Genetic Variants in Caveolin-1 and RhoA/ROCK1 Are Associated with Clear Cell Renal Cell Carcinoma Risk in a Chinese Population

PLoS One. 2015 Jun 12;10(6):e0128771. doi: 10.1371/journal.pone.0128771. eCollection 2015.

Abstract

Background: The RhoA/ROCK pathway and Caveolin-1 (Cav-1) participate in the process of tumorigenesis in numerous types of cancer. Up-regulation of RhoA/ROCK and Cav-1 expression is considered to be associated with the development and progression of clear cell renal cell carcinoma (ccRCC). We investigated the association between genetic variations of RhoA/ROCK and Cav-1 and the risk of ccRCC in the Chinese population.

Methods: Between May 2004 and March 2014, a total of 1,248 clear cell renal cell carcinoma cases and 1,440 cancer-free controls were enrolled in this hospital-based case-control study. Nine SNPs in RhoA/ROCK and Cav-1 were genotyped using the TaqMan assay.

Result: We found two SNPs (Cav-1 rs1049334 and ROCK1 rs35996865) were significantly associated with the increasing risk of ccRCC (P = 0.002 and P < 0.001 respectively). The analysis of combined risk alleles revealed that patients with 2-4 risk alleles showed a more remarkable growth of ccRCC risk than the patients with 0-1 risk alleles(OR = 1.66, 95%CI = 1.31-2.11, P < 0.001). Younger subjects (P = 0.001, OR = 1.83, 95%CI = 1.30-2.57), higher weight subjects (P = 0.001, OR = 1.76, 95%CI = 1.25-2.47), female subjects (P = 0.007, OR = 1.75, 95% CI = 1.17-2.62), nonsmokers (P < 0.001, OR = 1.67, 95%CI = 1.26-2.23), drinkers (P = 0.025, OR = 1.75, 95% CI = 1.07-2.85), subjects with hypertension (P = 0.025, OR = 1.75, 95% CI = 1.07-2.85) and diabetes (P = 0.026, OR = 4.31, 95% CI = 1.19-15.62) showed a stronger association between the combined risk alleles and the risk of ccRCC by using the stratification analysis. Furthermore, we observed higher Cav-1 mRNA levels in the presence of the rs1049334 A allele in normal renal tissues.

Conclusion: Our results indicate that the two SNPs (Cav-1 rs1049334 and ROCK1 rs35996865) and genotypes with a combination of 2-4 risk alleles were associated with the risk of ccRCC. The functional SNP rs1049334 may affect the risk of ccRCC by altering the expression of Cav-1 and the relevance between the risk effects and the functional impact of this polymorphism needs further validation.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Asian People
  • Carcinoma, Renal Cell* / epidemiology
  • Carcinoma, Renal Cell* / genetics
  • Carcinoma, Renal Cell* / metabolism
  • Caveolin 1* / genetics
  • Caveolin 1* / metabolism
  • China
  • Female
  • Humans
  • Kidney Neoplasms* / epidemiology
  • Kidney Neoplasms* / genetics
  • Kidney Neoplasms* / metabolism
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • rho-Associated Kinases* / genetics
  • rho-Associated Kinases* / metabolism
  • rhoA GTP-Binding Protein* / genetics
  • rhoA GTP-Binding Protein* / metabolism

Substances

  • CAV1 protein, human
  • Caveolin 1
  • RHOA protein, human
  • ROCK1 protein, human
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein

Grants and funding

This work was supported by the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), by the Jiangsu Provincial Special Program of Medical Science (BL2012027), by the Program for Development of Innovative Research Team in the First Affiliated Hospital of Nanjing Medical University and by the National Natural Science Foundation of China (grant numbers 81171963, 81201998 and 81201571). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.