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“An individual’s genetic inheritance of microRNA polymorphisms associated with disease progression, prognosis and treatment holds the key to create safer and more personalized drugs and can be a giant leap towards personalized medicine.”
Voltaire, one of the greatest French authors, once said:
“Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of whom they know nothing” .
Today, 200 years after Voltaire, we have learned a great deal about many drugs, disease and the human body, but still his words seem to challenge our scientific thinking to its very core when we think of personalized medicine. Although we are able to eradicate some epidemics and claim to have cures for many of the common infectious, mental, neoplastic and cardiovascular disorders, the limitations of our current medical approaches are evident in the form of poor response rates and adverse drug reactions (ADRs).
At present, most of the pharmaceutical companies follow a ‘one-size-fits-all’ approach in drug development. There is a lack of reliable and cost-effective ways to predict an individual’s response to a drug. Worldwide use of drugs has revealed that drug response can be as diverse as the genetic background of individuals. Moreover, a poor understanding of drug-resistance in patients might result in ADRs and sometimes death. ADRs have continued to be an important and growing public health concern in the USA and worldwide [1,2]. In 1988, the US FDA launched the Adverse Event Reporting System (AERS) and has taken some initiatives to facilitate the integration of pharmacogenomics into drug development and clinical practice [3,102]. Because ‘one drug does not fit all’ we need to invest in developing a tailor-made, individualized, medicinal approach. Recently, we have learned that interindividual differences in microRNA (miRNA) regulatory pathways can influence drug response .
MiRNA-polymorphisms (miR-polymorphisms or miRSNPs) are a novel class of functional polymorphisms present in the human genome [4-6]. MiR-polymorphisms have been shown to influence drug response by affecting the expression of drug target genes and have been associated with many diseases such as cancer, neurological disorders and cardiovascular disorders (FIGURE 1; reviewed in [7-9]). A personalized medicinal approach using miR-polymorphisms affecting drug response among geographically and ethnically distinct individuals may hold the key to limiting ADRs in patients.
MiR-polymorphisms are a boon of the ongoing miRNA revolution. Thanks to the Human Genome Project, we now know that what was once considered as ‘junk DNA’, encodes evolutionary conserved miRNAs – the micromanagers of gene expression . Essential for cellular and organism development, and predicted to regulate more than a third of the human genome, miRNAs are small, 21–23 nucleotide-long, independent, functional units of noncoding RNAs [11-14]. By binding to the 3′-untranslated region (UTR) of a target gene, miRNAs regulate gene expression either by inhibiting the translation of proteins and/or by destabilizing their target mRNAs [4,15,16]. To date, only 678 human miRNAs are known to exist, which may be only a fraction of the total in silico predictions; the total number may approach thousands or tens of thousands [17-19]. Gain or loss of miRNA function is associated with disease progression and prognosis (reviewed in ). Located within fragile genomic regions, miRNA genes are often deregulated in many cancers , such as papillary thyroid carcinoma , chronic lymphocytic leukemia [22,23] and breast cancer . MiRNAs can potentially regulate the expression of multiple genes and pathways, are associated with disease progression and can be used in the clinic to predict drug prognosis.
Other than miRNAs, the Human Genome Project also revealed the presence of millions of polymorphisms in both coding and noncoding regions. Some of these polymorphisms are found to be present in miRNA genes and in the UTRs of the target genes where a miRNA binds . Recent genome-wide analysis (GWA) studies of human SNPs have revealed: that several polymorphisms are present in the miRNA binding sites ; noncoding variations in the regulatory sites are more likely to be associated with disease than the coding region variations [26,27]; and there is a possibility that disease-associated variations may also interfere with functions of miRNAs . This suggests that noncoding regions may be a hotspot for pathology, and harbor individual differences which may be exploited for tailor-made therapy.
MiR-polymorphisms have been shown to affect drug response and have the potential to confer drug resistance . Recently, it was demonstrated that a C to T SNP, identified in a case–control study of childhood leukemia patients, occuring with 14.2% allelic frequency in the Japanese population, is present near the miR-24 binding site in the 3′-UTR of the dihydrofolate reductase (DHFR) gene . The T allele of the SNP results in loss of miR-24-mediated regulation of DHFR, high DHFR protein levels and confers methotrexate resistance [4,5]. This finding may also be useful in predicting the clinical outcome of methotrexate treatment [3-7]. The discovery of miR-polymorphisms has introduced ‘miRNA–pharmacogenomics’, a novel field that holds great promise for tailor-made personalized medicine. MiRNA–pharmacogenomics is the study of polymorphisms present in the miRNA regulatory pathway and its association with drug response to improve drug efficiency [3,6]. MiRNA–pharmacogenomics combines our knowledge in the fields of miRNA, pharmacology and genomics, to study how each individual’s own genetic inheritance of miR-polymorphisms can affect the body’s response to drugs, which has strong clinical implications.
