The association of miR-146a rs2910164 and miR-196a2 rs11614913 polymorphisms with cancer risk: a meta-analysis of 32 studies

JianboWang 2 QingweiWang 2 HongLiu 2 NaShao 1 BingxuTan 2 GuangyuZhang 2 KaiWang 0 YibinJia 2 WeiMa 2 NanaWang 2 YufengCheng 2 0 Department of Oncology, Wendeng Center Hospital , Weihai , People's Republic of China 1 Department of Oncology, Shandong Provincial Hospital , Jinan , Peoples' Republic of China 2 Department of Radiation, Oncology Center, Qilu Hospital of Shandong University , Jinan , Peoples' Republic of China The Author 2012. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: . - *To whom correspondence should be addressed: Tel:86-531-82169831; Fax: 86-531-86927544; E-mail: Received on February 10, 2012; revised on July 6, 2012; accepted on July 27, 2012 MicroRNAs (miRNAs) are small non-coding RNA molecules, which act as post-transcriptional regulators of gene expression and have been implicated in initiation, progression and treatment outcome of diverse cancers. Single nucleotide polymorphisms (SNPs), as the most common type of genetic variation, also exist in miRNA genes and can lead to alteration in miRNA expression resulting in diverse functional consequences. Emerging studies have evaluated the association of miRNA SNPs with cancer risk, but the results remain inconclusive. To assess the relationship between miRNA SNPs and cancer risk, we performed a meta-analysis of 18 studies involving 20 660 subjects for miR-146a rs2910164 polymorphism and 21 studies involving 26,018 subjects for miR-196a2 rs11614913 polymorphism. As for rs2910164, no significant association of cancer risk was found in the overall analysis. In subgroup analysis by cancer type, ethnicity, source of controls and sample size, significant association of cancer risk was mainly found in papillary thyroid carcinoma, primary liver cancer, cervical cancer, Caucasian population and small sample size studies. For rs11614913, significant results were found in all the tested genetic models and T allele or its carriers were associated with decreased cancer risk in overall analysis (T vs. C: OR = 0.888, 95% CI 0.840.938; TT+TC vs. CC: OR=0.897, 95% CI 0.828 0.971). In stratified analysis by cancer type and ethnicity, significant association of cancer risk was observed in breast cancer, lung cancer, colorectal cancer and Asian population, but not in Caucasian population. During further stratified analysis by source of controls and sample size, results similar to those of overall analysis were found in all of the subgroups. Taken together, our results indicated that miR-196a2 rs11614913 T variant probably contribute to decreased susceptibility to cancer. However, limited evidence was found for association of miR-146a rs2910164 with cancer risk, and further well-designed studies with large sample size will be necessary to validate the effect of miR-146a rs2910164 on cancer susceptibility. Introduction MiRNAs are a class of small, single-stranded endogenous RNAs with approximately 22 nucleotides in length, which act as post-transcriptional regulators of gene expression. It was estimated that a single miRNA could target hundreds of mRNAs and nearly 30% protein-coding genes in the human genome can be regulated by miRNAs (1). Emerging evidence indicates that miRNAs are involved in important biological processes related to apoptosis, proliferation, differentiation, angiogenesis and immune response, the deregulation of which is crucial to carcinogenesis (2). However, the exact mechanisms underlying miRNA deregulation in cancer remain largely unknown, which may possibly involve transcriptional deregulations, epigenetic or genetic variation, DNA copy number abnormalities and biogenesis defects in the miRNA machinery (3). Deregulated miRNAs, which function as tumor suppressors or oncogenes, are associated with initiation, progression and treatment outcome of diverse cancers (4). Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation, which are associated with population diversity, disease susceptibility and individual response to medicine (5). SNPs located in miRNA-related regions including primary and precursor miRNA sequences, seed sequence of miRNAs, miRNA processing genes and 3'-untranslated regions of target genes, which may function as regulatory SNPs to modify miRNA production as well as the target binding affinity and specificity (6). The first evidence that miRNA-related SNPs could affect disease susceptibility was provided by Abelson etal. who found that a variation in the miR-189-binding site of SLITRK1 was associated with Tourettes syndrome (7). It was estimated that around 10% of human precursor miRNAs have documented SNPs, less than 1% of miRNAs have SNPs in the functional seed region and 2.4% of the target genes are polymorphic in 3'-untranslated regions (8). Since a specific miRNA has the potential to regulate the expression of hundreds of target mRNAs, SNPs in miRNAs may produce more significant functional consequences and represent an ideal candidate for disease prediction. The first study that investigated the effect of genetic variation in miRNA genes on cancer susceptibility was conducted by Calin et al. (9), in which a germline mutation in pri-miR-16-1 was associated with low expression of miR-16-1 in familial chronic lymphocytic leukemia. Sine then, a number of studies were carried out to investigate the impact of miRNA SNPs on pathogenesis and susceptibility of malignant tumors. MiR-146a rs2910164 and miR-196a2 rs11614913 were the two most common studied miRNA polymorphisms (1014). MiR-146a rs2910164 polymorphism is located at position +60 relative to the first nucleotide of pre-miR-146a with a G to C change in the passenger strand, which results in a change from G:U pair to C:U mismatch in the stem structure of miR-146a precursor and a reduced production of mature miR-146a (11). Jazdzewski et al. (15) found that the MiR-146a rs2910164 CC genotype in pre-miR-146a was associated with decreased mature miR-146a expression and increased influenced report genes, including genes involved in the Toll-like receptor and cytokine signaling pathway. MiR-196a2 is composed of two different mature miRNAs (miR-196a-5P and miR-196a-3P) which are processed from the same stem-loop (16). The expression of 137 cancer-related transcripts could be significantly altered after introduction of pre-miR-196a. Rs11614913 locates in the mature sequence of miR-196a-3P and could lead to less efficient processing of the miRNA precursor to its mature form, as well as diminished capacity to regulate target genes. Hoffman etal. (17) found that miR-196a2 rs11614913 not only influences the production level of mature miR-196a, but also has a phenotypic effect on target gene expression, as a total of 684 transcripts altered expression following introduction of pre-miR-196a-C, and fewer than half that number were significantly altered after introduction of pre-miR-196a-T. In light of the biolog (...truncated)