Multiomics and Systematic Analyses Reveal the Roles of Hemoglobin and the HIF‐1 Pathway in Polycystic Ovary Syndrome
Abstract Polycystic ovary syndrome (PCOS) affects reproductive and cardiometabolic health, yet its pathogenesis remains unclear. Emerging evidence links hemoglobin levels to metabolic disorders, suggesting a potential role in PCOS development. Here, we integrated a large‐scale cohort study, Mendelia...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-04-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202411679 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849729666658598912 |
|---|---|
| author | Guiquan Wang Weian Mao Yurong Zhang Haiyan Yang Ming Zhu Yan Li Wei Chen Yi Chen Chen Lou Ping Li Hsun‐Ming Chang Shuai Yuan Yue Zhao Liangshan Mu |
| author_facet | Guiquan Wang Weian Mao Yurong Zhang Haiyan Yang Ming Zhu Yan Li Wei Chen Yi Chen Chen Lou Ping Li Hsun‐Ming Chang Shuai Yuan Yue Zhao Liangshan Mu |
| author_sort | Guiquan Wang |
| collection | DOAJ |
| description | Abstract Polycystic ovary syndrome (PCOS) affects reproductive and cardiometabolic health, yet its pathogenesis remains unclear. Emerging evidence links hemoglobin levels to metabolic disorders, suggesting a potential role in PCOS development. Here, we integrated a large‐scale cohort study, Mendelian randomization (A genetic tool to infer causal relationships), bioinformatics analyses, and in vitro experiments to investigate the relationship between hemoglobin levels and PCOS. In a cohort of 20 602 women, each 10 g L−1 elevation in hemoglobin levels is associated with 22% higher odds of PCOS (adjusted odds ratio: 1.22, 95% confidence interval: 1.15–1.29, P < 0.001) and PCOS manifestations, particularly hyperandrogenism. Mendelian randomization analysis confirms that higher hemoglobin levels are associated with increased PCOS risk and elevated testosterone levels. The hypoxia‐inducible factor 1 (HIF‐1) pathway is enriched, identifying three testosterone‐associated genes (nuclear factor kappa B (NFKB1), insulin receptor (INSR), protein kinase C alpha. Colocalization and druggability analysis supports shared genetic regions and confirmed these genes as druggable targets. Upregulation of NFKB1 and INSR are confirmed in both blood and ovarian granulosa cells of PCOS patients. The findings demonstrate that higher‐end normal hemoglobin levels are associated with increased PCOS risk, potentially through a mechanism of elevating testosterone levels involving the HIF‐1 pathway. |
| format | Article |
| id | doaj-art-d549cd5c4d9e47c7b733c215dde9b0d0 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-d549cd5c4d9e47c7b733c215dde9b0d02025-08-20T03:09:08ZengWileyAdvanced Science2198-38442025-04-011214n/an/a10.1002/advs.202411679Multiomics and Systematic Analyses Reveal the Roles of Hemoglobin and the HIF‐1 Pathway in Polycystic Ovary SyndromeGuiquan Wang0Weian Mao1Yurong Zhang2Haiyan Yang3Ming Zhu4Yan Li5Wei Chen6Yi Chen7Chen Lou8Ping Li9Hsun‐Ming Chang10Shuai Yuan11Yue Zhao12Liangshan Mu13Department of Reproductive MedicineWomen and Children's HospitalSchool of MedicineXiamen UniversityXiamen 361003 ChinaDepartment of Obstetrics and GynecologyThe Second Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325027 ChinaState Key Laboratory of Female Fertility PromotionCenter for Reproductive MedicineDepartment of Obstetrics and GynecologyPeking University Third HospitalNational Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital)Key Laboratory of Assisted ReproductionMinistry of EducationBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive TechnologyBeijing 100191 ChinaReproductive Medicine CenterThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000 ChinaThe First School of MedicineWenzhou Medical UniversityWenzhou 325035 ChinaReproductive Medicine CenterThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000 ChinaReproductive Medicine CenterZhongshan HospitalFudan UniversityShanghai 200032 ChinaThe First School of MedicineWenzhou Medical UniversityWenzhou 325035 ChinaThe First School of MedicineWenzhou Medical UniversityWenzhou 325035 ChinaDepartment of Reproductive MedicineWomen and Children's HospitalSchool of MedicineXiamen UniversityXiamen 361003 ChinaDepartment of Obstetrics and GynecologyChina Medical University HospitalTaichung 40400 TaiwanUnit of Cardiovascular and Nutritional EpidemiologyInstitute of Environmental MedicineKarolinska InstituteStockholm 17177 