Trends in Genetics

Trends in Genetics

Volume 24, Issue 10, October 2008, Pages 489-497
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Opinion
MicroRNA target site polymorphisms and human disease

https://doi.org/10.1016/j.tig.2008.07.004Get rights and content

MicroRNAs (miRNAs) are important regulators of eukaryotic gene expression. They have been implicated in a broad range of biological processes, and miRNA-related genetic alterations probably underlie more human diseases than currently appreciated. Several studies have identified genetic variants in miRNA target sites that are claimed to be associated with disorders ranging from Parkinson's disease to cancer. However, careful assessment of these studies indicates that very few provide a combination of rigorous genetic and functional evidence. We therefore suggest a set of concrete recommendations to guide future investigations. Specifically, we highlight the importance of unbiased association studies and follow-up functional experiments for providing a clearer picture of the extent to which microRNA target site variations are relevant in various human diseases.

Section snippets

Regulatory variants and human disease

Most complex diseases are caused by a combination of genetic risk variants and environmental factors. Although there are many different types of genetic variations, current state-of-the-art technology is most effective at identifying single nucleotide polymorphisms (SNPs), sites that differ by only one nucleotide among individuals in a population. Based on the expectation that many risk alleles for common diseases are likely to be themselves common, candidate gene(s) association studies (CGASs)

Putative disease-associated miRNA target SNPs

In the following, we review, in order of publication, each of the 11 studies that claim an association of a poly-miRTS with human disease, especially focusing on the specific biases and confounding factors. Table 2 provides a more detailed summary of the study designs.

Concluding remarks and future investigations of poly-miRTS in human disease

We suggest that there are three important aspects in analyzing the role of polymorphisms/mutations in miRNA target site (poly-miRTS) in a human disease: (i) functional: testing single nucleotide polymorphism (SNP)-mediated differential microRNA (miRNA) targeting, (ii) genetic: testing association of the SNP with a disease or quantitative trait and (iii) mechanistic: testing a mechanism by which the differential miRNA activity can lead to disease. Although the mechanistic component provides a

Acknowledgements

The authors thank Priya Rajasethupathy, Lori Bonnycastle, Sridhar Hannenhalli, Zissimos Mourelatos and three anonymous reviewers for helpful comments on the manuscript.

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