MicroRNA Polymorphisms

Abstract

MicroRNAs (miRNAs) are evolutionarily conserved small noncoding ribonucleic acids (RNAs). Owing to their ability to orchestrate a vast majority of tissue‐specific genes in a cell, miRNAs are referred to as microsheriffs or the micromanagers of gene expression. Accumulating evidence now suggests that genetic variation or polymorphisms present in the miRNA pathway are associated with the prognosis and progression of diseases and drug responses and are emerging as powerful tools to study the biology of diseases. MicroRNA polymorphisms (miR‐polymorphisms) can be defined as polymorphisms (SNPs, chromosomal changes, epigenetic defects, mutations, alterations and variations) that may potentially interfere with miRNA‐mediated regulation of cellular functions and can be present not only in the miRNA target gene but also in pri‐, pre‐, mature‐miRNA sequences, in the genes involved in miRNA biogenesis and in miRNA cis‐regulatory elements (e.g. promoter). A polymorphism in mature miRNAs may affect expression of several genes and have serious consequences, whereas a polymorphism in miRNA target site may be more target and/or pathway specific. The discovery of the role of miRNA in drug resistance and miR‐polymorphisms to predict drug response has led to the development of a new field in biomedical science called miRNA pharmacogenomics, a study of the miRNAs and miR‐polymorphisms affecting expressions of drug target genes, to predict drug behaviour and to improve drug efficacy. Detection of miRNA‐polymorphisms can potentially improve diagnosis, treatment and prognosis in patients and has profound implications in the fields of pharmacogenomics and personalised medicine.

Key Concepts:

  • miRNAs can potentially orchestrate expression of multiple genes and pathways.

  • miRNA‐polymorphisms/‐variations/‐SNPs/‐mutations can interfere with miRNA function and affect gene expression and its detection holds promise in the field of miRNA pharmacogenomics, molecular epidemiology and for individualised medicine.

  • In a population, miR‐polymorphisms can be present either in a heterozygous or homozygous configuration, in the form of insertions, deletions, amplifications or chromosomal translocations, resulting in loss or gain of a miRNA site/function.

  • A cell with a variant miRNA may be naturally selected. For example, a variation that gives rise to high levels of an oncogenic miRNA will be favourably selected in cancer cells to impart a growth advantage.

  • miR‐polymorphisms can be classified into several categories affecting various steps of miRNA biogenesis, that is, transcription, processing, targeting and can be present not only in the miRNA target gene but also in the genes involved in miRNA biogenesis and in pri‐, pre‐ and mature‐miRNA sequences.

  • A polymorphism in a processed miRNA may affect expression of several genes and have serious consequences, whereas a polymorphism in a miRNA target site, in target mRNA, may be more target and/or pathway specific.

  • miRNAs and miR‐polymorphisms could be potential predictors of drug response in the clinic and may provide more accurate methods of determining appropriate drug dosages based on a patient's genetic makeup.

  • miR‐polymorphisms are associated with progression and prognosis of diseases such as cancer, neurological disorders, muscular hypertrophy, gastric mucosal atrophy, cardiovascular disease and Type II diabetes, etc.

  • miRNAs and miR‐polymorphisms are powerful tools to study disease progression and can be used in the clinic to predict drug response (or efficacy).

Keywords: microRNA polymorphisms; genetic variations; mutations; drug resistance; disease; diagnosis; prognosis; classification; individualised medicine; personalised medicine; genome medicine; epidemiology; epigenetics; miRSNP; pharmacogenomics

Figure 1.

miRNA polymorphisms are associated with disease progression and can be used to predict drug resistance/drug response.

Figure 2.

miRNA biogenesis and function; miRNA polymorphisms can affect various steps involved in miRNA biogenesis and function. Adapted with permission from Mishra and Bertino © Future Medicine Ltd.

Figure 3.

miRNA polymorphisms affecting miRNA function and their classification. Adapted with permission from Mishra and Bertino © Future Medicine Ltd.

Figure 4.

A model describing the mechanism of action of a miR‐polymorphism by using drug response as an example. Adapted with permission from Mishra and Bertino © Future Medicine Ltd.

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References

Abelson JF, Kwan KY, O'Roak BJ et al. (2005) Sequence variants in SLITRK1 are associated with Tourette's syndrome. Science 310: 317–320.

Adams BD, Furneaux H and White BA (2007) The micro‐ribonucleic acid (miRNA) miR‐206 targets the human estrogen receptor‐α (ERα) and represses ERα messenger RNA and protein expression in breast cancer cell lines. Molecular Endocrinology 21: 1132–1147.

Alt FW, Kellems RE, Bertino JR and Schimke RT (1978) Selective multiplication of dihydrofolate reductase genes in methotrexate‐resistant variants of cultured murine cells. Journal of Biological Chemistry 253(5): 1357–1370.

