Rogers Miranda, Gill Dipender, Ahlqvist Emma, Robinson Tim, Mariosa Daniela, Johansson Mattias, Cortez Cardoso Penha Ricardo, Dossus Laure, Gunter Marc J, Moreno Victor, Davey Smith George, Martin Richard M, Yarmolinsky James
MRC Integrative Epidemiology Unit, University of Bristol, BS8 2BN Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, BS8 2PS Bristol, UK.
iScience. 2023 May 9;26(6):106848. doi: 10.1016/j.isci.2023.106848. eCollection 2023 Jun 16.
Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of a variant in , rs1800437 (E354Q), shown to impair long-term GIPR signaling and lower circulating glucose-dependent insulinotropic peptide concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis (breast, colorectal, endometrial, lung, pancreatic, and renal) in up to 235,698 cases and 333,932 controls. Each copy of E354Q was associated with a higher risk of overall and luminal A-like breast cancer and this association was consistent in replication and colocalization analyses. E354Q was also associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations. Our human genetics analysis suggests an adverse effect of the E354Q variant on breast cancer risk, supporting further evaluation of GIPR signaling in breast cancer prevention.
临床前和遗传学研究表明，葡萄糖依赖性促胰岛素多肽受体（GIPR）信号受损会使血糖控制恶化。GIPR信号与受葡萄糖稳态受损影响的癌症风险之间的关系尚不清楚。我们在多达235,698例病例和333,932例对照中，研究了rs1800437（E354Q）这一已显示会损害长期GIPR信号并降低循环中葡萄糖依赖性促胰岛素多肽浓度的变体与受葡萄糖稳态受损影响的6种癌症（乳腺癌、结直肠癌、子宫内膜癌、肺癌、胰腺癌和肾癌）风险之间的关联。E354Q的每个拷贝都与总体及管腔A型乳腺癌的较高风险相关，并且这种关联在重复和共定位分析中是一致的。E354Q还与餐后血糖浓度升高、胰岛素分泌减少和睾酮浓度降低有关。我们的人类遗传学分析表明E354Q变体对乳腺癌风险有不利影响，支持在乳腺癌预防中对GIPR信号进行进一步评估。
