Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

The impact of microRNAs and alternative splicing in pharmacogenomics

The Pharmacogenomics Journal volume 9, pages 1–13 (2009)Cite this article

Pharmacogenomic studies emphasize the use of genomic information to enhance success in finding new medicines and also to improve those that are already used in clinics. Therefore, this field has a special interest in knowing how patients metabolize drugs depending on their genetic background. Most of the studies so far have focused on the impact of single genetic differences on drug metabolism. However, this may be only the tip of the iceberg in terms of how interpatient variability can influence the response to drugs. For example, control of gene expression by microRNAs (miRNAs) and alternative splicing are cellular mechanisms that have an effect on proteome diversity and have already been implicated in complex diseases such as cancer, arthritis and others. Changes in the sequence of a miRNA and/or variations in the miRNA target region of a transcript can have a major impact on post-transcriptional regulation. Events of alternative splicing can occur in more than half of the human genes, thereby changing the sequence of key proteins related to drug resistance, activation and metabolism. Furthermore, alternative splicing and miRNAs can work together to differentially control genes. This perspective article will highlight recent exciting discoveries in pharmacogenomics and also discuss how players such as miRNAs and alternative splicing may affect the way we design and apply future therapies.

The improvement of patient treatment is always a concern for modern medicine. One aspect that can influence the effectiveness of therapies in patients during drug-based treatment is the genetic background. One of the major challenges for proper drug development by companies is the difference in response between individuals and between populations. The idea that genetic variability between patients might influence response to drugs was described and termed ‘pharmacogenetics’ by Vogel.1 Pharmacogenetics became a field of importance for scientists and physicians in the early 1950s, when available technologies were able to measure enzyme activity, drug metabolites and drug response (for a timeline review of the pharmacogenetic history see2). Since then, the number of cases described in the literature has increased exponentially and they were mainly focused on single-nucleotide polymorphism (SNP), insertions and deletions (indels) of nucleotides, copy number variation (CNV) and missense mutations (for review see Roses3 and Giacomini et al.4).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

References

  1. Vogel F . Moderne probleme der humangenetik. Ergebnisse Inneren Medizin und Keinderheilkunde 1959; 12: 52–125.

    Google Scholar 

  2. Meyer UA . Pharmacogenetics—five decades of therapeutic lessons from genetic diversity. Nat Rev Genet 2004; 5: 669–676.

    Article  CAS  PubMed  Google Scholar 

  3. Roses AD . Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Discov 2002; 1: 541–549.

    Article  CAS  PubMed  Google Scholar 

  4. Giacomini KM, Brett CM, Altman RB, Benowitz NL, Dolan ME, Flockhart DA et al. Pharmacogenetics Research Network. The pharmacogenetics research network: from SNP discovery to clinical drug response. Clin Pharmacol Ther 2007; 81: 328–345.

    Article  CAS  PubMed  Google Scholar 

  5. Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C . Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 2007; 116: 496–526.

    Article  CAS  PubMed  Google Scholar 

  6. Gardiner SJ, Begg EJ . Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev 2006; 58: 521–590.

    Article  CAS  PubMed  Google Scholar 

  7. Chauhan N, Padh SR . Pharmacogenetics: genetic basis for rational drug therapy. Indian J Pharm Sci 2007; 69: 180–189.

    Article  CAS  Google Scholar 

  8. Rodriguez-Antona C, Ingelman-Sundberg M . Cytochrome P450 pharmacogenetics and cancer. Oncogene 2006; 25: 1679–1691.

    Article  CAS  PubMed  Google Scholar 

  9. Oner Ozgon G, Langaee TY, Feng H, Buyru N, Ulutin T, Hatemi AC . VKORC and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients. Eur J Clin Pharmacol 2008; 64: 889–894.

    Article  CAS  PubMed  Google Scholar 

  10. Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 2005; 5: 262–270.