Arisawa T, Tahara T, Shibata T et al. (2007) A polymorphism of microRNA 27a genome region is associated with the development of gastric mucosal atrophy in Japanese male subjects. Digestive Diseases and Sciences 52: 1691–1697.

Baek D, Villen J, Shin C et al. (2008) The impact of microRNAs on protein output. Nature 455: 64–71.

Barnes MR, Deharo S, Grocock RJ, Brown JR and Sanseau P (2007) The micro RNA target paradigm: a fundamental and polymorphic control layer of cellular expression. Expert Opinion on Biological Therapy 7: 1387–1399.

Beetz C, Schule R, Deconinck T et al. (2008) REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain 131: 1078–1086.

Berezikov E, Guryev V, van de Belt J et al. (2005) Phylogenetic shadowing and computational identification of human microRNA genes. Cell 120: 21–24.

Bertino JR, Banerjee D and Mishra PJ (2007) Pharmacogenomics of microRNA: a miRSNP towards individualized therapy. Pharmacogenomics 8(12): 1625–1627.

Brendle A, Lei H, Brandt A et al. (2008) Polymorphisms in predicted microRNA binding sites in integrin genes and breast cancer: ITGB4 as prognostic marker. Carcinogenesis 29(7): 1394–1399.

Calin GA, Ferracin M, Cimmino A et al. (2005) A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. New England Journal of Medicine 353: 1793–1801.

Chen K and Rajewsky N (2006) Natural selection on human microRNA binding sites inferred from SNP data. Nature Genetics 38: 1452–1456.

Chen K, Song F, Calin G et al. (2008) Polymorphisms in microRNA targets: a gold mine for molecular epidemiology. Carcinogenesis 29(7): 1306–1311.

Clop A, Marcq F, Takeda H et al. (2006) A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nature Genetics 38: 813–818.

Collins FS, Green ED, Guttmacher AE and Guyer MS (2003) A vision for the future of genomics research. Nature 422(6934): 835–847.

Didiano D and Hobert O (2006) Perfect seed pairing is not a generally reliable predictor for miRNA‐target interactions. Nature Structural and Molecular Biology 13: 849–851.

Evans SC, Kourtidis A, Markham TS et al. (2007) MicroRNA target detection and analysis for genes related to breast cancer using MDL compress. EURASIP Journal on Bioinformatics and Systems Biology 2007: 43670.

Griffiths‐Jones S, Saini HK, van Dongen S and Enright AJ (2008) miRBase: tools for microRNA genomics. Nucleic Acids Research 36: D154–D158.

He H, Jazdzewski K, Li W et al. (2005) The role of microRNA genes in papillary thyroid carcinoma. Proceedings of the National Academy of Sciences of the USA 102: 19075–19080.

Hu Z, Chen J, Tian T et al. (2008a) Genetic variants of miRNA sequences and non‐small cell lung cancer survival. Journal of Clinical Investigation 118: 2600–2608.

Hu Z, Liang J, Wang Z et al. (2008b) Common genetic variants in pre‐microRNAs were associated with increased risk of breast cancer in Chinese women. Human Mutation 30(1): 79–84.

Jazdzewski K, Murray EL, Franssila K et al. (2008) Common SNP in pre‐miR‐146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proceedings of the National Academy of Sciences of the USA 105: 7269–7274.

Jensen KP, Covault J, Conner TS et al. (2009) A common polymorphism in serotonin receptor 1B mRNA moderates regulation by miR‐96 and associates with aggressive human behaviors. Molecular Psychiatry 14(4): 381–389.

Kapeller J, Houghton LA, Monnikes H et al. (2008) First evidence for an association of a functional variant in the microRNA‐510 target site of the serotonin receptor‐type 3E gene with diarrhea predominant irritable bowel syndrome. Human Molecular Genetics 17: 2967–2977.

Kertesz M, Iovino N, Unnerstall U, Gaul U and Segal E (2007) The role of site accessibility in microRNA target recognition. Nature Genetics 39: 1278–1284.

Lander ES (2011) Initial impact of the sequencing of the human genome. Nature 470(7333): 187–197.

Landi D, Gemignani F, Barale R and Landi S (2008a) A catalog of polymorphisms falling in microRNA‐binding regions of cancer genes. DNA and Cell Biology 27: 35–43.

Landi D, Gemignani F, Naccarati A et al. (2008b) Polymorphisms within micro‐RNA‐binding sites and risk of sporadic colorectal cancer. Carcinogenesis 29: 579–584.

Lee RC and Ambros V (2001) An extensive class of small RNAs in Caenorhabditis elegans. Science 294(5543): 862–864.

Lewis BP, Burge CB and Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15–20.

