Genetic Variants in RKIP Are Associated with Clear Cell Renal Cell Carcinoma Risk in a Chinese Population

Abstract

BackgroundRaf-1 kinase inhibitor protein (RKIP) plays a critical role in tumor development by regulating cell functions such as invasion, apoptosis and differentiation. Down-regulation of RKIP expression has been implicated in the development and progression of renal cell carcinoma (RCC). Herein, we hypothesized that genetic polymorphisms in RKIP might be associated with susceptibility and progression of RCC.MethodsA total of 5 tagging single-nucleotide polymorphisms (tSNPs) in RKIP were selected and genotyped by SNapShot method in a case-control study of 859 RCC patients and 1004 controls. The logistic regression was used to evaluate the genetic association with occurrence and progression of RCC. The functionality of the important SNP was preliminary examined by qRT-PCR.ResultWe found that the rs17512051 in the promoter region of RKIP was significantly associated with decreased clear cell RCC (ccRCC) risk (TA/AA vs. TT: P = 0.039, OR = 0.78, 95%CI = 0.62–0.99). Another SNP (rs1051470) in the 3′UTR region of RKIP was marginally associated with increased ccRCC risk (TT vs. CC+CT: OR = 1.45, 95%CI = 1.01–2.09). In the stratified analysis, the protective effect of rs17512051 was more predominant in the subgroups of male, non-smokers, non-drinkers as well as subjects without history of diabetes. Furthermore, we observed higher RKIP mRNA levels in the presence of the rs17512051A allele in normal renal tissues.ConclusionOur results suggest that the potentially functional RKIP rs17512051 polymorphism may affect ccRCC susceptibility through altering the endogenous RKIP expression level. Risk effects and the functional impact of this polymorphism need further validation.

RKIP is commonly downregulated in clear cell renal cell carcinoma (ccRCC)

“…Our observed transcription-mediated regulation of RKIP abundance is supported by a recent report that a single nucleotide polymorphism (rs17512051) in the promoter region of the RKIP gene enhanced RKIP expression in the kidney [37] . Interestingly, this RKIP upregulation was associated with a decrease of ccRCC risk, which was presumably resulted from the polymorphism-caused interference of RKIP reduction [37] in ccRCC. This observation is in accordance with our publication suggesting RKIP being a tumor suppressor of ccRCC [30] .…”

Genetic variation in IGF1 predicts renal cell carcinoma susceptibility and prognosis in Chinese population

“…The details of the inclusion criteria were described previously619. In brief, all subjects were genetically unrelated ethnic Han Chinese individuals.…”

Association between MTHFD1 polymorphisms and neural tube defect susceptibility

“…The primers to amplify different fragments containing each SNP as shown in Table 2 were designed using PSQ Assay Design Software Version 1.0.6. Briefly, the amplification program was performed using the 9800 Fast PCR System according to manufacturer's suggested protocol (all the assays were performed in a 20 μl reaction mix containing 0.5 μM each of forward and reverse primers and Applied Biosystems GeneAmp® Fast PCR Master Mix), at the start of 95 μC for 2 min, followed by 33 cycles of 94 μC for 20 s, 56 μC for 30 s and then 72 μC for 40 s [14]. After amplification, the pyrosequencing primer was used to extend the PCR product by adding nucleotides in a specific sequential order based on the known sequence [8] as described previously.…”

“…The pairwise option of the Haploview 4.2 software was used to identify the tag-SNPs and an r 2 of 0.8 was selected as a threshold for the analyses [14]. Finally, we selected three of them to represent all SNPs on MTHFD1, as they were supposed to result in translational modification and therefore may alter enzyme function [9].…”