The Association Between Genetically Predicted Systemic Inflammatory Regulators and Polycystic Ovary Syndrome: A Mendelian Randomization Study.

Hanxiao Chen,Shangwei Li,Yihong Yang,Kemin Cheng,Rui Gao,Yuanzhi Tao,Lang Qin,Yaoyao Zhang,Yan Wang,Wenming Xu

doi:10.3389/fendo.2021.731569

Abstract

Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic diseases among women of reproductive age. Inflammation may be involved in the pathogenesis of PCOS, but its exact relationship with PCOS remains unclear. Herein, we investigate the causal association between systemic inflammatory regulators and PCOS risk through a two-sample Mendelian randomization (MR) approach based on the latest and largest genome-wide association study (GWAS) of 41 systemic inflammatory regulators in 8293 Finnish participants and a GWAS meta-analysis consisting of 10,074 PCOS cases and 103,164 controls of European ancestry. Our results suggest that higher levels of IL-17 and SDF1a, as well as lower levels of SCGFb and IL-4, are associated with an increased risk of PCOS (OR = 1.794, 95% CI = 1.150 – 2.801, P = 0.010; OR = 1.563, 95% CI = 1.055 – 2.315, P = 0.026; OR = 0.838, 95% CI = 0.712 – 0.986, P = 0.034; and OR = 0.637, 95% CI = 0.413 – 0.983, P = 0.042, respectively). In addition, genetically predicted PCOS is related to increased levels of IL-2 and VEGF (OR = 1.257, 95% CI = 1.022 – 1.546, P = 0.030 and OR = 1.112, 95% CI = 1.006 – 1.229, P = 0.038, respectively). Our results indicate the essential role of cytokines in the pathogenesis of PCOS. Further studies are warranted to assess the possibility of these biomarkers as targets for PCOS prevention and treatment.

Highlights

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder among women of reproductive age [1, 2]
In the primary Mendelian randomization (MR) inverse-variance weighted (IVW) analyses using 17 systemic inflammatory regulators with SNPs that strongly predicted exposures at the genome-wide significance level (P < 5 × 10–8), our results show that only the stem cell growth factor beta (SCGFb) level is inversely associated with PCOS (OR = 0.752, 95% confidence intervals (CIs) = 0.605 – 0.934, P = 0.010)
In the MR analyses using the weighted median method, the SCGFb level remains inversely associated with PCOS (OR = 0.747, 95% CI = 0.576 – 0.970, P = 0.029), and the TNF-related apoptosisinducing ligand (TRAIL) level is inversely associated with PCOS (OR = 0.828, 95% CI = 0.708 – 0.968, P = 0.018)

Summary

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder among women of reproductive age [1, 2]. PCOS is a complex and multifaceted disorder that is often diagnosed based on hyperandrogenism, ovulatory dysfunction and polycystic ovaries [3]. Many studies have investigated potential risk factors for PCOS, which include genetic factors, excess androgen and insulin resistance (IR) [3]. Observational, epidemiological studies have demonstrated that circulating levels of several cytokines may be involved in the pathogenesis of PCOS. The association of the pathogenesis of PCOS with growth factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and pigment epithelium-derived factor (PEDF) has been investigated by previous studies [8,9,10]. Previous studies have found that anti-inflammatory therapy can benefit patients with PCOS [11]

Methods

Results

Conclusion