    Article  CAS  PubMed  Google Scholar 

  11. International HapMap consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 2007; 449: 851–861.

    Article  CAS  Google Scholar 

  12. Chen Y, Zhu J, Lum PY, Yang X, Pinto S, MacNeil DJ et al. Variations in DNA elucidate molecular networks that cause disease. Nature 2008; 452: 429–435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bertino JR, Banerjee D, Mishra PJ . Pharmacogenomics of microRNA: a miRSNP towards individualized therapy. Pharmacogenomics 2007; 12: 1625–1627.

    Article  Google Scholar 

  14. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J et al. Initial sequencing and analysis of the human genome. Nature 2001; 409: 860–921.

    Article  CAS  PubMed  Google Scholar 

  15. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG et al. The sequence of the human genome. Science 2001; 291: 1304–1351.

    Article  CAS  PubMed  Google Scholar 

  16. Kidd JM, Cooper GM, Donahue WF, Hayden HS, Sampas N, Graves T et al. Mapping and sequencing of structural variation from eight human genomes. Nature 2008; 453: 56–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. ENCODE Project Consortium et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007; 447: 799–816.

    Article  CAS  Google Scholar 

  18. Costa FF . Non-coding RNAs: new players in eukaryotic biology. Gene 2005; 2: 83–94.

    Article  CAS  Google Scholar 

  19. Costa FF . Non-coding RNAs: lost in translation? Gene 2007; 1-2: 1–10.

    Google Scholar 

  20. Costa FF . Non-coding RNAs, epigenetics and complexity. Gene 2008; 1: 9–17.

    Article  CAS  Google Scholar 

  21. Bartel D . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 2: 281–297.

    Article  Google Scholar 

  22. Calin GA, Liu CG, Ferracin M, Hyslop T, Spizzo R, Sevignani C et al. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell 2007; 3: 215–229.

    Article  CAS  Google Scholar 

  23. Hobert O . Gene regulation by transcription factors and microRNAs. Science 2008; 319: 1785–1786.

    Article  CAS  PubMed  Google Scholar 

  24. Gartel AL, Kandel ES . miRNAs: little known mediators of oncogenesis. Semin Cancer Biol 2008; 18: 103–110.

    Article  CAS  PubMed  Google Scholar 

  25. Clark TA, Schweitzer AC, Chen TX, Staples MK, Lu G, Wang H et al. Discovery of tissue-specific exons using comprehensive human exon microarrays. Genome Biol 2007; 8: R64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tress ML, Martelli PL, Frankish A, Reeves GA, Wesselink JJ, Yeats C . The implications of alternative splicing in the ENCODE protein complement. Proc Natl Acad Sci USA 2007; 104: 5495–5500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Romero PR, Zaidi S, Fang YY, Uversky VN, Radivojac P, Oldfield CJ et al. Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc Natl Acad Sci USA 2006; 103: 8390–8395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang G, van der Walt JM, Mayhew G, Li YJ, Züchner S, Scott WK et al. Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. Am J Hum Genet 2008; 82: 283–289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR, de la Chapelle A . Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci USA 2008; 105: 7269–7274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Georges M, Clop A, Marcq F, Takeda H, Pirottin D, Hiard S et al. SNPs can affect the way miRNAs regulate their targets pointing to a function in drug metabolism and in phenotypic variation. Cold Spring Harb Symp Quant Biol 2006; 71: 343–350.

    Article  CAS  PubMed  Google Scholar 

  31. Akgul C, Moulding DA, Edwards SW . Alternative splicing of Bcl-2-related genes: functional consequences and potential therapeutic applications. Cell Mol Life Sci 2004; 61: 2189–2199.

