Skip to main content
SpringerLink
Log in
Book cover

Pharmacogenomics in Drug Discovery and Development pp 379–393Cite as

From SNPs to Functional Studies in Cardiovascular Pharmacogenomics

  • Protocol

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 448))

Summary

Functional studies can be utilized to give importance/relevance to clinical associations. Once a clinical genetic or pharmacogenetic association is found, molecular studies can be utilized to explore the mechanism for the association. By employing cells in culture or transgenic mice modified with specific variant genes or sequence polymorphisms of interest, pathophysiological processes and response to pharmacological agents may be tested under conditions that are not approachable in human patients. These mechanistic studies may be particularly important when it comes to pharmacogenetic associations by providing significant, clinically relevant insights into the variable responses patients show to drug therapy.

This is a preview of subscription content, log in via an institution.

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Haga, S. B., and Burke, W. (2004) Using pharmacogenetics to improve drug safety and efficacy. JAMA. 291, 2869–2871.

    Article  CAS  PubMed  Google Scholar 

  2. Nadeau, J. H., and Topol, E. J. (2006) The genetics of health. Nat. Genet. 38, 1095–1098.

    Article  CAS  PubMed  Google Scholar 

  3. Wang, L., Fan, C., Topol, S. E., Topol, E. J., and Wang, Q. (2003) Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science. 302, 1578–1581.

    Article  CAS  PubMed  Google Scholar 

  4. Edmondson, D. G., Lyons, G. E., Martin, J. F., and Olson, E. N. (1994) Mef2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis. Development. 120, 1251–1263.

    CAS  PubMed  Google Scholar 

  5. Subramanian, S. V., and Nadal-Ginard, B. (1996) Early expression of the different isoforms of the myocyte enhancer factor-2 (MEF2) protein in myogenic as well as non-myogenic cell lineages during mouse embryogenesis. Mech. Dev. 57, 103–112.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J. M. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature. 372, 425–432.

    Article  CAS  PubMed  Google Scholar 

  7. Ingalls, A. M., Dickie, M. M., and Snell, G. D. (1950) Obese, a new mutation in the house mouse. J. Hered. 41, 317–318.

    CAS  PubMed  Google Scholar 

  8. Coleman, D. L., and Hummel, K. P. (1969) Effects of parabiosis of normal with genetically diabetic mice. Am. J. Physiol. 217, 1298–1304.

    CAS  PubMed  Google Scholar 

  9. Weigle, D. S., Bukowski, T. R., Foster, D. C., et al. (1995) Recombinant ob protein reduces feeding and body weight in the ob/ob mouse. J. Clin. Invest. 96, 2065–2070.

    Article  CAS  PubMed  Google Scholar 

  10. Halaas, J. L., Gajiwala, K. S., Maffei, M., et al. (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 269, 543–546.

    Article  CAS  PubMed  Google Scholar 

  11. Pelleymounter, M. A., Cullen, M. J., Baker, M. B., et al. (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 269, 540–543.

    Article  CAS  PubMed  Google Scholar 

  12. Rentsch, J., Levens, N., and Chiesi, M. (1995) Recombinant ob-gene product reduces food intake in fasted mice. Biochem. Biophys. Res. Commun. 214, 131–136.

    Article  CAS  PubMed  Google Scholar 

  13. Montague, C. T., Farooqi, I. S., Whitehead, J. P., et al. (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 387, 903–908.

    Article  CAS  PubMed  Google Scholar 

  14. Wang, Y. X., Zhang, C. L., Yu, R. T., et al. (2004) Regulation of muscle fiber type and running endurance by PPARdelta. PLoS. Biol. 2, e294.

    Article  PubMed  Google Scholar 

  15. Cheng, L., Ding, G., Qin, Q., et al. (2004) Cardiomyocyte-restricted peroxisome proliferatoractivated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat. Med. 10, 1245–1250.

    Article  CAS  PubMed  Google Scholar 

  16. Chiu, H. C., Kovacs, A., Blanton, R. M., et al. (2005) Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circ. Res. 96, 225–233.

    Article  CAS  PubMed  Google Scholar 

  17. Qin, Z. S., Gopalakrishnan, S., and Abecasis, G. R. (2006) An efficient comprehensive search algorithm for tagSNP selection using linkage disequilibrium criteria. Bioinformatics. 22, 220–225.

