COVID-19 biomarkers for severity mapped to polycystic ovary syndrome

To the Editor,

Large scale multi-omics analysis has identified significant differences in the biomarkers between COVID-19 disease and control subjects [1]. These protein panels target biological processes involved in vessel damage, platelet degranulation, the coagulation cascade and the acute phase response [1], with greater protein changes dependent on the COVID-19 severity. However, it is observed that in metabolic conditions such as polycystic ovary syndrome expressed proteins differ compared to control women [2] and PCOS patients have increased platelet aggregation and decreased plasma fibrinolytic activity, resulting in a prothrombotic propensity [3, 4], with elevated coagulation markers [5]. Therefore, any biomarkers reflecting COVID-19 disease and its severity would necessarily have to be independent of differentially-expressed proteins relating to other conditions; therefore, this proteomic analysis was undertaken in women with and without PCOS to compare with the proteomic biomarkers recently described in COVID-19 using shotgun proteomics followed by parallel reaction monitoring [1].

146 PCOS and 97 control women who presented sequentially to the Department of Endocrinology, Hull and East Yorkshire Hospitals NHS Trust were recruited to the local PCOS biobank (ISRCTN70196169) [2]. PCOS diagnosis was based on all three Rotterdam consensus diagnostic criteria. Proteins that were identified as being altered in COVID-19 disease for vessel damage (16 proteins), platelet degranulation (11 proteins), coagulation cascade (24 proteins) and acute phase response (9 proteins), shown in Table 1, were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement [6]. Statistics were performed using Graphpad Prism 8.0.

Table 1 Proteins identified as being altered in COVID-19 disease categorized according to biological processes: vessel damage (16 proteins), platelet degranulation (11 proteins), coagulation cascade (24 proteins) and acute phase response (9 proteins) in PCOS and control women

As reported previously [2], cohorts were age-matched, but PCOS women had increased insulin resistance, androgens and CRP (p < 0.001): systolic and diastolic blood pressure, and waist circumference were higher (p < 0.05).

For the 60 protein biomarkers described previously, 21 were found to differ in PCOS: for vessel damage 7 of 16 proteins differed, for platelet degranulation 2 of 11 proteins differed, for the coagulation cascade 9 of 24 proteins differed and for the acute phase response 3 of 9 proteins differed (Table 1).

These data show that altered protein expression relative to controls may occur in other conditions such as PCOS, and that COVID-19 biomarker changes found between respiratory patients with and without COVID-19 require validation before they can be confirmed to be related to COVID-19 disease and its severity. It is of concern that a number of significant protein biomarkers described for COVID-19 patients and its severity were also found in PCOS, spanning the biological processes involved in vessel damage, platelet degranulation, the coagulation cascade and the acute phase response, perhaps indicating why these patients may be at risk of more severe COVID-19 disease [7].

Limitations of the study include utilizing a different method of proteomic analysis compared to others that may not be directly comparable [1].

In conclusion, 21 of 60 protein biomarkers reported in respiratory patients with COVID-19 were found to differ between women with and without PCOS, showing the necessity for validation of such biomarkers, and suggesting that more severe COVID-19 disease may occur in PCOS.