    Article  CAS  PubMed  Google Scholar 

  32. Eulalio A, Huntzinger E, Izaurralde E . Getting to the root of miRNA-mediated gene silencing. Cell 2008; 132: 9–14.

    Article  CAS  PubMed  Google Scholar 

  33. Lee RC, Feinbaum RL, Ambros V . The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843–854.

    Article  CAS  PubMed  Google Scholar 

  34. Rajewsky N . microRNA target predictions in animals. Nat Genet 2006; 38 (Suppl): S8–13.

    Article  CAS  PubMed  Google Scholar 

  35. Filipowicz W, Bhattacharyya SN, Sonenberg N . Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 2008; 9: 102–114.

    Article  CAS  PubMed  Google Scholar 

  36. Bartel D . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281–297.

    Article  CAS  PubMed  Google Scholar 

  37. Wurdinger T, Costa FF . Molecular therapy in the microRNA era. Pharmacogenomics J 2007; 7: 297–304.

    Article  CAS  PubMed  Google Scholar 

  38. Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 2006; 3: 87–98.

    Article  CAS  PubMed  Google Scholar 

  39. Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 2004; 432: 226–230.

    Article  CAS  PubMed  Google Scholar 

  40. Hansen T, Olsen L, Lindow M, Jakobsen KD, Ullum H, Jonsson E et al. Brain expressed microRNAs implicated in schizophrenia etiology. PLoS ONE 2007; 2: e873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Garzon R, Fabbri M, Cimmino A, Calin GA, Croce CM . MicroRNA expression and function in cancer. Trends Mol Med 2006; 12: 580–587.

    Article  CAS  PubMed  Google Scholar 

  42. Mayr C, Hemann MT, Bartel DP . Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 2007; 315: 1576–1579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y et al. A microRNA component of the p53 tumour suppressor network. Nature 2007; 447: 1130–1134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ma L, Teruya-Feldstein J, Weinberg RA . Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 2007; 449 (7163): 682–688.

    Article  CAS  PubMed  Google Scholar 

  45. Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 2008; 451: 147–152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 2008; 299: 425–436.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Yu SL, Chen HY, Chang GC, Chen CY, Chen HW, Singh S et al. MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 2008; 13: 48–57.

    Article  CAS  PubMed  Google Scholar 

  48. Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 2006; 9: 435–443.

    Article  CAS  PubMed  Google Scholar 

  49. Brueckner B, Stresemann C, Kuner R, Mund C, Musch T, Meister M et al. The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res 2007; 67: 1419–1423.

    Article  CAS  PubMed  Google Scholar 

  50. Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008; 452: 633–637.

    Article  CAS  PubMed  Google Scholar 

  51. Carlson CS, Eberle MA, Kruglyak L, Nickerson DA . Mapping complex disease loci in whole-genome association studies. Nature 2004; 429: 446–452.

    Article  CAS  PubMed  Google Scholar 

  52. Dunckley T, Huentelman MJ, Craig DW, Pearson JV, Szelinger S, Joshipura K et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med 2007; 357: 775–788.

    Article  CAS  PubMed  Google Scholar 

  53. Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M et al. A whole-genome association study of major determinants for host control of HIV-1. Science 2007; 317: 944–947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yu Z, Li Z, Jolicoeur N, Zhang L, Fortin Y, Wang E et al. Aberrant allele frequencies of the SNPs located in microRNA target sites are potentially associated with human cancers. Nucleic Acids Res 2007; 35: 4535–4541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Saunders MA, Liang H, Li WH . Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci USA 2007; 104: 3300–3305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wu M, Jolicoeur N, Li Z, Zhang L, Fortin Y, Denis L et al. Genetic variations of microRNAs in human cancer and their effects on the expression of miRNAs. Carcinogenesis 2008; 29: 1710–1716.

    Article  CAS  PubMed  Google Scholar 

  57. Yang H, Dinney CP, Ye Y, Zhu Y, Grossman HB, Wu X . Evaluation of genetic variants in microRNA-related genes and risk of bladder cancer. Cancer Res 2008; 68: 2530–2537.

    Article  CAS  PubMed  Google Scholar 

  58. Brendle A, Lei H, Brandt A, Johansson R, Enquist K, Henriksson R . Polymorphisms in predicted microRNA binding sites in integrin genes and breast cancer: ITGB4 as prognostic marker. Carcinogenesis 2008; 29: 1394–1399.

