Identification of potential druggable targets for endometriosis through Mendelian randomization analysis
IntroductionEndometriosis (EM) is a widely recognized disorder in gynecological endocrinology. Although hormonal therapies are frequently employed for EM, their side effects and outcome limitations underscore the need to explore the genetic basis and potential drug targets for developing innovative...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2024.1371498/full |
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| author | Peng Chen Xin Wei Xiao-Ke Li Yi-Hang Zhou Yi-Hang Zhou Qi-Fang Liu Ling Ou-Yang |
| author_facet | Peng Chen Xin Wei Xiao-Ke Li Yi-Hang Zhou Yi-Hang Zhou Qi-Fang Liu Ling Ou-Yang |
| author_sort | Peng Chen |
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| description | IntroductionEndometriosis (EM) is a widely recognized disorder in gynecological endocrinology. Although hormonal therapies are frequently employed for EM, their side effects and outcome limitations underscore the need to explore the genetic basis and potential drug targets for developing innovative therapeutic approaches. This study aimed to identify both cerebrospinal fluid (CSF) and plasma protein markers as promising therapeutic targets for EM.MethodsWe utilized Mendelian randomization (MR) analysis to explore potential disease-causing proteins, utilizing genetic datasets from genome-wide association studies (GWAS) and protein quantitative trait loci (pQTL) analyses. We applied a range of validation techniques, including reverse causality detection, phenotype scanning, Bayesian co-localization (BC) analysis, and external validations to substantiate our findings. Additionally, we conducted a protein-protein interaction (PPI) network as well as functional enrichment analyses to unveil potential associations among target proteins.ResultsMR analysis revealed that a decrease of one standard deviation (SD) in plasma R-Spondin 3 (RSPO3) level had a protective effect on EM (OR = 1.0029; 95% confidence interval (95% CI): 1.0015–1.0043; P = 3.2567e-05; Bonferroni P < 5.63 × 10−5). BC analysis showed that RSPO3 shared the same genetic variant with EM (coloc.abf-PPH4 = 0.874). External validation further supported this causal association. Galectin-3 (LGALS3; OR = 0.9906; 95% CI: 0.9835–0.9977; P = 0.0101), carboxypeptidase E (CPE; OR = 1.0147; 95% CI: 1.0009–1.0287; P = 0.0366), and alpha-(1,3)-fucosyltransferase 5 (FUT5; OR = 1.0053; 95% CI: 1.0013–1.0093; P = 0.002) were detected as potential targets for EM in CSF. PPI analysis showed that fibronectin (FN1) had the highest combined score. Furthermore, several EM-linked proteins were involved in the glycan degradation pathway.DiscussionIn conclusion, this comprehensive study offers valuable insights into potential drug targets for EM, with RSPO3 emerging as a promising candidate. Additionally, mechanistic roles of FN1, glycan degradation pathway, LGALS3, CPE, and FUT5 in EM warrant further investigation. |
| format | Article |
| id | doaj-art-99a14ab6e0c34db595028b53ebdc0a90 |
| institution | Kabale University |
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| publishDate | 2025-01-01 |
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| series | Frontiers in Endocrinology |
| spelling | doaj-art-99a14ab6e0c34db595028b53ebdc0a902025-01-22T05:19:20ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922025-01-011510.3389/fendo.2024.13714981371498Identification of potential druggable targets for endometriosis through Mendelian randomization analysisPeng Chen0Xin Wei1Xiao-Ke Li2Yi-Hang Zhou3Yi-Hang Zhou4Qi-Fang Liu5Ling Ou-Yang6Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, Shenyang, ChinaDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, Shenyang, ChinaDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, Shenyang, ChinaDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, Shenyang, ChinaDepartment of Obstetrics and Gynecology, Fushun Central Hospital, Liaoning, Fushun, ChinaDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, Shenyang, ChinaDepartment of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, Shenyang, ChinaIntroductionEndometriosis (EM) is a widely recognized disorder in gynecological endocrinology. Although hormonal therapies are frequently employed for EM, their side effects and outcome limitations underscore the need to explore the genetic basis and potential drug targets for developing innovative therapeutic approaches. This study aimed to identify both cerebrospinal fluid (CSF) and plasma protein markers as promising therapeutic targets for EM.MethodsWe utilized Mendelian randomization (MR) analysis to explore potential disease-causing proteins, utilizing genetic datasets from genome-wide association studies (GWAS) and protein quantitative trait loci (pQTL) analyses. We applied a range of validation techniques, including reverse causality detection, phenotype scanning, Bayesian co-localization (BC) analysis, and external validations to substantiate our findings. Additionally, we conducted a protein-protein interaction (PPI) network as well as functional enrichment analyses to unveil potential associations among target proteins.ResultsMR analysis revealed that a decrease of one standard deviation (SD) in plasma R-Spondin 3 (RSPO3) level had a protective effect on EM (OR = 1.0029; 95% confidence interval (95% CI): 1.0015–1.0043; P = 3.2567e-05; Bonferroni P < 5.63 × 10−5). BC analysis showed that RSPO3 shared the same genetic variant with EM (coloc.abf-PPH4 = 0.874). External validation further supported this causal association. Galectin-3 (LGALS3; OR = 0.9906; 95% CI: 0.9835–0.9977; P = 0.0101), carboxypeptidase E (CPE; OR = 1.0147; 95% CI: 1.0009–1.0287; P = 0.0366), and alpha-(1,3)-fucosyltransferase 5 (FUT5; OR = 1.0053; 95% CI: 1.0013–1.0093; P = 0.002) were detected as potential targets for EM in CSF. PPI analysis showed that fibronectin (FN1) had the highest combined score. Furthermore, several EM-linked proteins were involved in the glycan degradation pathway.DiscussionIn conclusion, this comprehensive study offers valuable insights into potential drug targets for EM, with RSPO3 emerging as a promising candidate. Additionally, mechanistic roles of FN1, glycan degradation pathway, LGALS3, CPE, and FUT5 in EM warrant further investigation.https://www.frontiersin.org/articles/10.3389/fendo.2024.1371498/fullendometriosisMendelian randomizationdrug targetPPI networkenrichment analysis |
| spellingShingle | Peng Chen Xin Wei Xiao-Ke Li Yi-Hang Zhou Yi-Hang Zhou Qi-Fang Liu Ling Ou-Yang Identification of potential druggable targets for endometriosis through Mendelian randomization analysis Frontiers in Endocrinology endometriosis Mendelian randomization drug target PPI network enrichment analysis |
| title | Identification of potential druggable targets for endometriosis through Mendelian randomization analysis |
| title_full | Identification of potential druggable targets for endometriosis through Mendelian randomization analysis |
| title_fullStr | Identification of potential druggable targets for endometriosis through Mendelian randomization analysis |
| title_full_unstemmed | Identification of potential druggable targets for endometriosis through Mendelian randomization analysis |
| title_short | Identification of potential druggable targets for endometriosis through Mendelian randomization analysis |
| title_sort | identification of potential druggable targets for endometriosis through mendelian randomization analysis |
| topic | endometriosis Mendelian randomization drug target PPI network enrichment analysis |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2024.1371498/full |
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