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Vitamin D Association with Coagulation Factors in Polycystic Ovary Syndrome Is Dependent Upon Body Mass Index Abu Saleh Md Moin1, Thozhukat Sathyapalan2, Alexandra E

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Vitamin D Association with Coagulation Factors in Polycystic Ovary Syndrome Is Dependent Upon Body Mass Index Abu Saleh Md Moin1, Thozhukat Sathyapalan2, Alexandra E Moin et al. J Transl Med (2021) 19:239 https://doi.org/10.1186/s12967-021-02897-0 Journal of Translational Medicine LETTER TO THE EDITOR Open Access Vitamin D association with coagulation factors in polycystic ovary syndrome is dependent upon body mass index Abu Saleh Md Moin1, Thozhukat Sathyapalan2, Alexandra E. Butler1*† and Stephen L. Atkin3† Keywords: Polycystic ovary syndrome, Vitamin D, Obesity, Fibrinogen, Coagulation To the Editor: seasonal fuctuation in vitamin D levels, the period of Polycystic ovary syndrome (PCOS) is associated with vitamin D sampling in this study was done between metabolic consequences including obesity and insulin March to September of each year that would allow vita- resistance that are related to the excess prevalence of type min D targets being achieved through 9 min of sunlight 2 diabetes, hypertension, and cardiovascular diseases exposure alone in the North of England [6]. Te New- in later life [1]. It is reported that PCOS subjects show castle & North Tyneside Ethics committee approved this marked platelet dysfunction [2] and decreased plasma study; all patients gave written informed consent. PCOS fbrinolytic activity, resulting in a prothrombotic state diagnosis was based on all three Rotterdam consensus [3]. In addition, coagulation variables such as thrombin- diagnostic criteria [7] and all had a liver ultrasound to activatable fbrinolysis inhibitor, plasminogen activator exclude non-alcoholic fatty liver disease [8].” None of the inhibitor-1 (PAI-1), D-dimer, Antithrombin and throm- women were taking vitamin D supplements at the time of bomodulin have been reported to be elevated in PCOS enrolment, nor had they taken any in the 6 months prior compared to control subjects [4], and the functional to enrolment in the study which was one of the exclusion coagulation tests including prothrombin time, thrombin criteria. time and fbrin degradation products may be predic- Blood samples were collected and were measured in tive of PCOS [5]. Tis suggests that PCOS women have the Chemistry Laboratory, Hull Royal Infirmary, UK a propensity to a hypercoagulable state; therefore, to as previously described [8]. Insulin, C reactive pro- determine whether this was the case in a cohort of PCOS tein (CRP) and sex hormone binding globulin (SHBG) women, and whether there was an association with vita- were measured by an immunometric assay with fluo- min D status, this study was undertaken. rescence detection on the DPC Immulite 2000 ana- 99 PCOS and 68 control Caucasian women “who pre- lyzer using the manufacturer’s recommended protocol sented sequentially to the Department of Endocrinol- [8]. Testosterone was measured by isotope dilution ogy, Hull and East Yorkshire Hospitals NHS Trust were liquid chromatography-tandem mass spectrometry recruited to the local PCOS biobank (ISRCTN70196169) (Waters Corporation, Manchester, UK) as previously from January 2014 to December 2016. To account for described [8]. “The free androgen index (FAI) was calculated as the total testosterone × 100/SHBG. The *Correspondence: [email protected]; [email protected] insulin resistance was calculated using the HOMA †Alexandra E. Butler and Stephen L. Atkin joint senior authors method [HOMA-IR (insulin glucose)/22.5]. Serum 1 Diabetes Research Center (DRC), Qatar Biomedical Research Institute = × (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO vitamin D levels and testosterone were quantified Box 34110, Doha, Qatar using isotope-dilution liquid chromatography tan- Full list of author information is available at the end of the article dem mass spectrometry (LC–MS/MS)” [8]. Vitamin D © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Moin et al. J Transl Med (2021) 19:239 Page 2 of 5 sufficiency was defined as > 70 ng/ml, insufficiency as plasma kallikrein (p = 0.0009), fbrinogen gamma chain 50–69 ng/ml and deficiency as < 50 ng/ml [8]. (p < 0.0001), fbronectin (p = 0.013) and its fragments, Circulating levels of coagulation-related proteins fragment 3 (p = 0.03) and 4 (p = 0.004). For antico- were