    Article  CAS  PubMed  Google Scholar 

  59. Landi D, Gemignani F, Naccarati A, Pardini B, Vodicka P, Vodickova L . Polymorphisms within micro-RNA-binding sites and risk of sporadic colorectal cancer. Carcinogenesis 2008; 29: 579–584.

    Article  CAS  PubMed  Google Scholar 

  60. Hu Z, Chen J, Tian T, Zhou X, Gu H, Xu L . Genetic variants of miRNA sequences and non-small cell lung cancer survival. J Clin Invest 2008; 118: 2600–2608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sethupathy P, Borel C, Gagnebin M, Grant GR, Deutsch S, Elton TS et al. 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. Am J Hum Genet 2007; 81: 405–413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tan Z, Randall G, Fan J, Camoretti-Mercado B, Brockman-Schneider R, Pan L et al. Allele-specific targeting of microRNAs to HLA-G and risk of asthma. Am J Hum Genet 2007; 81: 829–834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Martin MM, Buckenberger JA, Jiang J, Malana GE, Nuovo GJ, Chotani M et al. The human angiotensin II type 1 receptor +1166 A/C polymorphism attenuates microrna-155 binding. J Biol Chem 2007; 282: 24262–24269.

    Article  CAS  PubMed  Google Scholar 

  64. Mishra PJ, Humeniuk R, Mishra PJ, Longo-Sorbello GS, Banerjee D, Bertino JR . A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc Natl Acad Sci USA 2007; 104: 13513–13518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lal A, Kim HH, Abdelmohsen K, Kuwano Y, Pullmann Jr R, Srikantan S et al. p16(INK4a) translation suppressed by miR-24.PLoS ONE. 2008; 3: e1864.

  66. Wang Q, Huang Z, Xue H, Jin C, Ju XL, Han JD et al. MicroRNA miR-24 inhibits erythropoiesis by targeting activin type I receptor ALK4. Blood 2008; 111: 588–595.

    Article  CAS  PubMed  Google Scholar 

  67. Sun Q, Zhang Y, Yang G, Chen X, Zhang Y, Cao G et al. Transforming growth factor-beta-regulated miR-24 promotes skeletal muscle differentiation. Nucleic Acids Res 2008; 36: 2690–2699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Duan R, Pak C, Jin P . Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet 2007; 16: 1124–1131.

    Article  CAS  PubMed  Google Scholar 

  69. Bao L, Zhou M, Wu L, Lu L, Goldowitz D, Williams RW et al. PolymiRTS Database: linking polymorphisms in microRNA target sites with complex traits. Nucleic Acids Res 2007; 35 (Database issue): D51–D54.

    Article  CAS  PubMed  Google Scholar 

  70. Gilbert W . Why genes in pieces? Nature 1978; 271: 501.

    Article  CAS  PubMed  Google Scholar 

  71. Smith CW, Valcárcel J . Alternative pre-mRNA splicing: the logic of combinatorial control. Trends Biochem Sci 2000; 25: 381–388.

    Article  CAS  PubMed  Google Scholar 

  72. Valadkhan S . The spliceosome: caught in a web of shifting interactions. Curr Opin Struct Biol 2007; 17: 310–315.

    Article  CAS  PubMed  Google Scholar 

  73. House AE, Lynch KW . Regulation of alternative splicing: more than just the ABCs. J Biol Chem 2008; 283: 1217–1221.

    Article  CAS  PubMed  Google Scholar 

  74. Sampath J, Long PR, Shepard RL, Xia X, Devanarayan V, Sandusky GE et al. Human SPF45, a splicing factor, has limited expression in normal tissues, is overexpressed in many tumors, and can confer a multidrug-resistant phenotype to cells. Am J Pathol 2003; 163: 1781–1790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Perry III WL, Shepard RL, Sampath J, Yaden B, Chin WW, Iversen PW et al. Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed—a phenotype partially reversed by selective estrogen receptor modulators. Cancer Res 2005; 65: 6593–6600.

