Genetic variation in targets of roxadustat and risk of common cancers: A Mendelian randomization analysis.

[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.