Genetic Variability in Antioxidative and Inflammatory Pathways Modifies the Risk for PCOS and Influences Metabolic Profile of the Syndrome.

Rok Herman,Andrej Janež,Mojca Jensterle,Vita Dolžan,Katja Goričar

doi:10.3390/metabo10110439

Rok Herman, Andrej Janež + Show 3 more

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https://doi.org/10.3390/metabo10110439

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Abstract

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder of multifactorial etiopathology likely to involve the interactions between genetics and lifestyle. Chronic inflammation and oxidative stress (OS) may participate in the pathophysiology of the syndrome. The question of the extent to which OS and inflammation are causally related to the development of the syndrome and metabolic complications remains unanswered. By our knowledge, the role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome as an important trigger of inflammatory pathways and NLRP3 and CARD8 polymorphisms has never been addressed in PCOS yet. We conducted a case-control study conducting of total 169 Slovenian PCOS patients and 83 healthy blood donors. They were genotyped for polymorphisms in antioxidative (SOD2 rs4880, CAT rs1001179, PON1 rs854560, and rs662) and inflammatory pathways genes (NLRP3 rs35829419, CARD8 rs2043211, TNF rs1800629, IL1B rs1143623, and rs16944, IL6 rs1800795) using competitive allele-specific polymerase chain reaction (PCR). Logistic regression and the Mann–Whitney test were used in the statistical analysis. SOD2 rs4880, CARD8 rs2043211, and IL1B rs16944 were associated with the risk of developing PCOS. Furthermore, the interactions between CARD8 rs2043211 and IL6 rs1800795 and between IL1B rs1143623 and IL6 rs1800795 also significantly affected the risk for PCOS. With regard to glucose homeostasis, CAT rs1001179, SOD2 rs4880, PON1 rs854560, NLRP3 rs35829419, and TNF rs1800629 were significantly associated with response to the glycemic load. Our data indicate that the genetic variability in the antioxidative and inflammatory pathways influences the development of PCOS and glucose homeostasis in PCOS patients.

Highlights

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women in the reproductive period as it affects between 4 and 12% of the female population
A meta-analysis showed that tumor necrosis factor α (TNF) levels in women with PCOS were significantly higher compared to healthy controls and that high serum TNF concentration was related to insulin resistance (IR) and androgen excess but not to the body mass index (BMI) [6]
Since CARD8, NLR family pyrin domain containing 3 (NLRP3), IL1B, and interleukin 6 (IL6) cooperate in the same pathways, we evaluated if interactions between polymorphisms in those genes affect PCOS risk

Summary

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women in the reproductive period as it affects between 4 and 12% of the female population. It has been shown that both genetic and environmental factors play a role in PCOS development and its numerous clinical manifestations [1]. TNF seems to play a significant role in various clinical manifestations of PCOS. It is one of the most well-known inflammatory factors, and there is strong evidence that it is an essential mediator in obesity, insulin resistance (IR), and androgen expression [5]. Genetic variability in NLRP3, but not CARD8, was shown to increase the risk for the development of macrovascular complications, especially myocardial infarction in patients with type 2 diabetes [11]. There are no data on the role of the NLRP3 inflammasome and NLRP3 and CARD8 polymorphisms in PCOS patients

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