Cardiovascular Risk Biomarkers in Women with and Without Polycystic Ovary Syndrome

Abstract

Objective: Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder with an increased risk for cardiovascular disease (CVD) that is enhanced by obesity. This study sought to determine whether a panel of cardiovascular risk proteins (CVRPs) would be dysregulated in overweight/obese PCOS patients, highlighting potential biomarkers for CVD in PCOS.

Methods: In this exploratory cross-sectional study, plasma levels of 54 CVRPs were analyzed in women with PCOS (n = 147) and controls (n = 97). CVRPs were measured using the SOMAscan proteomic platform (version 3.1), with significant proteins identified through linear models, regression analysis, and receiver operating characteristic (ROC) analysis. Analysis on BMI-matched subsets of the cohort were undertaken. Functional enrichment and protein-protein interaction analyses elucidated the pathways involved.

Results: Eleven CVRPs were dysregulated in PCOS (whole set, without matching for body mass index (BMI) or insulin resistance (IR)): leptin, Interleukin-1 receptor antagonist protein (IL-1Ra), polymeric immunoglobulin receptor (PIGR), interleukin-18 receptor (IL-18Ra), C-C motif chemokine 3 (MIP-1a), and angiopoietin-1 (ANGPT1) were upregulated whilst advanced glycosylation end product-specific receptor, soluble (sRAGE), bone morphogenetic protein 6 (BMP6); growth/differentiation factor 2 (GDF2), superoxide dismutase [Mn] mitochondrial (MnSOD), and SLAM family member 5 (SLAF5) were downregulated versus the controls. In BMI-matched (overweight/obese, BMI ≥ 26 kg/m²) subset analysis, six CVRPs were common to the whole set: ANGPT1 and IL-1Ra were upregulated; and sRAGE, BMP6, GDF2, and Mn-SOD were downregulated. In addition, lymphotactin (XCL1) was upregulated and placenta growth factor (PIGF), alpha-L-iduronidase (IDUA), angiopoietin-1 receptor, and soluble (sTie-2) and macrophage metalloelastase (MMP12) were downregulated. A subset analysis of BMI-matched plus insulin resistance (IR)-matched women revealed only upregulation of tissue factor (TF) and renin in PCOS, potentially serving as biomarkers for cardiovascular risk in overweight/obese women with PCOS.

Conclusions: A combination of upregulated obesity-related CVRPs (ANGPT1/IL/1Ra/XCL1) and downregulated cardioprotective proteins (sRAGE/BMP6/Mn-SOD/GDF2) in overweight/obese PCOS women may contribute to the increased risk for CVD. TF and renin upregulation observed in the BMI- and IR-matched limited sample PCOS subgroup indicates their potential risk of CVD.

Keywords: PCOS; biomarkers; cardiovascular risk; polycystic ovary syndrome; proteomics.

Figure 1

Analyses performed on whole set (A) and each subset (B,C) of women with and without polycystic ovary syndrome (PCOS). Overall cohort PCOS (n = 147) and controls (n = 97) in whom 54 cardiovascular risk proteins (CVRPs) were measured. Whole cohort was then divided into subsets: (B) body mass index (BMI) matched for BMI (≥26 kg/m²), PCOS (n = 114) and controls (n = 42); (C) matched for normal insulin resistance (HOMA-IR < 1.9) and BMI ≥ 26 kg/m², PCOS (n = 9) and controls (n = 6). Significantly increased proteins shown with upward facing red arrows, significantly decreased proteins shown with downward facing green arrows. Cardiovascular risk proteins (CVRPs); bone morphogenetic protein 6 (BMP6); growth/differentiation factor 2 (GDF2); polymeric immunoglobulin receptor (PIGR); superoxide dismutase [Mn] mitochondrial (MnSOD); interleukin-18 receptor (IL-18Ra); C-C motif chemokine 3 (MIP-1a); SLAM family member 5 (SLAF5); angiopoietin-1 (ANGPT1); interleukin-1 receptor antagonist protein (IL-1Ra); advanced glycosylation end product-specific receptor, soluble (sRAGE); placenta growth factor (PIGF); lymphotactin (XCL1); alpha-L-iduronidase (IDUA); angiopoietin-1 receptor, soluble (s Tie-2); macrophage metalloelastase (MMP12); tissue factor (TF).

Figure 2

Bar plots of individual dysregulated CVRPs (mean ± SE) in whole cohort, control (n = 97) and PCOS (n = 147); (A–F) indicates levels of upregulated and (G–K) indicates levels of downregulated CVRPs in PCOS. ** p < 0.01, * p < 0.05.

Figure 3

Bar plots of individual dysregulated CVRPs (mean ± SE) for BMI (≥26 kg/m²)-matched cohort, control (n = 47) and PCOS (n = 114); (A–C) indicates levels of upregulated and (D–K) indicates levels of downregulated CVRPs in PCOS. ** p < 0.01, * p < 0.05.

Figure 4

Bar plots of individual dysregulated CVRPs (mean ± SE) for matched normal insulin resistance (HOMA-IR < 1.9) and BMI ≥ 26 kg/m² (A,B), PCOS (n = 9) and controls (n = 6), indicating upregulated CVRPs in PCOS, * p < 0.05.

Figure 5

The ROC curve of renin. The area under the curve (AUC) indicates the potential of renin in discriminating women with PCOS from the controls in the subset of women with normal insulin resistance (HOMA-IR < 1.9) and BMI in the overweight/obese range (BMI ≥ 26 kg/m²).

Figure 6

STRING (version 12.0) protein–protein interaction network between cardiovascular risk biomarkers (CVRPs) that differed (A) between whole set of women with and without PCOS and their predicted immediate binding partners and (B) in subset of matched overweight/obese women (BMI ≥ 26 kg/m²) with and without PCOS. ‘Co-expression’ is indicated by black edge. Interactions obtained through text mining indicated by yellow edges.