ساخت اکانت کاربری رایگان

مقالات پذیرفته شده کنگره

  • صفحه نخست
  • مقالات پذیرفته شده اولین کنگره بین المللی ژنتیک سرطان
بازنشر

  • LGALS3 as a Potential Therapeutic Target for Endometriosis in an East Asian Population: A Study That Repeats European Drug-Target Mendelian Randomization Findings

  • Neda Shaghaghi,1,*
    1. Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran


  • Introduction: Endometriosis is a disease of the female reproductive system that affects 5-10% of women of reproductive age, characterized by chronic pelvic pain, infertility, and poor quality of life. Limitations of hormonal therapies include decreased bone mineral density, early menopausal symptoms, and recurrences of symptoms after the cessation of treatment, emphasizing the search for new therapeutic targets. Endometriosis is also connected with increased risk of ovarian clear cell carcinoma (OCCC) and endometrioid ovarian cancer; the latter is about threefold more common than OCCC. The method Mendelian randomization (MR) can be used to investigate potential causal connections between a therapeutic target and a disease based on genetic information from instrumental variable analyses. Drug-target MR combines data on pQTLs with GWAS results. Recently, several drug-target MR studies carried out in Europeans have shown several candidate therapeutic targets for endometriosis, including EPHB4, RSPO3, FLT1, FSHB, LGALS3, CPE and FUT5, confirmed by colocalization studies and clinical data. However, all these studies are based on data from the European population, pQTLs, and GWAS. In turn, allele frequency and linkage disequilibrium (LD) pattern differences can make these results difficult to generalize to other populations, such as East Asian populations, which have not been considered previously. This study intends to replicate the results of previous drug-target MR studies in the East Asian population using population-matched pQTL and GWAS data, to analyze the generalizability of these findings and to provide a basis for further pharmacogenomic research in non-European populations.
  • Methods: Exposure: cis-pQTL data on the East Asian subpopulation were obtained from the UK Biobank Pharma Proteomics Project (UKB-PPP) for 7 candidate genes previously studied in Europeans: EPHB4, RSPO3, FLT1, FSHB, KDR, LGALS3, FN1. We used the most powerful cis-acting SNP within 1 Mb of each gene as an instrumental variable. Outcome: We used data from a subset of East Asians (approximately 2,044 cases and 88,000 controls) included in a multi-ethnic GWAS on endometriosis published in Nature Genetics, 2026. For KDR, where no matching SNP is available, the BioBank Japan GWAS (Sakaue & Kanai, 2020; 645 cases) was additionally used as a sensitivity analysis. Statistics: Causal estimates were calculated based on the Wald ratio (outcome beta/exposure beta) and expressed as odds ratios (OR) with 95% CI (confidence intervals).
  • Results: Out of the 7 genes tested, 6 (EPHB4, RSPO3, FLT1, FSHB, LGALS3, and FN1) were evaluable from the same outcome source (large-scale EAS GWAS): LGALS3 was found to be statistically significant. The direction of effect for EPHB4, RSPO3, and FSHB genes was consistent with previous European literature; however, the direction for FLT1 and FN1 was reversed (although not significant). For KDR (sensitivity analysis, BioBank Japan alone), an exaggerated odds ratio (OR) of 10.75 (95% CI: 2.70-42.75) was seen, most probably due to weak instrument bias.
  • Conclusion: These results indicate that LGALS3 could be an effective and replicable causal drug target for the treatment of endometriosis in East Asian populations. The directional consistency of EPHB4, RSPO3, and FSHB with the European studies, even though not statistically significant, shows the generalizability of some biological pathways in other populations. The primary issue is the relatively small size of the East Asian pQTL sample (N=256). Future research using larger Asian pQTL samples should replicate these results. Since the increased risk of endometriosis is associated with ovarian cancer and LGALS3 plays a role in cancer development (Newlaczyl & Yu, 2011), these results could serve as a basis for studying LGALS3 as a common treatment target for endometriosis and ovarian cancer.
  • Keywords: Endometriosis, LGALS3 (Galectin-3), Ovarian cancer, Mendelian randomization, Druggable targets

به خانواده بزرگ کنسر ژنتیکس و ژنومیکس سرطان بپیوندید!

ایجاد حساب کاربری رایگان