Identification of microRNAs associated with an impaired metabolic profile in women with polycystic ovary syndrome

Study question: Can we identify microRNAs associated with an altered metabolic profile in women with Polycystic Ovary Syndrome (PCOS), which can serve as biomarkers for early diabetes? Summary answer: Circulating miR-122-5p is a possible marker of prediabetes in women with PCOS and is associated with the severity of metabolic disease. What is known already:It is well established that women with PCOS are at greater risk of developing metabolic syndrome and type 2 diabetes. Recent discoveries indicate that miRNAs play an important role in development of diabetes in general and reflect the clinical status of patients. However, to date there are no existing studies of circulating miRNAs as biomarkers for a challenged metabolism and a prediabetic phenotype in women with PCOS. Study design,size,duration:A prospective follow-up-study with a cohort of 46 women with PCOS diagnosed according to Rotterdam 2003 criteria and nine healthy controls, aged 18 to 39 years. The women were examined twice 6 yearsapart.CirculatingmiRNAlevelswereanalyzedatbothvisitsandcompared with clinical data. A cross sectional cohort of 162 PCOS patients (133 PCOS and 29 controls) were investigated for biological validation of findings. Participants/materials,setting,methods:Relevant clinical data of PCOS status and measurements of metabolic disease were obtained at both visits. Peripheral fasting serum samples collected at both time points were used for microRNA analysis. Total RNA was extracted using TriReagent. MiRNA levels were measured using custom Taqman® Array cards of 96 selected miRNAs. MiRNArelativelevelswerequantifiedbythe2-Ct method.MiR-122-5pwere analyzed with individual qRT-PCR in the validation cohort. Main results and the role of chance:During the 6-year follow-up, more participants became prediabetic (defined by Impaired Glucose Tolerance (IGT) or Impaired Fasting Glucose (IFG)) (Six (10.9%) participants at baseline vs 10 (18.2%) participants at follow-up). Analysis of miRNA did not reveal significant differences in circulating levels of any of the tested miRNAs comparing PCOS Abstracts of the 35th Annual Meeting of the ESHRE,Vienna,Austria 24 to 26 June 2019 i431 with controls neither at baseline nor at follow-up. However, comparing the non-prediabetic with prediabetic, we found that miR-122-5p was significantly upregulatedintheprediabeticgroupbothatfollow-up(p=0.03)andatbaseline, as predictor of prediabetic status at follow-up (p=0.03, OR=7.7 (95%CI: 1.251.3)adjustedforBMI,smokingandage).Next,theparticipantswereevaluated for degree of metabolic disease by numbers of metabolic factors present (0-5: hypertension, dyslipidemia, triglyceridemia, increased waist circumference and IGT or IFG). Applying linear regression on the levels of miR-122-5p vs the degree of metabolic disease, the models were statistically significant both at baseline(R2=0.10,B=0.51,p=0.05)andfollow-up(R2=0.17B=0.9,p<0.01).In thevalidationof findingsinthecohortof 162participants,wefoundsignificantly elevated levels of miR-122-5p in participants with IFG both in PCOS patients alone(p<0.05)andinthecohortasawhole(p<0.01)afteradjustmentforBMI and age. Limitations,reasons for caution:Few participants with prediabetes in the follow-up study causes weak modelling. Wider implications of the findings: Our results are in line with earlier studies of miR-122-5p, which have demonstrated strong correlation with both metabolic and hepatic disease. Further, validation in the larger cohort strengthen the findings, but suggests that miR-122-5p is probably more a generalmarkerof metabolicdisease,thanaPCOS-specificmarkerof metabolic disease. Trial registration number:ClinicalTrials.gov. Identifier: NCT03142633