    Article  CAS  PubMed  Google Scholar 

  76. Black DL . Protein diversity from alternative splicing: a challenge for bioinformatics and post-genome biology. Cell 2000; 103: 367–370.

    Article  CAS  PubMed  Google Scholar 

  77. Kim E, Magen A, Ast G . Different levels of alternative splicing among eukaryotes. Nucleic Acids Res 2007; 35: 125–131.

    Article  CAS  PubMed  Google Scholar 

  78. Wang GS, Cooper TA . Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 2007; 8: 749–761.

    Article  CAS  PubMed  Google Scholar 

  79. Skotheim RI, Nees M . Alternative splicing in cancer: noise, functional, or systematic? Int J Biochem Cell Biol 2007; 39: 1432–1449.

    Article  CAS  PubMed  Google Scholar 

  80. Thorsen K, Sørensen KD, Brems-Eskildsen AS, Modin C, Gaustadnes M, Hein AM et al. Alternative splicing in colon, bladder, and prostate cancer identified by exon-array analysis. Mol Cell Proteomics 2008; 7: 1214–1224.

    Article  CAS  PubMed  Google Scholar 

  81. Ben-Dov C, Hartmann B, Lundgren J, Valcárcel J . Genome-wide analysis of alternative pre-mRNA splicing. J Biol Chem 2008; 283: 1229–1233.

    Article  CAS  PubMed  Google Scholar 

  82. Schmucker D, Clemens JC, Shu H, Worby CA, Xiao J, Muda M et al. Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 2000; 101: 671–684.

    Article  CAS  PubMed  Google Scholar 

  83. Schmucker D . Molecular diversity of Dscam: recognition of molecular identity in neuronal wiring. Nat Rev Neurosci 2007; 8: 915–920.

    Article  CAS  PubMed  Google Scholar 

  84. Hummel T, Vasconcelos ML, Clemens JC, Fishilevich Y, Vosshall LB, Zipursky SL . Axonal targeting of olfactory receptor neurons in Drosophila is controlled by Dscam. Neuron 2003; 37: 221–231.

    Article  CAS  PubMed  Google Scholar 

  85. Kim N, Alekseyenko AV, Roy M, Lee C . The ASAP II database: analysis and comparative genomics of alternative splicing in 15 animal species. Nucleic Acids Res 2007; 35 (Database issue): D93–D98.

    Article  CAS  PubMed  Google Scholar 

  86. Lee Y, Lee Y, Kim B, Shin Y, Nam S, Kim P et al. ECgene: an alternative splicing database update. Nucleic Acids Res 2007; 35 (Database issue): D99–D103.

    Article  CAS  PubMed  Google Scholar 

  87. Holste D, Huo G, Tung V, Burge CB . HOLLYWOOD: a comparative relational database of alternative splicing. Nucleic Acids Res 2006; 34 (Database issue): D56–D62.

    Article  CAS  PubMed  Google Scholar 

  88. Dahmcke CM, Büchmann-Møller S, Jensen NA, Mitchelmore C . Altered splicing in exon 8 of the DNA replication factor CIZ1 affects subnuclear distribution and is associated with Alzheimer's disease. Mol Cell Neurosci 2008; 38: 589–594.

    Article  CAS  PubMed  Google Scholar 

  89. Ariyoshi N, Shimizu Y, Kobayashi Y, Nakamura H, Nakasa H, Nakazawa K . Identification and partial characterization of a novel CYP2C9 splicing variant encoding a protein lacking eight amino acid residues. Drug Metab Pharmacokinet 2007; 22: 187–194.

    Article  CAS  PubMed  Google Scholar 

  90. Zhu-Ge J, Yu YN . Enzyme activity analysis of CYP2C18 with exon 5 skipped. Acta Pharmacol Sin 2004; 25: 1065–1069.

    PubMed  Google Scholar 

  91. Ibeanu GC, Blaisdell J, Ferguson RJ, Ghanayem BI, Brosen K, Benhamou S et al. A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin. J Pharmacol Exp Ther 1999; 290: 635–640.