Like a miRNA, a miR-polymorphism can also potentially affect expression of multiple miRNA target genes and pathways by affecting miRNA function. MiR-polymorphisms act as a double-edged sword. By creating or destroying a miRNA binding site within a target mRNA, miR-polymorphisms can result in a gain or loss of a miRNA function [3,4,6]. Evident from the relatively high number of miR-polymorphisms at the 3′-UTRs of target genes , a variant miRNA may be naturally selected . Primarily, a miRNA consists of two regions, the 5′-region of a miRNA from positions 2–7 called the ‘seed’ region, and the 3′-mismatch tolerant region (hereafter referred to as 3′-MTR) . The seed region is thought to confer much of the target recognition specificity and is predicted to have less than a 1% likelihood of a polymorphism . Unlike the 5′-seed region, the 3′-MTR is able to tolerate mismatches. Although miRNA seed region variations seem to be rare, they have the potential to affect the expression and function of the miRNA itself, and can influence expression of hundreds of genes and related pathways.
In a recent review, based on the current information within the miRNA field, we have proposed a classifi cation of miR-polymorphisms (see ). There are several types of miR-polymorphisms that can exist in a cell. Polymorphisms affecting various steps of miRNA biogenesis, such as miRNA transcription, processing, export and targeting can potentially affect global biogenesis of all miRNAs with severe consequences. Polymorphisms present in pri-, pre- and mature-miRNA can potentially influence expression of hundreds of genes and pathways, broadly affecting miRNA function. Unlike polymorphisms affecting miRNA-biogenesis, miRNA target site polymorphisms have a more specific effect and are more abundant (reviewed in ).
MiRNA-polymorphisms were recently found to be associated with progression and prognosis of different types of cancers. Identified in some patients with familial chronic lymphocytic leukemia (CLL), a C to T polymorphism in the primary transcript of miR-15a/miR-16 was found to be associated with reduced expression of miR-15 and miR-16 [30,31]. Since 70% of CLL cases express low levels of miR-15a/miR-16, the C to T miR-polymorphism may have implications in leukemogenesis [30-33]. In individuals with non-small-cell lung cancer (NSCLC), a significant decrease in survival was recently observed in patients that were homozygous (CC) for a pre-miR-196a2 SNP (rs11614913), suggesting that the miRSNP rs11614913 could be a prognostic marker for NSCLC . More recently, a study identified rs11614913 (T to C), along with a miRSNP A to G (rs3746444) in miR-499, as being significantly associated with an increased susceptibility to breast cancer . Also, a miRSNP C to T (rs93410170) in the 3′-UTR of estrogen receptor-α (ER-α), was found to influence miR-206-mediated regulation of ER-α, and was implicated in breast cancer . An integrin, β-4 SNP, was suggested to influence breast tumor aggressiveness and survival . A chromosomal translocation associated with human tumors, was shown to disrupt the let-7 miRNA-mediated regulation of High Mobility Group A2, and resulted in oncogenic transformation .
“MiRNA–pharmacogenomics combines our knowledge in the fields of miRNA, pharmacology and genomics, to study how each person’s own genetic inheritance of miR-polymorphisms can affect the body’s response to drugs, which has strong clinical implicaons.”
Approximately 4.7% of papillary thyroid carcinoma (PTC) tumors have been shown to acquire a somatic mutation of rs2910164, a G/C pre-miR-146a. By affecting miR-146 expression, somatic mutation rs2910164 has been shown to be associated with the genetic predisposition to PTC . Two miR-polymorphisms in the miR-221/222 and miR-146a/146b miRNA binding sites of the KIT gene were found to be associated with deregulated expression of the KIT protein, contributing to PTC . Epidemiological data suggests an association of miRNA-related genetic variants to the risk of developing bladder cancer  and sporadic colorectal cancer . In the 3′-UTR of the cluster of the differentiation 86 (CD86) genes, a C to G polymorphism (rs17281995), predicted to affect the binding of five miRNAs (miR-337, miR-582, miR-200a, miR-184 and miR-212), was significantly associated with colorectal cancer. The study also identified rs1051690 within the insulin receptor, as predicted, to affect miR-618 and miR-612 .
