Aberrant allele frequencies of the SNPs located in microRNA target sites are potentially associated with human cancers

Abstract

MicroRNAs (miRNAs) are a class of noncoding small RNAs that regulate gene expression by base pairing with target mRNAs at the 3′-terminal untranslated regions (3′-UTRs), leading to mRNA cleavage or translational repression. Single-nucleotide polymorphisms (SNPs) located at miRNA-binding sites (miRNA-binding SNPs) are likely to affect the expression of the miRNA target and may contribute to the susceptibility of humans to common diseases. We herein performed a genome-wide analysis of SNPs located in the miRNA-binding sites of the 3′-UTR of various human genes. We found that miRNA-binding SNPs are negatively selected in respect to SNP distribution between the miRNA-binding ‘seed’ sequence and the entire 3′-UTR sequence. Furthermore, we comprehensively defined the expression of each miRNA-binding SNP in cancers versus normal tissues through mining EST databases. Interestingly, we found that some miRNA-binding SNPs exhibit significant different allele frequencies between the human cancer EST libraries and the dbSNP database. More importantly, using human cancer specimens against the dbSNP database for case-control association studies, we found that twelve miRNA-binding SNPs indeed display an aberrant allele frequency in human cancers. Hence, SNPs located in miRNA-binding sites affect miRNA target expression and function, and are potentially associated with cancers.

Genetic susceptibility of lung cancer associated with common variants in the 3′ untranslated regions of the adenosine triphosphate‐binding cassette B1 (ABCB1) and ABCC1 candidate transporter genes for carcinogen export

“…It also has been also reported that SNPs in miRNA-binding sites affect miRNA target expression and function and, thus, potentially are associated with cancer. 36 Although it remains to be determined whether the common variant of rs3842 in the 3 0 UTR of ABCB1 could affect gene regulation, the current case-control study indicates that this SNP may be associated with lung cancer through a possible miRNA-mediated mechanism.…”

MicroRNAs and Their Role in Progressive Kidney Diseases

“…Recently, SNPs that could affect response to miRs were noted in miR target site sequences (159,160). Correlations between miR polymorphisms and SNPs in miR target sites with risk of bladder and colorectal cancers were reported (161)(162)(163). Hence, examination of SNPs in miR-binding sites may also provide key insights into various human diseases.…”

The impact of microRNAs and alternative splicing in pharmacogenomics

“…30 For example, two groups have evaluated the presence of SNPs located in miRNA-binding sites of the 3 0 UTR of several genes and SNPs in the micro-RNA seed regions by genome-wide analyses. 54,55 Yu et al 54 were able to identify twelve miRNA binding SNPs that display an aberrant allele frequency in human cancers. Moreover, Saunders et al 55 were able to identify approximately 250 SNPs that create novel target sites for miRNAs in humans and may result in phenotypic differences.…”