    Article  CAS  PubMed  Google Scholar 

  18. de Bakker, P. I., Yelensky, R., Pe'er, I., Gabriel, S. B., Daly, M. J., and Altshuler, D. (2005) Efficiency and power in genetic association studies. Nat. Genet. 37, 1217–1223.

    Article  PubMed  Google Scholar 

  19. Sandelin, A., Bailey, P., Bruce, S., et al. (2004) Arrays of ultraconserved non-coding regions span the loci of key developmental genes in vertebrate genomes. BMC Genomics. 5, 99.

    Article  PubMed  Google Scholar 

  20. Bejerano, G., Pheasant, M., Makunin, I., et al. (2004) Ultraconserved elements in the human genome. Science. 304, 1321–1325.

    Article  CAS  PubMed  Google Scholar 

  21. Freimuth, R. R., Stormo, G. D., and McLeod, H. L. (2005) PolyMAPr: programs for polymorphism database mining, annotation, and functional analysis. Hum. Mutat. 25, 110–117.

    Article  CAS  PubMed  Google Scholar 

  22. Current protocols in molecular biology. John Wiley and Sons, Inc., Hoboken, New Jersey. (2007)

    Google Scholar 

  23. Vanttinen, M., Nuutila, P., Kuulasmaa, T., et al. (2005) Single nucleotide polymorphisms in the peroxisome proliferator-activated receptor delta gene are associated with skeletal muscle glucose uptake. Diabetes. 54, 3587–3591.

    Article  CAS  PubMed  Google Scholar 

  24. Skogsberg, J., Kannisto, K., Cassel, T. N., Hamsten, A., Eriksson, P., and Ehrenborg, E. (2003) Evidence that peroxisome proliferator-activated receptor delta influences cholesterol metabolism in men. Arterioscler. Thromb. Vasc. Biol. 23, 637–643.

    Article  CAS  PubMed  Google Scholar 

  25. Liggett, S. B., Mialet-Perez, J., Thaneemit-Chen, S., et al. (2006) A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc. Natl. Acad. Sci. U. S. A. 103, 11288–11293.

    Article  CAS  PubMed  Google Scholar 

  26. Mason, D. A., Moore, J. D., Green, S. A., and Liggett, S. B. (1999) A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J. Biol. Chem. 274, 12670–12674.

    Article  CAS  PubMed  Google Scholar 

  27. Mialet, P. J., Rathz, D. A., Petrashevskaya, N. N., et al. (2003) Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat. Med. 9, 1300–1305.

    Article  Google Scholar 

  28. Small, K. M., Wagoner, L. E., Levin, A. M., Kardia, S. L., and Liggett, S. B. (2002) Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N. Engl. J. Med. 347, 1135–1142.

    Article  CAS  PubMed  Google Scholar 

  29. Kajaste-Rudnitski, A., Mashimo, T., Frenkiel, M. P., Guenet, J. L., Lucas, M., and Despres, P. (2006) The 2′,5″-oligoadenylate synthetase 1b is a potent inhibitor of West Nile virus replication inside infected cells. J. Biol.Chem. 281, 4624–4637.

    Article  CAS  PubMed  Google Scholar 

  30. Lucas, M., Mashimo, T., Frenkiel, M. P., et al. (2003) Infection of mouse neurones by West Nile virus is modulated by the interferon-inducible 2′-5″ oligoadenylate synthetase 1b protein. Immunol. Cell Biol. 81, 230–236.

    Article  CAS  PubMed  Google Scholar 

  31. Mashimo, T., Lucas, M., Simon-Chazottes, D., et al. (2002) A nonsense mutation in the gene encoding 2′,5′-oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice. Proc. Natl. Acad. Sci. U. S. A. 99, 11311–11316.

    Article  CAS  PubMed  Google Scholar 

  32. Field, L. L., Bonnevie-Nielsen, V., Pociot, F., Lu, S., Nielsen, T. B., and Beck-Nielsen, H. (2005) OAS1 splice site polymorphism controlling antiviral enzyme activity influences susceptibility to type 1 diabetes. Diabetes. 54, 1588–1591.

    Article  CAS  PubMed  Google Scholar 

  33. Bonnevie-Nielsen, V., Field, L. L., Lu, S., et al. (2005) Variation in antiviral 2′,5′-oligoadenylate synthetase (2′5″AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene. Am. J. Hum. Genet. 76, 623–633.

