Evidence for causal effects of polycystic ovary syndrome on oxidative stress: a two-sample mendelian randomisation study

Abstract

Background: Polycystic ovary syndrome (PCOS) is often accompanied by increased oxidative stress levels; however, it is still unclear whether PCOS itself is causally related to oxidative stress (OS), whether OS can increase the occurrence of PCOS, and which characteristics of PCOS increase OS levels. Therefore, this study explored the causal relationship between PCOS, its characteristics, and OS.

Methods: Two-sample bidirectional and two-sample Mendelian randomisation studies were performed based on publicly available statistics from genome-wide association studies. PCOS; its characteristics, such as testosterone, low-density lipoprotein, high-density lipoprotein; and 11 major OS markers (superoxide dismutase, glutathione S-transferase, glutathione peroxidase, catalase, uric acid, zinc, tocopherol, ascorbic acid, retinol, albumin, and total bilirubin), were studied. The main analytical method used was inverse variance weighting (IVW). Pleiotropy was evaluated using the Mendelian randomisation-Egger intercept. Q and P values were used to assess heterogeneity.

Results: There was no causal relationship between PCOS and the OS indices (all P > 0.05). There was a causal relationship between the OS index, ascorbate level, and PCOS (IVW, odds ratio: 2.112, 95% confidence interval: 1.257-3.549, P = 0.005). In addition, there was a causal relationship between testosterone, low-density lipoprotein, high-density lipoprotein, sex hormone-binding globulin, body mass index, triacylglycerol, age at menarche, and most OS indices according to the IVW method. The F statistics showed that there was no weak instrumental variable. A sensitivity analysis was performed using the leave-one-out method. No pleiotropy was observed. The results were robust, and the conclusions were reliable.

Conclusions: This study showed for the first time that there was no causal relationship between PCOS and OS. However, there was a causal relationship between the OS index, ascorbate level, and PCOS. It revealed that PCOS itself could not increase OS, and the increase in OS in PCOS was related to other potential factors, such as testosterone, low-density lipoprotein, high-density lipoprotein, sex hormone-binding globulin, body mass index, triacylglycerol, and age at menarche.

Keywords: Mendelian randomisation study; Oxidative stress; Polycystic ovary syndrome.

Fig. 1

Flow chart of the Two-sample MR study design. Step 1, A two-sample bidirectional Mendelian randomisation study for PCOS and 11 oxidative stress indices; Step 2, Some two-sample Mendelian randomisation studies for characteristics indices of PCOS and 11 oxidative stress indices. IVs, instrumental variables; PCOS, polycystic ovary syndrome; GST, glutathione S-transferase; CAT, catalase; SOD, superoxide dismutase; GPX, glutathione peroxidase; UA, uric acid; SNP, single nucleotide polymorphism;T, testosterone; LDL, low-density lipoprotein; HDL, high-density lipoprotein; SHBG, sex hormone-binding globulin; BMI, body mass index; TAG, triacylglycerol

Fig. 2

MR effect size for PCOS on SOD PCOS, polycystic ovary syndrome; SOD, superoxide dismutase

Fig. 3

Scatter plot of the MR analysis of PCOS on SOD PCOS, polycystic ovary syndrome; SOD, superoxide dismutase

Fig. 4

Leave-one-out regression analysis of PCOS on SOD PCOS, polycystic ovary syndrome; SOD, superoxide dismutase

Fig. 5

Funnel plot of the MR analysis of PCOS on SOD PCOS, polycystic ovary syndrome; SOD, superoxide dismutase