HOL2: Epigenetic biomarkers for metabolic syndrome in women with Polycystic Ovary Syndrome
This study is performed at the Regional Fertility Clinic of Zealand in collaboration with Roskilde University Center.
Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder of reproductive-aged women and affects approximately 5-10%. Younger women with PCOS are typically characterized by infertility, anovulation and hyperandrogenism, while older women with PCOS tend to demonstrate insulin resistance (IR), glucose intolerance, hypertension, dyslipidemia and overweight or obesity. Some PCOS women will with time develop Type 2 Diabetes, but today there are no good marker for detecting which women who are at the highest risk. This PhD-project seeks to explore the epigenetics of PCOS to find possible markers or predictors of metabolic syndrome and Type 2 Diabetes.
MicroRNAs (miRNAs) are single-stranded and small noncoding RNA molecules. They regulate the expression of target genes. Altered miRNA levels have been associated with diabetes, insulin resistance, inflammation and various cancers. Although the exact mechanisms and pathogenism of miRNA in PCOS have not been mapped, research have shown that specific circulating miRNA are upregulated in PCOS. As free molecules, miRNA could serve as a biomarker, diagnosing impaired glucose tolerance or identifying subjects of risk for developing metabolic syndrome at an earlier stage.
The methylation pattern of the insulin gene and its promoter has also been suggested as a biomarker of β-cell death in the pancreas, as the insulin gene promotor of circulating cell free DNA (INScfDNA) is demethylated when originating from β-cells and methylated from other cells. This has previously been demonstrated in patients with risk of Type 1 and Type 2 Diabetes. As PCOS women are known to develop both insulin resistance and loss of β-cell function with time, an increased number of demethylated copies of INScfDNA in these women, could serve as a precursor of impaired β-cell function.
This study falls into two distinct parts:
- A 6-year follow-up study of 55 women with PCOS and healthy controls. The women were examined at baseline and at follow-up with characterization of their PCOS and anthropometrics, followed by blood sampling and an oral glucose tolerance test. Parred serum samples were used both for analysis of 96 selected microRNAs and for digital droplet qPCR to estimate the number of demethylated and methylated copies of INScfDNA
- A cross-sectional study of a cohort of 170 women with PCOS and healthy controls with analysis of 24 selected microRNAs. This study serves also to validate our previous findings in study 1.
At the moment analysis is still ongoing. Preliminary results shows that one microRNA was both phenotype specific by being upregulated in hyperandrogenic PCOS women, but also correlated to other markers of metabolic disease. Further, it was stable over the follow-up period, which makes it a potential candidate for a biomarker.
Hopefully, this study will be able to demonstrate that epigenetic markers can serve as biomarkers and early predictors for later development of various chronic diseases.