    Article  CAS  PubMed  Google Scholar 

  34. Yamada, H., Shinmura, K., Tsuneyoshi, T., and Sugimura, H. (2005) Effect of splice-site polymorphisms of the TMPRSS4, NPHP4 and ORCTL4 genes on their mRNA expression. J. Genet. 84, 131–136.

    Article  CAS  PubMed  Google Scholar 

  35. Thomas, D. J., Trumbower, H., Kern, A. D., et al. (2007) Variation resources at UC Santa Cruz. Nucleic Acids Res. 35, D716–D720.

    Article  CAS  PubMed  Google Scholar 

  36. Kent, W. J., Hsu, F., Karolchik, D., et al. (2005) Exploring relationships and mining data with the UCSC Gene Sorter. Genome Res. 15, 737–741.

    Article  CAS  PubMed  Google Scholar 

  37. Sandelin, A., Alkema, W., Engstrom, P., Wasserman, W. W., and Lenhard, B. (2004) JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res. 32, D91–D94.

    Article  CAS  PubMed  Google Scholar 

  38. Vlieghe, D., Sandelin, A., De Bleser, P. J., et al. (2006) A new generation of JASPAR, the open-access repository for transcription factor binding site profiles. Nucleic Acids Res. 34, D95–D97.

    Article  CAS  PubMed  Google Scholar 

  39. Lenhard, B., Sandelin, A., Mendoza, L., Engstrom, P., Jareborg, N., and Wasserman, W. W. (2003) Identification of conserved regulatory elements by comparative genome analysis. J. Biol. 2, 13.

    Article  PubMed  Google Scholar 

  40. Sandelin, A., Wasserman, W. W., and Lenhard, B. (2004) ConSite: Web-based prediction of regulatory elements using cross-species comparison. Nucleic Acids Res. 32, W249–W252.

    Article  CAS  PubMed  Google Scholar 

  41. Zhao, T., Chang, L. W., McLeod, H. L., and Stormo, G. D. (2004) PromoLign: a database for upstream region analysis and SNPs. Hum. Mutat. 23, 534–539.

    Article  CAS  PubMed  Google Scholar 

  42. Wingender, E., Chen, X., Hehl, R., et al. (2000) TRANSFAC: an integrated system for gene expression regulation. Nucleic Acids Res. 28, 316–319.

    Article  CAS  PubMed  Google Scholar 

  43. Wingender, E., Chen, X., Fricke, E., et al. (2001) The TRANSFAC system on gene expression regulation. Nucleic Acids Res. 29, 281–283.

    Article  CAS  PubMed  Google Scholar 

  44. Matys, V., Fricke, E., Geffers, R., et al. (2003) TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res. 31, 374–378.

    Article  CAS  PubMed  Google Scholar 

  45. Enright, A. J., John, B., Gaul, U., Tuschl, T., Sander, C., and Marks, D. S. (2003) MicroRNA targets in Drosophila. Genome Biol. 5, R1.

    Google Scholar 

  46. Mignone, F., Grillo, G., Licciulli, F., et al. (2005) UTRdb and UTRsite: a collection of sequences and regulatory motifs of the untranslated regions of eukaryotic mRNAs. Nucleic Acids Res. 33, D141–D146.

    Article  CAS  PubMed  Google Scholar 

  47. Grillo, G., Licciulli, F., Liuni, S., Sbisa, E., and Pesole, G. (2003) PatSearch: a program for the detection of patterns and structural motifs in nucleotide sequences. Nucleic Acids Res. 31, 3608–3612.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Washington University School of Medicine, St. Louis, Missouri

    Sharon Cresci

Authors
  1. Sharon Cresci
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. PharmTao, Santa Clara, CA, USA

    Qing Yan

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press, a part of Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Cresci, S. (2008). From SNPs to Functional Studies in Cardiovascular Pharmacogenomics. In: Yan, Q. (eds) Pharmacogenomics in Drug Discovery and Development. Methods in Molecular Biology™, vol 448. Humana Press. https://doi.org/10.1007/978-1-59745-205-2_12

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-205-2_12

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-887-4

  • Online ISBN: 978-1-59745-205-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation