levels of miR-21-3p and miR-21-5p were related to a greater reduction in FRS (β[SE]=11.020 [5.025], P =0.029 and β[SE]=0.023 [0.008], P =0.005, respectively) over 6 months. The trajectory of the FRS across the 2-year intervention period differed between the patterns of pre-intervention miR-21 ( P time*miR-21-3p =0.002 and P time*miR-21-5p =0.033). Compared to those with a higher level of miR-21, participants with a lower level of miR-21 had a greater decrease in FRS from baseline to 6 months and then increased substantially from 6 months to 2 years. We also found significant interactions between baseline miR-21-5p and dietary fat on change in FRS ( P fat diets* miR-21-5p =0.04). Participants with a lower level of baseline miR-21-5p on the low-fat diet group showed a greater reduction of FRS than those on the high-fat diet at 6 months. In addition, a greater decrease in miR-21-3p rather than miR-21-5p was significantly associated with a greater reduction in body weight (P<0.0001), waist circumference ( P =0.002), and improvement in trimethylamine N-oxide ( P =0.011) at 6 months. These associations were attenuated at 2 years of the intervention. Conclusions: In conclusion, decreased circulating miR-21 levels were related to a significant reduction in overall CVD risk and improvement in individual cardiovascular risk factors in response to dietary weight-loss interventions.