Genetically-proxied impaired GIPR signalling and risk of 6 cancers

Abstract

Background: Preclinical and human genetics studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling worsens glycaemic control. The relationship between GIPR signalling and risk of cancers influenced by impaired glucose homeostasis is unclear. Methods: We examined the association of a missense variant in GIPR, rs1800437 (E354Q), shown to impair long-term GIPR signalling and lower circulating GIP concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis. Summary genetic association data on breast, colorectal, endometrial, lung, pancreatic, and renal cancer risk were obtained from GWAS consortia (235,698 cases, 333,932 controls). Replication analyses were performed in the FinnGen consortium (8,401 breast cancer cases, 99,321 controls). Colocalisation was performed to examine robustness of findings to genetic confounding. Finally, we examined the association of E354Q with potential downstream molecular mediators of GIPR signalling to identify possible mechanisms underpinning an effect on cancer risk. Results: Each copy of E354Q was associated with a higher risk of overall breast cancer (OR:1.05,95%CI:1.03-1.06,P=4.23x10-9) and luminal A-like breast cancer (OR:1.05,95%CI:1.03-1.06,P=6.02x10-7). In replication analysis, E354Q was likewise associated with breast cancer risk (OR:1.06,95%CI:1.02-1.08,P=1.09x10-3) and in colocalisation there was a >99.9% posterior probability of circulating GIP concentrations sharing a causal variant with overall and luminal A-like breast cancer in GIPR. E354Q was not associated with risk of the 5 other cancers examined. In mechanistic analysis, this variant was associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations. Conclusion: Our comprehensive drug target-Mendelian randomization analysis across 6 cancers suggests an adverse effect of the GIPR E354Q variant on overall and luminal A-like breast cancer risk. These findings provide genetic evidence to support further evaluation of the therapeutic potential of GIPR signalling in breast cancer prevention.