Genetic Variant in Long Non-Coding RNA H19 Modulates Its Expression and Predicts Renal Cell Carcinoma Susceptibility and Mortality

Abstract

The long non-coding RNA (lncRNA) H19 has been demonstrated to play a crucial role in carcinogenesis, including renal cell carcinoma (RCC). However, the impact of genetic variations in <i>H19</i> gene on RCC has not been investigated before. In the present study, we sought to evaluate whether genetic polymorphisms in <i>H19</i> are related to the susceptibility and mortality of RCC. We genotyped four widely studied polymorphisms in <i>H19</i> and assessed their relationship with susceptibility and prognosis of RCC in a case-control study compromising 1,027 cases and 1,094 controls. The functionality of the important polymorphism was further investigated by real-time polymerase chain reaction and luciferase reporter assay. We found that <i>H19</i> rs2839698 was significantly associated with risk and prognosis of RCC. Compared with the <i>H19</i> rs2839698 CC genotype, the variant genotypes (CT/TT) were significantly associated with increased risk of RCC (<i>P</i> = 0.023, OR = 1.21; 95% CI = 1.03-1.45). Besides, patients with variant genotypes (CT/TT) were more likely to develop large tumor (<i>P</i> = 0.003, OR = 1.47; 95% CI = 1.16-1.85) and advanced disease (<i>P</i> = 0.010, OR = 1.59; 95% CI = 1.12-2.26); and had a significantly unfavorable overall survival than those with the rs2839698 CC genotype (CT/TT vs. CC: Log-rank <i>P</i> = 0.026, HR = 2.25, 95%CI = 1.07-4.75). Furthermore, the CT/TT genotypes were associated with significantly increased expression of <i>H19</i> in renal tissue. The luciferase reporter assays revealed the potential effect of rs2839698 variant on the binding of microRNAs to <i>H19</i>. Our results suggest that the <i>H19</i> rs2839698 variant may be a genetic predictor of susceptibility and mortality of RCC. The risk effects and the functional impact of the variant on <i>H19</i> still need further validation.