Lv K, Guo Y, Zhang Y et al. (2008) Allele‐specific targeting of hsa‐miR‐657 to human IGF2R creates a potential mechanism underlying the association of ACAA‐insertion/deletion polymorphism with type 2 diabetes. Biochemical and Biophysical Research Communications 374: 101–105.

Manolio TA, Brooks LD and Collins FS (2008) A HapMap harvest of insights into the genetics of common disease. Journal of Clinical Investigation 118: 1590–1605.

Martin MM, Buckenberger JA, Jiang J et al. (2007) The human angiotensin II type 1 receptor +1166 A/C polymorphism attenuates microRNA‐155 binding. Journal of Biological Chemistry 282: 24262–24269.

Mayr C, Hemann MT and Bartel DP (2007) Disrupting the pairing between let‐7 and HMGA2 enhances oncogenic transformation. Science 315: 1576–1579.

Mishra PJ, Banerjee D and Bertino J (2007b) A microRNA binding site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. AACR Meeting April 2007. Proceedings of the American Association for Cancer Research 48: 4516.

Mishra PJ and Bertino JR (2009) MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine. Pharmacogenomics 10(3): 399–416.

Mishra PJ, Humeniuk R, Mishra PJ et al. (2007a) A miR‐24 microRNA binding‐site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proceedings of the National Academy of Sciences of the USA 104(33): 13513–13518.

Mishra PJ and Merlino G (2009) MicroRNA reexpression as differentiation therapy in cancer. Journal of Clinical Investigation 119(8): 2119–2123.

Mishra PJ, Mishra PJ, Banerjee D and Bertino JR (2008) MiRSNPs or MiR‐polymorphisms, new players in microRNA mediated regulation of the cell: introducing microRNA pharmacogenomics. Cell Cycle 7: 853–858.

Mishra PJ, Song B, Mishra PJ et al. (2009) MiR‐24 tumor suppressor activity is regulated independent of p53 and through a target site polymorphism. PLoS ONE 4(12): e8445. doi:10.1371/journal.pone.0008445.

Mishra PJ (2009) MicroRNA polymorphisms: a giant leap towards personalized medicine. Peronalized Medicine 6(2): 119–125.

Mishra PJ (2012) The microRNA‐drug resistance connection: a new era of personalized medicine using noncoding RNA begins. Pharmacogenomics 13(12): 1321–1324.

Raveche ES, Salerno E, Scaglione BJ et al. (2007) Abnormal microRNA‐16 locus with synteny to human 13q14 linked to CLL in NZB mice. Blood 109: 5079–5086.

Rigoutsos I, Huynh T, Miranda K et al. (2006) Short blocks from the noncoding parts of the human genome have instances within nearly all known genes and relate to biological processes. Proceedings of the National Academy of Sciences of the USA 103: 6605–6610.

Saunders MA, Liang H and Li WH (2007) Human polymorphism at microRNAs and microRNA target sites. Proceedings of the National Academy of Sciences of the USA 104: 3300–3305.

Selbach M, Schwanhausser B, Thierfelder N et al. (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455: 58–63.

Sethupathy P, Borel C, Gagnebin M et al. (2007) Human microRNA‐155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3′ untranslated region: a mechanism for functional single‐nucleotide polymorphisms related to phenotypes. American Journal of Human Genetics 81: 405–413.

Tan Z, Randall G, Fan J et al. (2007) Allele‐specific targeting of microRNAs to HLA‐G and risk of asthma. American Journal of Human Genetics 81: 829–834.

Wang G, van der Walt JM, Mayhew G et al. (2008) Variation in the miRNA‐433 binding site of FGF20 confers risk for Parkinson disease by overexpression of α‐synuclein. American Journal of Human Genetics 82: 283–289.

Yang H, Dinney CP, Ye Y et al. (2008) Evaluation of genetic variants in microRNA‐related genes and risk of bladder cancer. Cancer Research 68: 2530–2537.

Zhao Y, Samal E and Srivastava D (2005) Serum response factor regulates a muscle‐specific microRNA that targets Hand2 during cardiogenesis. Nature 436: 214–220.

Zuchner S, Wang G, Tran‐Viet KN et al. (2006) Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. American Journal of Human Genetics 79: 365–369.

Further Reading

Ambros V (2008) The evolution of our thinking about microRNAs. Nature Medicine 14(10): 1036–1040.

Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136: 215–233.

Calin GA and Croce CM (2009) Chronic lymphocytic leukemia: interplay between noncoding RNAs and protein‐coding genes. Blood 114(23): 4761–4770.

Novina CD and Sharp PA (2004) The RNAi revolution. Nature 430(6996): 161–164.

Yanaihara N, Caplen N, Bowman E et al. (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9(3): 189–198.

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Mishra, Prasun J, and Humeniuk, Rita(Apr 2013) MicroRNA Polymorphisms. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022428]