The Association Study Of Genetic Variants On IL-4/IL-13/IL-4R Axis And Renal Cell Carcinoma Susceptibility

Background: Renal cell carcinoma(RCC)is the most important type of renal cancer,accounting for about 2% to 3% of adult malignant tumors.It is difficult to detect RCC at early stage and most patients are accidentally found to have asymptomatic RCC during physical examination.Radical nephrectomy is the most effective treatment,but the patient’s postoperative life quality is significantly reduced,and the five-year survival rate of advanced renal cancer is less than 10%.Therefore,it is essential to screen reliable biomarkers for predicting RCC.Abnormal signal transduction of interleukin-4(IL-4)/IL-13/IL-4 receptor(IL-4R)-mediated pathways are associated with the progression of multiple tumors.Single-nucleotide polymorphisms(SNPs)are the most common genetic variants.Previous studies have found that certain functional SNPs located on the IL-4/IL-13/IL-4R signaling axis may be associated with RCC.In this study,we aimed to screen out all the SNPs on IL-4/IL-13/IL-4R gene regions which may be associated with susceptibility to RCC and explore possible molecular mechanisms.Methods: This study was based on the 1000-genome project database.SNPs should have a minimum allele frequency of > 0.05 and the genotype distribution should be consistent with Hardy-Weinberg Equilibrium.Linkage disequilibrium analysis was performed to screen out the TagSNPs.All TagSNPs were performed functional annotation to select candidate SNPs included in following case-control study.This study totally collected plasma samples from 620 cases of RCC and 623 matched controls.The logistic regression model was used to analyze the relationship between candidate SNP genotypes and the risk of RCC.We also performed luciferase reporter assay and electrophoretic mobility shift assay to explore the molecular mechanisms of SNPs.Results: Five candidate SNPs were included(IL-13 rs1881457,IL-13 rs2066960,IL-13 rs2069744,IL-4R rs8832 and IL-4R rs4787951).We found that IL-4R rs4787951 was associated with RCC risk.Compared with TT genotype,individuals carrying CC genotype were prone to suffer RCC.The CC genotype significantly increased the incidence of RCC(adjusted OR = 1.57,95% CI = 1.07-2.28,P = 0.020).In addition,the transcriptional activity of IL-4R with T allele was significantly induced,and the mutations from T to C reduced the binding affinity of IL-4R to NFATc.No association of other SNPs with RCC risk was found.Conclusions: IL-4R rs4787951 was associated with susceptibility of RCC.And rs4787951 could affect the binding affinity of IL-4R to NFATc and influence the tumorigenesis of RCC.Therefore,IL-4R rs4787951 may serve as a potential biomarker for early diagnosis of RCC.