SwedenState Key Laboratory of Female Fertility PromotionCenter for Reproductive MedicineDepartment of Obstetrics and GynecologyPeking University Third HospitalNational Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital)Key Laboratory of Assisted ReproductionMinistry of EducationBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive TechnologyBeijing 100191 ChinaReproductive Medicine CenterZhongshan HospitalFudan UniversityShanghai 200032 ChinaAbstract Polycystic ovary syndrome (PCOS) affects reproductive and cardiometabolic health, yet its pathogenesis remains unclear. Emerging evidence links hemoglobin levels to metabolic disorders, suggesting a potential role in PCOS development. Here, we integrated a large‐scale cohort study, Mendelian randomization (A genetic tool to infer causal relationships), bioinformatics analyses, and in vitro experiments to investigate the relationship between hemoglobin levels and PCOS. In a cohort of 20 602 women, each 10 g L−1 elevation in hemoglobin levels is associated with 22% higher odds of PCOS (adjusted odds ratio: 1.22, 95% confidence interval: 1.15–1.29, P < 0.001) and PCOS manifestations, particularly hyperandrogenism. Mendelian randomization analysis confirms that higher hemoglobin levels are associated with increased PCOS risk and elevated testosterone levels. The hypoxia‐inducible factor 1 (HIF‐1) pathway is enriched, identifying three testosterone‐associated genes (nuclear factor kappa B (NFKB1), insulin receptor (INSR), protein kinase C alpha. Colocalization and druggability analysis supports shared genetic regions and confirmed these genes as druggable targets. Upregulation of NFKB1 and INSR are confirmed in both blood and ovarian granulosa cells of PCOS patients. The findings demonstrate that higher‐end normal hemoglobin levels are associated with increased PCOS risk, potentially through a mechanism of elevating testosterone levels involving the HIF‐1 pathway.https://doi.org/10.1002/advs.202411679causalityhemoglobinhyperandrogenismhypoxia‐inducible factorpolycystic ovary syndrome |
| spellingShingle | Guiquan Wang Weian Mao Yurong Zhang Haiyan Yang Ming Zhu Yan Li Wei Chen Yi Chen Chen Lou Ping Li Hsun‐Ming Chang Shuai Yuan Yue Zhao Liangshan Mu Multiomics and Systematic Analyses Reveal the Roles of Hemoglobin and the HIF‐1 Pathway in Polycystic Ovary Syndrome Advanced Science causality hemoglobin hyperandrogenism hypoxia‐inducible factor polycystic ovary syndrome |
| title | Multiomics and Systematic Analyses Reveal the Roles of Hemoglobin and the HIF‐1 Pathway in Polycystic Ovary Syndrome |
| title_full | Multiomics and Systematic Analyses Reveal the Roles of Hemoglobin and the HIF‐1 Pathway in Polycystic Ovary Syndrome |
| title_fullStr | Multiomics and Systematic Analyses Reveal the Roles of Hemoglobin and the HIF‐1 Pathway in Polycystic Ovary Syndrome |
| title_full_unstemmed | Multiomics and Systematic Analyses Reveal the Roles of Hemoglobin and the HIF‐1 Pathway in Polycystic Ovary Syndrome |
| title_short | Multiomics and Systematic Analyses Reveal the Roles of Hemoglobin and the HIF‐1 Pathway in Polycystic Ovary Syndrome |
| title_sort | multiomics and systematic analyses reveal the roles of hemoglobin and the hif 1 pathway in polycystic ovary syndrome |
| topic | causality hemoglobin hyperandrogenism hypoxia‐inducible factor polycystic ovary syndrome |
| url | https://doi.org/10.1002/advs.202411679 |
| work_keys_str_mv | AT guiquanwang multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT weianmao multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT yurongzhang multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT haiyanyang multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT mingzhu multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT yanli multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT weichen multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT yichen multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT chenlou multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT pingli multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT hsunmingchang multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT shuaiyuan multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT yuezhao multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome AT liangshanmu multiomicsandsystematicanalysesrevealtherolesofhemoglobinandthehif1pathwayinpolycysticovarysyndrome |