    CAS  PubMed  Google Scholar 

  92. Roh HK, Dahl ML, Tybring G, Yamada H, Cha YN, Bertilsson L . CYP2C19 genotype and phenotype determined by omeprazole in a Korean population. Pharmacogenetics 1996; 6: 547–551.

    Article  CAS  PubMed  Google Scholar 

  93. Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukaemia in mice by the P210 bcr/abl gene of the Philadelphia chromosome. Science 1990; 247: 824–830.

    Article  CAS  PubMed  Google Scholar 

  94. Faderl S, Kantarjian HM, Thomas DA, Cortes J, Giles F, Pierce S et al. Outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Leuk Lymphoma 2000; 36: 263–273.

    Article  CAS  PubMed  Google Scholar 

  95. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl JMed 2001; 344: 1031–1037.

    Article  CAS  Google Scholar 

  96. Gruber FX, Hjorth-Hansen H, Mikkola I, Stenke L, Johansen T . A novel Bcr-Abl splice isoform is associated with the L248V mutation in CML patients with acquired resistance to imatinib. Leukemia 2006; 20: 2057–2060.

    Article  CAS  PubMed  Google Scholar 

  97. Lewis-Tuffin LJ, Cidlowski JA . The physiology of human glucocorticoid receptor beta (hGRbeta) and glucocorticoid resistance. Ann NY Acad Sci 2006; 1069: 1–9.

    Article  CAS  PubMed  Google Scholar 

  98. Piotrowski P, Burzynski M, Lianeri M, Mostowska M, Wudarski M, Chwalinska-Sadowska H . Glucocorticoid receptor beta splice variant expression in patients with high and low activity of systemic lupus erythematosus. Folia Histochem Cytobiol 2007; 45: 339–342.

    CAS  PubMed  Google Scholar 

  99. Hamilos DL, Leung DY, Muro S, Kahn AM, Hamilos SS, Thawley SE et al. GRbeta expression in nasal polyp inflammatory cells and its relationship to the anti-inflammatory effects of intranasal fluticasone. J Allergy Clin Immunol 2001; 108: 59–68.

    Article  CAS  PubMed  Google Scholar 

  100. Towers R, Naftali T, Gabay G, Carlebach M, Klein A, Novis B . High levels of glucocorticoid receptors in patients with active Crohn's disease may predict steroid resistance. Clin Exp Immunol 2005; 141: 357–362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Masui H, Kawamoto T, Sato JD, Wolf B, Sato G, Mendelsohn J . Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 1984; 44: 1002–1007.

    CAS  PubMed  Google Scholar 

  102. Mendelsohn J . Anti-EGF receptor monoclonal antibodies: biological studies and potential clinical applications. Trans Am Clin Climatol Assoc 1989; 100: 31–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Kowalski ML, Borowiec M, Kurowski M, Pawliczak R . Alternative splicing of cyclooxygenase-1 gene: altered expression in leucocytes from patients with bronchial asthma and association with aspirin-induced 15-HETE release. Allergy 2007; 62: 628–634.

    Article  CAS  PubMed  Google Scholar 

  104. Censarek P, Freidel K, Hohlfeld T, Schrör K, Weber AA . Human cyclooxygenase-1b is not the elusive target of acetaminophen. Eur J Pharmacol 2006; 551: 50–53.

    Article  CAS  PubMed  Google Scholar 

  105. Censarek P, Freidel K, Udelhoven M, Ku SJ, Hohlfeld T, Meyer-Kirchrath J et al. Cyclooxygenase COX-2a, a novel COX-2 mRNA variant, in platelets from patients after coronary artery bypass grafting. Thromb Haemost 2004; 92: 925–928.

    Article  CAS  PubMed  Google Scholar 

  106. Hor SY, Lee SC, Wong CI, Lim YW, Lim RC, Wang LZ . PXR, CAR and HNF4alpha genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients. Pharmacogenomics J 2008; 2: 139–146.

