A functional polymorphism in the miR-146a gene is associated with the risk for hepatocellular carcinoma

Abstract

A G > C polymorphism (rs2910164) is located in the stem region opposite to the mature miR-146a sequence, which results in a change from G:U pair to C:U mismatch in the stem structure of miR-146a precursor. Here, we elucidated the biological significance of this polymorphism, based on cancer association study and cell model system. The cancer association study included 479 hepatocellular carcinoma (HCC) and 504 control subjects. We found that the genotype distribution of this polymorphism in HCC cases was significantly different from that in control subjects (P = 0.026). The association between the genotype and the risk of HCC was further analyzed using multivariate unconditional logistic regression, with adjustment for sex, age and hepatitis B virus status. The results revealed that male individuals with GG genotype were 2-fold more susceptible to HCC (odds ratio = 2.016, 95% confidence interval = 1.056-3.848, P = 0.034) compared with those with CC genotype. We next examined the influence of this polymorphism on the production of mature miR-146a and found that G-allelic miR-146a precursor displayed increased production of mature miR-146a compared with C-allelic one. Further investigations disclosed that miR-146a could obviously promote cell proliferation and colony formation in NIH/3T3, an immortalized but non-transformed cell line. These data suggest that the G > C polymorphism in miR-146a precursor may result in important phenotypic traits that have biomedical implications. Our findings warrant further investigations on the relation between microRNA polymorphism and human diseases.

Association Analysis of Single Nucleotide Polymorphisms in miR-146a and miR-196a2 on the Prevalence of Cancer in Elderly Japanese: A Case-Control Study

“…The rs2910164 (G/C) polymorphism is a G to C nucleotide change leading to C:U mismatch on the stem region of miR-146a which is one of the variant of miR-146. The compiling evidence indicate that rs2910164 is associated with different types of cancer phenotypes including breast cancer (Shen et al, 2008) gastric cancer Zeng et al, 2010;Kogo et al, 2011), hepatocellular carcinoma (Xu et al, 2008), glioma (Permuth-Wey et al, 2011) prostate and others . The G allele carriers were shown to have higher mature miR-146a synthesis (Xu et al, 2008).…”

“…The compiling evidence indicate that rs2910164 is associated with different types of cancer phenotypes including breast cancer (Shen et al, 2008) gastric cancer Zeng et al, 2010;Kogo et al, 2011), hepatocellular carcinoma (Xu et al, 2008), glioma (Permuth-Wey et al, 2011) prostate and others . The G allele carriers were shown to have higher mature miR-146a synthesis (Xu et al, 2008). The rs2910164 (G/C) may involve in negative feedback regulation of Toll-like receptors (TLR) and cytokine receptor signalling (Taganov et al, 2006).…”

“…The nucleotide change of T to C may affect the miR-196a2 expression (Saunders et al, 2007;Chu et al, 2011). Recent studies show that rs11614913 may influence lung cancer (Tian et al, 2009;Hong et al, 2011;Yuan et al, 2013), breast cancer (Hoffman et al, 2009;Linhares et al, 2012), head and neck cancer (Christensen et al, 2010), hepatocellular carcinoma (Xu et al, 2008;Qi et al, 2010;Hao et al, 2013), gastric cancer (Peng et al, 2010), prostate cancer (George et al, 2011) and others . On the contrary, there are also several studies for both rs2910164 and rs11614913 polymorphisms indicate conflicting results asserting either lack of association or decreased cancer risk (Xu et al, 2011;Hezova et al, 2012;He et al, 2012;Xu et al, 2013;Zhang et al, 2013).…”

Common genetic variants in pre-microRNAs and risk of gallbladder cancer in North Indian population

“…[9][10][11][12][13] It is possible that association of miRNA polymorphisms may be cancer specific. However, the non-significant results of our study could be explained because of inherent difficulties in validating and replicating association studies with complex traits such as cancer and/or as a consequence of ethnic variation.…”

“…6,7 Various single nucleotide polymorphisms (SNPs) are known to exist in miRNA genes, which can lead to variations in the quantity of miRNAs resulting in diverse functional consequences and, therefore, may represent ideal candidate biomarkers for cancer prognosis. 8 Various genetic association studies have explored the function of pre-miRNA polymorphisms in cancers including non-small cell lung cancer (NSCLC), 9 breast cancer, 10 hepatocellular carcinoma, 11 bladder cancer 12 and papillary thyroid carcinoma. 13 However, the function of genetic variants of miRNA genes in GBC is yet to be determined.…”