RESUMO
Polycystic ovary syndrome (PCOS) is often associated with metabolic abnormalities in the affected patients such as obesity or a dysregulated glucose metabolism/insulin resistance (IR). IR affects the serum levels of several circulating microRNAs; however, studies on the association between IR-related microRNAs and PCOS are scarce. Therefore, we quantified the serum levels of the IR-associated microRNAs miR-93, miR-148a, miR-216a, miR-224 and miR-320a via qPCR in a cohort of 358 infertility patients, of whom 136 were diagnosed with PCOS. In bivariate correlation analyses, the serum levels of miR-93 and miR-216a were inversely associated with dipeptidyl peptidase 4 serum concentrations, and the miR-320a serum levels were significantly downregulated in PCOS patients (p = 0.02, Mann-Whitney U test). Interestingly, in all patients who achieved pregnancy after Assisted Reproductive Technology (ART) cycles, the serum levels of the five IR-associated microRNAs were significantly elevated compared to those of non-pregnant patients. In cell culture experiments, we detected a significant upregulation of miR-320a expression following testosterone stimulation over 24 and 48 h in KGN and COV434 granulosa carcinoma cells. In conclusion, we demonstrated a significantly reduced serum level of the IR-associated miR-320a in our patient cohort. This result once again demonstrates the close relationship between metabolic disorders and the dysregulation of microRNA expression patterns in PCOS.
RESUMO
BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.