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

Jan 12, 2026Communications medicine

Genetic study of how GLP-1R influences ovarian cancer types through metabolism

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Abstract

Gene expression of GLP-1R in the pancreas is associated with a reduced overall ovarian cancer risk (odds ratio [OR] = 0.94).

The expression of GLP-1R in the pancreas shows a significant association with a decreased risk of endometrioid ovarian cancer (ENOC; OR = 0.83).
A splicing event of GLP-1R in the pancreas is linked to an even lower risk of overall ovarian cancer (OR = 0.13).
No association is observed between GLP-1R expression in the pancreas and other ovarian cancer subtypes.
Six body composition and metabolic factors are identified as potential mediators of the GLP-1R effect on ovarian cancer risk.

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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.

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

Abstract

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