Association of glucose-lowering drug target and risk of gastrointestinal cancer: a mendelian randomization study

Yi Yang; Bo Chen; Chongming Zheng; Hao Zeng; Junxi Zhou; Yaqing Chen; Qing Su; Jingxian Wang; Juejin Wang; Yurong Wang; Hongli Wang; Ruxue Jin; Zhiyuan Bo; Gang Chen; Yi Wang

doi:10.1186/s13578-024-01214-8

Association of glucose-lowering drug target and risk of gastrointestinal cancer: a mendelian randomization study

Cell Biosci. 2024 Mar 19;14(1):36. doi: 10.1186/s13578-024-01214-8.

Authors

Yi Yang¹, Bo Chen^{2

3}, Chongming Zheng^{2

3}, Hao Zeng¹, Junxi Zhou¹, Yaqing Chen¹, Qing Su¹, Jingxian Wang¹, Juejin Wang¹, Yurong Wang⁴, Hongli Wang⁴, Ruxue Jin⁴, Zhiyuan Bo^{5

6}, Gang Chen^{7

8

9}, Yi Wang¹⁰

Affiliations

¹ Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China.
² Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
³ Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁴ Wenzhou Medical University, Wenzhou, China.
⁵ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. drbozhiyuan@163.com.
⁶ Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. drbozhiyuan@163.com.
⁷ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. chen.gang@wmu.edu.cn.
⁸ Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. chen.gang@wmu.edu.cn.
⁹ Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumor and Bioengineering, Zhejiang, China. chen.gang@wmu.edu.cn.
¹⁰ Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China. wang.yi@wmu.edu.cn.

Abstract

Background & aims: Glucose-lowering drug is associated with various cancers, but the causality with gastrointestinal cancer risk is rarely reported. We aimed to explore the causality between them in this Mendelian randomization (MR) study.

Methods: Two-sample MR, summary-data-based (SMR), mediation MR, and colocalization analyses was employed. Ten glucose-lowering drug targets (PPARG, DPP4, GLP1R, INSR, SLC5A2, ABCC8, KCNJ11, ETFDH, GPD2, PRKAB1) and seven types of gastrointestinal cancer (anal carcinoma, cardia cancer, gastric cancer, hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), pancreatic cancer, rectum cancer) were included. Patients with gastrointestinal cancers from six different large GWAS databases, including the UK Biobank and Finnish cohorts were incorporated, for discovery and external validation. Meta-analysis was employed to integrate the results from both discovery and validation cohorts, thereby ensuring the reliability of findings.

Results: ABCC8/KCNJ11 were associated with pancreatic cancer risk in both two-sample MR (odds ratio (OR): 15.058, per standard deviation unit (SD) change of glucose-lowering durg target perturbation equivalent to 1 SD unit of HbA_1c lowering; 95% confidence interval (95% CI): 3.824-59.295; P-value = 0.0001) and SMR (OR: 1.142; 95% CI: 1.013-1.287; P-value = 0.030) analyses. The mediation effect of body mass index (OR: 0.938; 95% CI: 0.884-0.995; proportion of mediation effect: 3.001%; P-value = 0.033) on ABCC8/KCNJ11 and pancreatic cancer was uncovered. Strong connections of DPP4 with anal carcinoma (OR: 0.123; 95% CI: 0.020-0.745; P-value = 0.023) and ICC (OR: 7.733; 95% CI: 1.743-34.310; P-value = 0.007) were detected. PPARG was associated with anal carcinoma (OR: 12.909; 95% CI: 3.217-51.795; P-value = 0.0003), HCC (OR: 36.507; 95% CI: 8.929-149.259; P-value < 0.0001), and pancreatic cancer (OR: 0.110; 95% CI: 0.071-0.172; P-value < 0.0001). SLC5A2 was connected with pancreatic cancer (OR: 8.096; 95% CI: 3.476-18.857; P-value < 0.0001). Weak evidence indicated the connections of GLP1R, GPD2, and PRKAB1 with anal carcinoma, cardia cancer, ICC, and rectum cancer. In addition, the corresponding results were consistently validated in both the validation cohorts and the integrated outcomes.

Conclusions: Some glucose-lowering drugs were associated with gastrointestinal cancer risk, which might provide new ideas for gastrointestinal cancer treatment.

Keywords: Causality; Gastrointestinal cancer risk; Glucose-lowering drug target; Mendelian randomization.

Abstract

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