    Article  CAS  Google Scholar 

  107. Medina MW, Gao F, Ruan W, Rotter JI, Krauss RM . Alternative Splicing of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Is Associated With Plasma Low-Density Lipoprotein Cholesterol Response to Simvastatin. Circulation 2008; 118: 355–362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Laudadio J, Deininger MW, Mauro MJ, Druker BJ, Press RD . An intron-derived insertion/truncation mutation in the BCR-ABL kinase domain in chronic myeloid leukemia patients undergoing kinase inhibitor therapy. J Mol Diagn 2008; 10: 177–180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bueno MJ, Pérez de Castro I, Gómez de Cedrón M, Santos J, Calin GA, Cigudosa JC et al. Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell 2008; 6: 496–506.

    Article  CAS  Google Scholar 

  110. Lu NZ, Cidlowski JA . Glucocorticoid receptor isoforms generate transcription specificity. Trends Cell Biol 2006; 16: 301–307.

    Article  CAS  PubMed  Google Scholar 

  111. Pujols L, Mullol J, Picado C . Alpha and beta glucocorticoid receptors: relevance in airway diseases. Curr Allergy Asthma Rep 2007; 7: 93–99.

    Article  CAS  PubMed  Google Scholar 

  112. Oakley RH, Sar M, Cidlowski JA . The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J Biol Chem 1996; 271: 9550–9559.

    Article  CAS  PubMed  Google Scholar 

  113. Goleva E, Li LB, Eves PT, Strand MJ, Martin RJ, Leung DY . Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. Am J Respir Crit Care Med 2006; 173: 607–616.

    Article  CAS  PubMed  Google Scholar 

  114. Yarden Y, Sliwkowski MX . Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2: 127–137.

    Article  CAS  PubMed  Google Scholar 

  115. Reiter JL, Threadgill DW, Eley GD, Strunk KE, Danielsen AJ, Sinclair CS et al. Comparative genomic sequence analysis and isolation of human and mouse alternative EGFR transcripts encoding truncated receptor isoforms. Genomics 2001; 71: 1–20.

    Article  CAS  PubMed  Google Scholar 

  116. Lafky JM, Baron AT, Cora EM, Hillman DW, Suman VJ, Perez EA et al. Serum soluble epidermal growth factor receptor concentrations decrease in postmenopausal metastatic breast cancer patients treated with letrozole. Cancer Res 2005; 65: 3059–3062.

    Article  CAS  PubMed  Google Scholar 

  117. Asgeirsson KS, Agrawal A, Allen C, Hitch A, Ellis IO, Chapman C et al. Serum epidermal growth factor receptor and HER2 expression in primary and metastatic breast cancer patients. Breast Cancer Res 2007; 9: R75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hudelist G, Köstler WJ, Gschwantler-Kaulich D, Czerwenka K, Kubista E, Müller R et al. Serum EGFR levels and efficacy of trastuzumab-based therapy in patients with metastatic breast cancer. Eur J Cancer 2006; 42: 186–192.

    Article  CAS  PubMed  Google Scholar 

  119. Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008, e-pub ahead of print.

  120. Diaz A, Reginato AM, Jimenez SA . Alternative splicing of human prostaglandin G/H synthase mRNA and evidence of differential regulation of the resulting transcripts by transforming growth factor beta 1, interleukin 1 beta, and tumor necrosis factor alpha. J Biol Chem 1992; 267: 10816–10822.

    CAS  PubMed  Google Scholar 

  121. Kitzler J, Hill E, Hardman R, Reddy N, Philpot R, Eling TE . Analysis and quantitation of splicing variants of the TPA-inducible PGHS-1 mRNA in rat tracheal epithelial cells. Arch Biochem Biophys 1995; 316: 856–863.

    Article  CAS  PubMed  Google Scholar 

  122. Hersh EV, Lally ET, Moore PA . Update on cyclooxygenase inhibitors: has a third COX isoform entered the fray? Curr Med Res Opin 2005; 8: 1217–1226.

