Genetic Variants in RKIP Are Associated with Clear Cell Renal Cell Carcinoma Risk in a Chinese Population
Genetic Variants in RKIP Are Associated with Clear Cell Renal Cell Carcinoma Risk in a Chinese Population
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RKIP 的遗传变异与中国人群的透明细胞肾细胞癌风险相关
DOI：
10.1371/journal.pone.0109285
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发表时间：
2014-10-16
期刊：
影响因子：
3.7
通讯作者：
Yin, Changjun
中科院分区：
文献类型：
--
作者：
Cao, Qiang;Wang, Jian;Yin, Changjun
背景Raf-1激酶抑制蛋白（Raf-1 kinase inhibitor protein，RKIP）通过调节细胞的侵袭、凋亡和分化等功能在肿瘤的发生、发展中起重要作用。RKIP表达下调与肾细胞癌（RCC）的发生和发展有关。因此，我们推测RKIP基因多态性可能与肾细胞癌的易感性和进展有关。方法采用SNapShot法对859例肾细胞癌患者和1004例正常对照进行RKIP基因5个单核苷酸多态性（tSNPs）的检测。应用Logistic回归分析肾癌发生、发展的遗传相关性。通过qRT-PCR初步检查重要SNP的功能性。结果发现RKIP基因启动子区rs 17512051与透明细胞肾细胞癌（ccRCC）风险降低显著相关（TA/AA vs. TT：P = 0.039，OR = 0.78，95%CI = 0.62-0.99）。 RKIP 3′UTR区域的另一个SNP（rs 1051470）与ccRCC风险增加略微相关（TT vs. CC+CT：OR = 1.45，95%CI = 1.01-2.09）。 在分层分析中，rs 17512051的保护作用在男性、不吸烟者、不饮酒者以及无糖尿病史的受试者亚组中更显著。此外，我们观察到rs 17512051 A等位基因在正常肾组织中存在较高的RKIP mRNA水平。结论RKIP基因rs 17512051多态性可能通过改变内源性RKIP的表达水平而影响肾细胞癌的易感性。这种多态性的风险效应和功能影响需要进一步验证。
Background Raf-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. Methods A 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. Result We 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. Conclusion Our 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.