
==== Front
Int J Surg
Int J Surg
JS9
International Journal of Surgery (London, England)
1743-9191
1743-9159
Lippincott Williams & Wilkins Hagerstown, MD

38814292
IJS-D-24-01986
10.1097/JS9.0000000000001725
00145
3
Correspondence
A commentary on ‘Association of glucagon-like peptide-1 receptor agonists with risk of cancers-evidence from a drug target Mendelian randomization and clinical trials’
Zhang Guolin MD a2690521486@qq.com

Wang Zhen MD zhl8247@163.com
b
Yu Hanlin MD c*yuwenhanlin163@163.com

Liu Xiangzhe MD c*liuxiangzhe@163.com

a Department of Cardiology, The Second Hospital of Dalian Medical University
b Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning
c Department of Encephalology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, People’s Republic of China
* Corresponding author. Address: Department of Encephalology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450046, Henan, People’s Republic of China. Tel.: +861 323 396 2199. E-mail: yuwenhanlin163@163.com (H. Yu), and Tel.: +861 363 381 1923. E-mail: liuxiangzhe@163.com (X. Liu).
9 2024
29 5 2024
110 9 60346035
11 5 2024
19 5 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0/

OPEN-ACCESSTRUE
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pmc Dear Editor,

We read carefully with interest the article by Sun et al.1 published in the International Journal of Surgery. They used Mendelian randomization (MR) combined with data from previous clinical trials for the association between glucagon-like peptide 1 receptor agonists (GLP1RA) and the risk of developing cancers. This study found a causal relationship between GLP1RA and multiple cancers and was associated with an increased risk of cancers (e.g. colon cancer) and a decreased risk of cancers (e.g. breast cancer). This finding contributes to the understanding of the genetic association between GLP1RA and cancer risk, provides a valuable scientific basis for cancer prevention and treatment, and offers constructive guidance for the clinical application of GLP1RA. We sincerely admire this innovative research, but would like to share some different thoughts about this study.

We believe that the choice of methodology for this study may be questionable or needs to be supplemented. This study used the available cis eQTL for the drug target gene (GLP1R) as a proxy for GLP1RA exposure and used the inverse variance weighting (IVW) method for MR analysis. Typically, the use of cis eQTL as instrumental variables requires the use of summary data-based Mendelian randomization (SMR)2 methods. For example, Ji et al. adopted the use of SMR rather than IVW for MR analyses to explore the causal relationship between GLP-1 agonists and diabetic retinopathy in the context of using cis eQTL of GLP1R as an instrumental variable. Therefore, we believe that incorporating the SMR approach may be warranted. Specifically, there may be too many inappropriate instrumental variables incorporated when using cis eQTL as instrumental variables, in which case the IVW approach alone may lead to the emergence of false-positive results.

Second, the MAGIC Consortium recently released the latest randomised glucose genome-wide association (GWAS) data derived from 476 326 individuals3. In their study, GLP1R coding variants (including newly identified low-frequency coding variants) associated with random glucose were identified. In addition, these variants were shown to be strongly associated with insulin release after GLP1R activation by functional follow-up and molecular dynamics modelling. Therefore, we believe that using these coding variants as pharmacogenetic proxies for GLP1RA for MR (using the IVW approach) is more reliable and could be a strong complement to the present study. Meanwhile, the method of Bayesian co-localization and the use of multiple hypothesis testing can make the results of this study more rigorous and better.

In conclusion, we would like to express our sincere gratitude and admiration to Mr Lei et al. in recognition of their work and efforts in studying the causal relationship between GLP1RA and cancer. This study has provided a valuable resource for our in-depth understanding of the potential association between GLP1RA and cancer risk. However, despite the important clinical value and significance of this study, we also raise some necessary concerns and areas of possible improvement in the study. We hope that the present study incorporating our thoughts contributes to further basic or clinical research on GLP1RA in cancer.

Ethical approval

Not applicable.

Consent

Not applicable.

Source of funding

2024 Henan Province Science and Technology Research Project (242102311277); Henan Province “Double First-Class” Creation Discipline Traditional Chinese Medicine Research Project (HSRP–DFCTCM-2023-2-18).

Author contribution

G.Z., Z.W., H.Y., and X.L.: conception, design, and writing – original draft; X.L.: funding acquisition and writing – review and editing; G.Z. and Z.W.: investigation, project administration, and resources supervision. All authors were involved in the final approval of the manuscript.

Conflicts of interest disclosure

The authors declare that they have no conflicts of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

All authors.

Data availability statement

Not applicable.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Guolin Zhang and Zhen Wang have contributed equally to this work.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Published online 29 May 2024
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References

1 Sun Y Liu Y Dian Y . Association of glucagon-like peptide-1 receptor agonists with risk of cancers-evidence from a drug target Mendelian randomization and clinical trials. Int J Surg (London, England) 2024. [Epub ahead of print]. doi:10.1097/js9.0000000000001514
2 Zhu Z Zhang F Hu H . Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet 2016;48 :481–487.27019110
3 Lagou V Jiang L Ulrich A . GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification. Nat Genet 2023;55 :1448–1461.37679419