    Article  CAS  Google Scholar 

  123. Zimmermann N, Kienzle P, Weber AA, Winter J, Gams E, Schrör K et al. Aspirin resistance after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2001; 121: 982–984.

    Article  CAS  PubMed  Google Scholar 

  124. Gasparyan AY, Watson T, Lip GY . The role of aspirin in cardiovascular prevention: implications of aspirin resistance. J Am Coll Cardiol 2008; 51: 1829–1843.

    Article  CAS  PubMed  Google Scholar 

  125. Weber AA, Zimmermann KC, Meyer-Kirchrath J, Schrör K . Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance. Lancet 1999; 353: 900.

    Article  CAS  PubMed  Google Scholar 

  126. Zimmermann N, Wenk A, Kim U, Kienzle P, Weber AA, Gams E et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 2003; 108: 542–547.

    Article  CAS  PubMed  Google Scholar 

  127. Lamba J, Lamba V, Schuetz E . Genetics variants of PXR (NR1I2) and CAR (NR1I3) and their implications in drug metabolism and pharmacogenetics. Curr Drug Metab 2005; 4: 369–383.

    Article  Google Scholar 

  128. Heinzen EL, Yoon W, Tate SK, Sen A, Wood NW, Sisodiya SM . Nova2 interacts with a cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A. Am J Hum Genet 2007; 5: 876–883.

    Article  CAS  Google Scholar 

  129. Kwan T, Benovoy D, Dias C, Gurd S, Provencher C, Beaulieu P et al. Genome-wide analysis of transcript isoform variation in humans. Nat Genet 2008; 40: 225–231.

    Article  CAS  PubMed  Google Scholar 

  130. Tan S, Guo J, Huang Q, Chen X, Li-Ling J, Li Q et al. Retained introns increase putative microRNA targets within 3′ UTRs of human mRNA. FEBS Lett 2007; 6: 1081–1086.

    Article  CAS  Google Scholar 

  131. Sandberg R, Neilson JR, Sarma A, Sharp PA, Burge CB . Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 2008; 5883: 1643–1647.

    Article  CAS  Google Scholar 

  132. Makeyev EV, Zhang J, Carrasco MA, Maniatis T . The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 2007; 3: 435–448.

    Article  CAS  Google Scholar 

  133. Duursma AM, Kedde M, Schrier M, le Sage C, Agami R . miR-148 targets human DNMT3b protein coding region. RNA 2008; 5: 872–877.

    Article  CAS  Google Scholar 

  134. Makeyev EV, Maniatis T . Multilevel regulation of gene expression by microRNAs. Science 2008; 5871: 1789–1790.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the insights and suggestions from Dr Tom Wurdinger, Dr Patricia Savio de Araujo Souza, Dr Alexandre da Costa Pereira, Dr Elio Vanin and Kelly Arndt. FP and CGF are supported by the Swiss Bridge Foundation and Fundação Ary Frauzino para Pesquisa e Controle do Câncer. FFC is supported by the Maeve McNicholas Memorial Foundation and Children's Memorial Research Center.

Author information

Authors and Affiliations

  1. Division of Clinical and Translational Research, Laboratory of Bioinformatics and Computational Biology, Research Coordination (CPQ), Instituto Nacional de Câncer, Rio de Janeiro, Brazil

    F Passetti

  2. Division of Clinical and Translational Research, Research Coordination (CPQ), Instituto Nacional de Câncer, Rio de Janeiro, Brazil

    C G Ferreira

  3. Cancer Biology and Epigenomics Program, Children's Memorial Research Center, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA

    F F Costa

Authors
  1. F Passetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C G Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F F Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F F Costa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Passetti, F., Ferreira, C. & Costa, F. The impact of microRNAs and alternative splicing in pharmacogenomics. Pharmacogenomics J 9, 1–13 (2009). https://doi.org/10.1038/tpj.2008.14

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2008.14

Keywords

This article is cited by

Search

Advanced search

Quick links