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Background <p>Ovarian cancer is a major female reproductive health issue with heterogeneous biological features on its subtypes, which may require different therapeutic strategies. Glucagon-like peptide-1 receptor (GLP-1R) agonists were reported to be beneficial for ovarian cancer, but the causal effects and mechanisms on its heterogeneous subtypes remain unclear.</p> Methods <p>We used genetic variants robustly associated with gene expression, protein level, splicing event, and DNA methylation of <i>GLP-1R</i> in six endocrine-related tissues (N ≤ 35,431) as genetic instruments to proxy the effect of GLP-1R agonism. To increase power, we conducted a meta-analysis of genome-wide association studies of ovarian cancer (29,066 cases, 461,542 controls), and identified 12 genome-wide associated variants, including two previously unreported variants: rs77247401 (<i>MIR1208</i>) and rs56159231 (<i>PLEKHM1</i>).</p> Results <p>Here we show that gene expression of <i>GLP-1R</i> in pancreas is associated with a reduced risk of overall ovarian cancer risk odds ratio ([OR] = 0.94, 95% confidence interval [CI] 0.89-1.00) and endometrioid ovarian cancer (ENOC; OR = 0.83, 95% CI = 0.72-0.95), which the finding is validated using splicing event of <i>GLP-1R</i> in pancreas (OR = 0.13, 95% CI = 0.02-0.86). However, null association is found for <i>GLP-1R</i> expression in pancreas with other ovarian cancer subtypes. The phenome-wide MR followed by mediation MR identifies six body composition and metabolic factors as mediators, including 18:2 linoleic acid.</p> Conclusions <p>The protective effect of GLP-1R agonists on ovarian cancer, especially ENOC, needs further validation in large-scale and well-conducted clinical trials.</p>

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Mendelian randomization study of GLP-1R effects on ovarian cancer subtypes mediated by metabolic factors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月12日

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  • Jiajia Liu,
  • Zhihe Chen,
  • Qian Yang,
  • Hong Lin,
  • Shuangyuan Wang,
  • Mian Li,
  • Tiange Wang,
  • Zhiyun Zhao,
  • Min Xu,
  • Yuhong Chen,
  • Yu Xu,
  • Jieli Lu,
  • Qiuhong Gong,
  • Guang Ning,
  • Limin Wang,
  • Weiqing Wang,
  • Yufang Bi,
  • Jie Zheng

摘要

Background

Ovarian cancer is a major female reproductive health issue with heterogeneous biological features on its subtypes, which may require different therapeutic strategies. Glucagon-like peptide-1 receptor (GLP-1R) agonists were reported to be beneficial for ovarian cancer, but the causal effects and mechanisms on its heterogeneous subtypes remain unclear.

Methods

We used genetic variants robustly associated with gene expression, protein level, splicing event, and DNA methylation of GLP-1R in six endocrine-related tissues (N ≤ 35,431) as genetic instruments to proxy the effect of GLP-1R agonism. To increase power, we conducted a meta-analysis of genome-wide association studies of ovarian cancer (29,066 cases, 461,542 controls), and identified 12 genome-wide associated variants, including two previously unreported variants: rs77247401 (MIR1208) and rs56159231 (PLEKHM1).

Results

Here we show that gene expression of GLP-1R in pancreas is associated with a reduced risk of overall ovarian cancer risk odds ratio ([OR] = 0.94, 95% confidence interval [CI] 0.89-1.00) and endometrioid ovarian cancer (ENOC; OR = 0.83, 95% CI = 0.72-0.95), which the finding is validated using splicing event of GLP-1R in pancreas (OR = 0.13, 95% CI = 0.02-0.86). However, null association is found for GLP-1R expression in pancreas with other ovarian cancer subtypes. The phenome-wide MR followed by mediation MR identifies six body composition and metabolic factors as mediators, including 18:2 linoleic acid.

Conclusions

The protective effect of GLP-1R agonists on ovarian cancer, especially ENOC, needs further validation in large-scale and well-conducted clinical trials.