MiR-polymorphisms are associated with some neurological disorders. A var321-SLITRK1 miR-polymorphism that strengthens an existing miR-189 target site in the 3′-UTR of the human Slit and Trk-like-1 (SLITRK1) gene was implicated in Tourette syndrome (TS) and attention deficit hyperactivity disorder. The reduced levels of SLITRK1 protein (required at high levels in the human brain for normal neurite growth) due to the miR-polymorphism might be associated with TS . Implicated in hereditary spastic paraplegia patients, three different polymorphisms present in the 3′-UTR of receptor expression-enhancing protein 1 (REEP1) were identified in silico [43,44]. An A to G polymorphism (rs13212041) affects miR-96-mediated regulation of the 5-hydroxy-tryptamine (serotonin) receptor 1B (HTR1B) protein. Since deletion or down-regulation of the HTR1B gene in mice results in aggressive behavior, individuals with ancestral A alleles exhibited more conduct-disorder behaviors than individuals with the allele G . The polymorphism rs12720208 in the 3′-UTR of fibroblast growth factor 20 (FGF20) is identified as a risk factor for Parkinson’s disease (PD). The PD-risk-allele for rs12720208 disrupts a binding site for miR-433, resulting in increased expression of FGF20, which is a risk factor for PD . A 1166A to C miR-polymorphism (rs5186) results in abrogation of miR-155-mediated regulation and overexpression of the angiotensin receptor 1 (AGTR1) gene. Since AGTR1 overexpression results in hypertension, the miRSNP was implicated in hypertension and cardiovascular disease [47,48].
MiR-polymorphisms are shown to be associated with other diseases such as diarrhea, predominant irritable bowel syndrome (IBS-D), gastric mucosal atrophy and Type 2 diabetes. A miRSNP rs62625044 G>A was shown to affect the binding of miR-510 to the serotonin receptor Type 3 subunit gene HTR3A 3′-UTR, resulting in higher expression of the receptor subunit. Identified in a case–control study, rs62625044 has a strong association with female IBS-D . A polymorphism of the miRNA 27 genome region was found to be associated with the development of gastric mucosal atrophy in Japanese male subjects . Recently, it was demonstrated that a Type 2 diabetes-associated ACAA-insertion/deletion polymorphism is a miR-polymorphism that results in the loss of miR-657-mediated regulation of human insulin-like growth factor 2 receptor (IGF2R) . Hence, a polymorphic difference in the inherited DNA sequence of individuals that affects function of a miRNA can have a profound effect and is responsible for disease progression, prognosis and can affect drug response.
“MiR-polymorphisms are emerging as a powerful tool for studying the biology of disease and will aid in its diagnosis and prognosis.”
Although we have identified and validated some key miR-polymorphisms in the past 2 years, many more still need to be identified and characterized. As great acts are often made up of small deeds , identification and validation of miR-polymorphisms associated with human disease will revolutionalize the field of personalized medicine. With recent advances in human genome research, this might not be a difficult task. Due to its affordability, more families are now interested in the genome sequencing of a child either at its birth or later in life. In May 2008, the US Congress passed the US Genetic Information and Nondiscrimination Act to legally protect the misuse of an individual’s genetic information [104,105]. This is one more positive step towards personalized medicine whose need is absolute and urgent to prevent ADRs. Approximately 2.2 million hospitalized patients suffered from ADRs and 106,000 deaths were reported yearly . Identifying and characterizing disease-specific miR-polymorphisms may be one more step towards avoiding ADRs.
In conclusion, by affecting miRNA function, miR-polymorphisms can affect the expression of hundreds of genes and related pathways in a cell. MiR-polymorphisms are emerging as a powerful tool for studying the biology of disease and will aid in its diagnosis and prognosis. MiRNA–pharmacogenomics, with the knowledge of functional miR-polymorphisms, may provide a better understanding of pharmacological responses to a drug and will revolutionize drug discovery and the developmental process. A better understanding of the role of miR-polymorphism in drug response will allow the development of a more personalized and/or a population-specific treatment, providing greater degrees of success. Hence, an individual’s genetic inheritance of miR-polymorphisms associated with disease progression, prognosis and treatment holds the key to create safer and more personalized drugs, and can be a giant leap towards personalized medicine.
The author thanks Dr Glenn Merlino, Laboratory of Cancer Biology and Genetics, and Dr Rita Humeniuk, Laboratory of Cellular Oncology, at the National Cancer Institute, NIH for the critical review of the manuscript.
Prasun J Mishra
Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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