Contribution of labor related gene subtype classification on heterogeneity of polycystic ovary syndrome

PLOS ONE RESEARCH ARTICLE Contribution of labor related gene subtype classification on heterogeneity of polycystic ovary syndrome Jue Zhou1‡, Zhou Jiang2‡, Leyi Fu3, Fan Qu3, Minchen Dai3, Ningning Xie3, Songying Zhang2*, Fangfang Wang ID3* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China, 2 Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China, 3 Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China ‡ JZ and ZJ authors contributed equally to this work and share first authorship. * (FW); (SZ) Abstract OPEN ACCESS Citation: Zhou J, Jiang Z, Fu L, Qu F, Dai M, Xie N, et al. (2023) Contribution of labor related gene subtype classification on heterogeneity of polycystic ovary syndrome. PLoS ONE 18(3): e0282292. https://doi.org/10.1371/journal. pone.0282292 Editor: Antonio Simone Laganà, University of Palermo: Universita degli Studi di Palermo, ITALY Objective As one of the most common endocrine disorders in women of reproductive age, polycystic ovary syndrome (PCOS) is highly heterogeneous with varied clinical features and diverse gestational complications among individuals. The patients with PCOS have 2-fold higher risk of preterm labor which is associated with substantial infant morbidity and mortality and great socioeconomic cost. The study was designated to identify molecular subtypes and the related hub genes to facilitate the susceptibility assessment of preterm labor in women with PCOS. Received: November 1, 2022 Accepted: February 11, 2023 Methods Published: March 1, 2023 Four mRNA datasets (GSE84958, GSE5090, GSE43264 and GSE98421) were obtained from Gene Expression Omnibus database. Twenty-eight candidate genes related to preterm labor or labor were yielded from the researches and our unpublished data. Then, we utilized unsupervised clustering to identify molecular subtypes in PCOS based on the expression of above candidate genes. Key modules were generated with weighted gene coexpression network analysis R package, and their hub genes were generated with CytoHubba. The probable biological function and mechanism were explored through Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. In addition, STRING and Cytoscape software were used to identify the protein-protein interaction (PPI) network, and the molecular complex detection (MCODE) was used to identify the hub genes. Then the overlapping hub genes were predicted. Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0282292 Copyright: © 2023 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: The data that support the findings of this study are available in NCBI-GEO database of GEO accession at GSE84958 (https:// www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc= Results Two molecular subtypes were found in women with PCOS based on the expression similarity of preterm labor or labor-related genes, in which two modules were highlighted. The key PLOS ONE | https://doi.org/10.1371/journal.pone.0282292 March 1, 2023 1 / 13 PLOS ONE GSE84958), GSE5090 (https://www.ncbi.nlm.nih. gov/geo/query/acc.cgi?acc=GSE5090), GSE43264 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE43264) and GSE98421 (https://www.ncbi. nlm.nih.gov/geo/query/acc.cgi?acc=GSE98421). Funding: This study was supported by the National Natural Science Foundation of China (81873837 to Fangfang Wang and 81973900 to Jue Zhou). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Labor related gene and PCOS modules and PPI network have five overlapping five hub genes, two of which, GTF2F2 and MYO6 gene, were further confirmed by the comparison between clustering subgroups according to the expression of hub genes. Conclusions Distinct PCOS molecular subtypes were identified with preterm labor or labor-related genes, which might uncover the potential mechanism underlying heterogeneity of clinical pregnancy complications in women with PCOS. Competing interests: The authors have declared that no competing interests exist. Introduction Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age [1]. Its primary features are menstrual dysfunction, hyperandrogenism and polycystic ovary, but highly heterogeneous [2]. The current treatment strategies for the patients with PCOS are to reduce insulin resistance in order to reach a reduction of compensatory hyperinsulinemia, and to improve the metabolic and ovulatory features. For the overweight and obese PCOS patients, although physical activity and lifestyle change are the first steps to achieve weight loss, insulin-sensitizer drugs are the recommended first-line therapy, and many new insights have also been provided in the strategies for PCOS [3]. Myo-inositol and d-chiro-inositol have very specific physiological roles, however, they should be evaluated on the patients’ conditions before the treatment and the effects of inositol therapy on different PCOS phenotypes needs further investigation [4]. Moreover, as PCOS causes a rising risk of maternal, fetal, and neonatal complications, including pregnancy-induced hypertension, preeclampsia, gestational diabetes mellitus, spontaneous preterm birth, an increased necessity for a cesarean section, elevated neonatal morbidity, prematurity, fetal growth restriction, birth weight variations, and transfer to the Neonatal Intensive Care Unit, a closer follow-up should be offered to PCOS women during pregnancy [5]. Although the causes of PCOS remain obscure, it is underpinned by a complex genetic and epigenetic architecture [1, 6, 7]. PCOS and PCOS-related gestational complications influence the intrauterine environment, leading to adverse developmental programming of the offspring for long-term, chronic health conditions [8, 9]. As preterm birth affects 1 in 10 pregnancies worldwide [10], the women with PCOS seemed to have a 2-fold increased risk of preterm labor, including both spontaneous preterm labor and indicated preterm labor which attributes to certain medical scenarios [11, 12].The preterm labor was associated with the substantial infant morbidity and mortality, long-term consequences of offspring as well as a huge socioeconomic cost [13–15]. Although the etiology of spontaneous preterm birth and the mechanism of lab (...truncated)