Also a significant difference was found in miR-499 genotypes frequency when compared between HCC and cirrhosis groups as the GG genotype was significantly lower in HCC cases than cirrhosis group (P = 0.006) while the combined miR-499 (AA+AG) genotypes were significantly higher in HCC cases than in cirrhosis group (P = 0.003) [OR (95% CI) = 0.131 (0.028-0.601)].
In the subgroup analysis of hepatitis virus status, patients with HBV and miR-499rs3746444 polymorphism showed increased HCC risk (OR = 1.38; 95% CI, 1.17-1.64; P = 0.0002).
Subgroup analysis based on type of tumor was also performed, miR-499rs3746444 is associated with susceptibility of cervical squamous cell carcinoma, lung cancer, prostate cancer, and hepatocellular carcinoma.
Association of miR-499 with HCC risk was only detected in the subgroup of studies which did not use polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) under the allelic, heterozygote and dominant models.
Subgroup analysis was performed by ethnicity, miR-499rs3746444 was significantly associated with an increased the risk of HCC in Asians (OR = 1.31, 95% CI = 1.10-1.55; P = 0.002).
However, no significant association was observed between miR-196a2 and miR-499 variants and risk of hepatocellular carcinoma in the co-dominant, dominant, and recessive models.
The miR196a2 SNP was also linked with larger tumor size in RCC and advanced tumor stage in HCC. miR196a2 and miR499a combined genotypes were associated with RCC and HCC.
Moreover, subjects carrying the miR-499 A allele showed a greatly increased risk of HCC in subjects infected with HBV compared with subjects carrying the miR-499 A allele, with an adjusted odds ratio (95% confidence interval) of 1.53 (1.34-2.41).
Predictive role of miR-146a rs2910164 (C>G), miR-149 rs2292832 (T>C), miR-196a2 rs11614913 (T>C) and miR-499rs3746444 (T>C) in the development of hepatocellular carcinoma.
Meta-analysis was performed on the associations between the miR-146a rs2910164 C > G and miR-499rs3746444 T > C polymorphisms and hepatocellular carcinoma, using: allele contrast, dominant, and recessive models.
However, we did not find that the miR-149 CC and miR-499 GG genotypes were associated with risk of HCC, and no interaction was found between miR-149C>T and miR-499A>G polymorphisms and hepatitis B virus infection.
Our findings suggest that the SNPs in miR-196a2 C > T and miR-499 C > T confer HCC risk and that affect the clinical laboratory characteristics of HCC patients.
The MiR-499 G allele was significantly associated with decreased risk of HCC among patients infected with HBV in a dominant model (OR=0.09, 95%CI= 0.02-0.29).
It has been suggested that two common SNPs rs2910164 in miR-146a and rs3746444 in miR-499 are associated with susceptibility to hepatocellular carcinoma (HCC).
We found that miR-499 AG was significantly associated with decreased risk for hepatocellular carcinoma when compared with miR-499 AA genotype (adjusted odds ration = 0.74, 95% confidence interval = 0.24-0.96).
No statistically significant differences were found in the allele or genotype distributions of the miR-499rs3746444 polymorphism among HCC and cancer-free control subjects (P>0.05).