A genome-wide Mendelian randomization study focusing on endoplasmic reticulum stress reveals novel genetic markers for renal cell carcinoma

The causal association between endoplasmic reticulum stress and renal cell carcinoma remains poorly defined. The present study aimed to identify potential causal relationships between endoplasmic reticulum (ER) stress-related genes and renal cell carcinoma (RCC) by integrating multi-omics datasets using summary data-based Mendelian randomization (SMR). Data on the methylation, expression and protein levels of ER stress-related genes were obtained from quantitative trait loci studies. Genetic associations with RCC were derived from 11 studies comprising 5,219 RCC cases of European descent. SMR and colocalization analyses were performed to assess correlations and identify shared causal genetic variants. Molecular experiments were conducted for validation. In total, 1,193 ER stress-related genes were identified. SMR analysis revealed 3 DNA methylation probes (cg07431106, cg12446953 and cg08884395), 1 gene (polycystin 1) and 3 protein probes (SeqId_4125_52, SeqId_3448_13 and SeqId_17161_1) as key causal variants for RCC (SMR, P<0.01; Heterogeneity In Dependent Instruments, P>0.01). Bayesian colocalization analysis corroborated a strong causal relationship for all 7 variables (posterior probability for H4 >0.7). Multi-omics data integration identified PTEN induced kinase 1 as a protective factor and Estrogen receptor 1 as a progression factor in RCC. Molecular experiments demonstrated that ER stress may be a mechanism for RCC progression and sunitinib resistance. The 7 key variables showed significant differences in an RCC cell line model, supporting the SMR results. In conclusion, the results of the present study suggested a potential association between ER stress and RCC. SMR analysis identified 3 cytosine-phosphate-guanine sites, 1 gene and 3 protein sites as causal variants associated with RCC.