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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Haga, S. B., and Burke, W. (2004) Using pharmacogenetics to improve drug safety and efficacy. JAMA. 291, 2869–2871.
Nadeau, J. H., and Topol, E. J. (2006) The genetics of health. Nat. Genet. 38, 1095–1098.
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.
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.
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.
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.
Ingalls, A. M., Dickie, M. M., and Snell, G. D. (1950) Obese, a new mutation in the house mouse. J. Hered. 41, 317–318.
Coleman, D. L., and Hummel, K. P. (1969) Effects of parabiosis of normal with genetically diabetic mice. Am. J. Physiol. 217, 1298–1304.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Bejerano, G., Pheasant, M., Makunin, I., et al. (2004) Ultraconserved elements in the human genome. Science. 304, 1321–1325.
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.
Current protocols in molecular biology. John Wiley and Sons, Inc., Hoboken, New Jersey. (2007)
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Thomas, D. J., Trumbower, H., Kern, A. D., et al. (2007) Variation resources at UC Santa Cruz. Nucleic Acids Res. 35, D716–D720.
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.
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.
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.
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.
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.
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.
Wingender, E., Chen, X., Hehl, R., et al. (2000) TRANSFAC: an integrated system for gene expression regulation. Nucleic Acids Res. 28, 316–319.
Wingender, E., Chen, X., Fricke, E., et al. (2001) The TRANSFAC system on gene expression regulation. Nucleic Acids Res. 29, 281–283.
Matys, V., Fricke, E., Geffers, R., et al. (2003) TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res. 31, 374–378.
Enright, A. J., John, B., Gaul, U., Tuschl, T., Sander, C., and Marks, D. S. (2003) MicroRNA targets in Drosophila. Genome Biol. 5, R1.
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.
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.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights 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