determined by Slow Of-rate Modifed Aptamer agulation proteins, in PCOS, antithrombin was lower (SOMA)-scan plasma protein measurement as previously (p = 0.002), while PECAM1 (CD31; p = 0.03), tissue type described [9]. “Te SOMAscan assay used to quantify plasminogen activator (p < 0.0001), protein S (p = 0.0008) proteins was performed on an in-house Tecan Freedom and heparin cofactor II (p = 0.0014) were higher. Vita- EVO liquid handling system (Tecan Group, Maennedorf, min D correlated negatively with PAI-1 in PCOS (r = Switzerland) utilizing bufers and SOMAmers from the 0.24, p = 0.016). SOMAscan HTS Assay 1.3 K plasma kit (SomaLogic, Signifcant correlations of vitamin D with BMI and Boulder, CO) according to manufacturer’s instructions coagulation-related proteins are shown in Fig. 1A–C. and as described previously [9]. Initial Relative Fluores- In the PCOS women, vitamin D correlated negatively cent Units (RFUs) were obtained from microarray inten- with BMI in PCOS, and negatively with plasminogen sity images using the Agilent Feature Extraction Software activator inhibitor 1 (r = 0.24, p = 0.016), while in the (Agilent, Santa Clara, CA). Raw RFUs were normalized control women there was a negative correlation of vita- and calibrated using the software pipeline provided by min D with tissue type plasminogen activator (r = 0.27, SomaLogic. Statistical analyses were performed on log2 p = 0.026). Tere was no correlation of vitamin D with RFU values using R version 3.5.2 (R Foundation for Sta- BMI in control women. tistical Computing, Vienna, Austria) including base R Te PCOS and control women were then stratifed package. Data handling and diferential protein expres- according to vitamin D status: sufcient, insufcient and sion were analyzed using the autonomics and limma and defcient. Of the 99 PCOS women, 16 (16%) were suf- P values were corrected using the Benjamini–Hochberg cient, 11 (11%) were insufcient and 72 (73%) were def- method.” cient. Of the 68 control women, 26 (38%) were sufcient, Data trends were visually evaluated for each parameter 22 (32%) insufcient and 20 (29%) defcient (Fig. 1D). Te and non-parametric tests were applied on data that vio- only proteins that difered between vitamin D subsets lated the assumptions of normality when tested using the were in controls: tissue plasminogen activator (p = 0.003, Kolmogorov–Smirnov Test. Comparison between groups sufcient vs. defcient) and integrin alpha1:beta1 com- was performed using Student’s t-test. A p-value of < 0.05 plex (p = 0.009, sufcient vs. insufcient) (data not was considered statistically signifcant. Statistics were shown). When BMI, infammation and insulin resistance performed using Graphpad Prism 8.0 (San Diego, CA, were accounted for, there was no diference in either the USA). procoagulant or anticoagulant proteins between controls No power analysis could be performed for this study and PCOS in vitamin D defciency. because there is no data available relating the efect of Tese data show that within group analysis in PCOS vitamin D upon coagulation proteins in PCOS. patients between vitamin D defcient and sufcient Te PCOS women were older (29.8 ± 0.9 vs. patients revealed no alteration in the coagulation or anti- 27.5 ± 0.6 years (± SEM), PCOS vs. control, p = 0.03) and coagulation proteins, suggesting that the mechanism had a higher BMI (p < 0.001), weight (p < 0.0001), waist of vitamin D defciency on thrombosis is not through and hip circumference (p < 0.0001), systolic (p < 0.001) enhanced coagulopathy. In the control patients, antico- and diastolic (p = 0.03) blood pressure. Biochemically, agulant tissue plasminogen activator increased (sufcient the PCOS women had elevated anti-mullerian hor- vs. defcient) and integrin alpha1:beta1 complex (suf- mone (AMH) (p < 0.0001), triglycerides (p = 0.003), CRP cient vs. insufcient) increased. 1,25 Dihydroxyvitamin (p < 0.0001), testosterone (p = 0.001), androstenedione D has been shown to increase expression of tissue plas- (p = 0.003), free androgen index (p < 0.0001), insulin minogen activator [10], but the 1,25 dihydroxyvitamin (p < 0.0001) white cell count (p < 0.0001) and platelets D levels were not measured in this study. No association (p = 0.01). Vitamin D was signifcantly lower in the PCOS between vitamin D and integrin alpha1:beta complex has group (p < 0.0001) and correlated negatively with BMI in been described before; however, given the large number PCOS
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