Abstract

Background: Roxadustat is used for treating chronic kidney disease (CKD) patients, particularly those on hemodialysis with comorbid cancer. Some studies suggest a link between roxadustat and cancer progression, but the mechanisms remain unclear, highlighting the need for further investigation into potential causal links.
Materials and methods: We employed a two-sample Mendelian randomization (MR) analysis to explore associations between genetic variations in Roxadustat targets and 14 cancer types. Single-nucleotide polymorphisms (SNPs) in the Egl-9 family hypoxia inducible factor 1 (EGLN1) and Egl-9 family hypoxia inducible factor 2 EGLN2 genes, related to hemoglobin levels, were chosen as instrumental variables. Analyses used inverse variance-weighted (IVW)-MR and summary data-based MR (SMR) approaches, assessing horizontal pleiotropy with Mendelian randomization Egger (MR-Egger) and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and using the heterogeneity in dependent instrumental variables (HEIDI) test for SMR.
Results: Summary statistics were derived from three UK studies involving 172,925 individuals. IVW-MR revealed a positive association between EGLN1 variants and breast cancer (OR = 1.644) and lung adenocarcinoma (OR = 2.117), while negative associations were found for malignant non-melanoma skin cancer and kidney cancer. SMR confirmed the links to breast cancer and a decrease in skin cancer risk. EGLN2 expression was positively associated with prostate and lung cancers and negatively with estrogen receptor (ER)– breast and brain cancers.
Conclusion: Our findings support a potential causal relationship between the inhibition of EGLN1 and EGLN2 and the development of specific cancer types.

*Xiaona He and Hongxi Chen contributed equally to this paper and are thus co-first authors.

Author Details

Authors

• Xiaona He^{1, 2}*
• Hongxi Chen^{2, 3}*
• Yue Qi⁴
• Wenjie Long^{2, 3}
• Yangang Zhou^{3, 5}
• Xin Ma^{2, 3, 6}

Departments

• ¹ Department of Nephrology, Dazhou Dachuan District People’s Hospital (Dazhou Third People’s Hospital), Dazhou, Sichuan,
• ² Department of Clinical Medicine, School of Clinical Medicine, Chengdu Medical College,
• ³ Department of Nephrology, The First Affiliated Hospital of Chengdu Medical College,
• ⁴ Department of Nephrology, Chengdu First People’s Hospital,
• ⁵ Department of Oncology, and
• ⁶ Sichuan Clinical Research Center for Geriatrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China

Address

Xin Ma, MD, Dr.
Department of Nephrology
Dazhou Dachuan District People’s Hospital
(Dazhou Third People’s Hospital)
Dazhou, Sichuan, 636150, China
or
Yangang Zhou
Department of Oncology
The First Affiliated Hospital of Chengdu Medical College
Chengdu, 610500, China
Email: [email protected]; [email protected]

Citation