Work

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

Year: 2026

Type: article

Abstract: 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. 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). 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. The protective effect of GLP-1R agonists on ovarian cancer, especially ENOC, needs further validation in large-scale and well-conducted clinical trials. Liu, Chen, Yang et al. investigate the effect of GLP-1 receptor activation on ovarian cancer risk across different subtypes. They show that it specifically lowers the risk of one subtype, endometrioid ovarian cancer, mediated in part by specific metabolic factors. The class of drugs known as GLP-1 receptor (GLP-1R) agonists are known to have a range of health benefits. However, their effect on ovarian cancer, which is a significant health concern for women worldwide, has been unclear. GLP-1R agonists act on a protein expressed in the outside of cells, called the GLP-1 receptor. In our study, we used human genetic data to predict activity of the GLP-1 receptor in over 490,000 individuals. We found that GLP-1R activity in the pancreas was associated with a lower risk of a specific subtype of ovarian cancer called endometrioid ovarian cancer. This protective effect appeared to be partly influenced by changes in body composition and molecules in the blood, such as linoleic acid. Our results suggest that GLP-1R agonists could help prevent certain forms of ovarian cancer. Further clinical studies are needed to confirm this possibility.

Source: Communications Medicine

DOI: 10.1038/s43856-026-01379-y