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Overview of Pharmacogenetics
Publication Name:
Current Protocols in Human Genetics
Unit Number:
Unit 9.19
DOI:
10.1002/0471142905.hg0919s60
Online Posting Date:
January, 2009 Abstract
Pharmacogenetics is the study of relationships between genetic variation and inter-individual differences with respect to drug response. As the field has matured over the past 15 years, a remarkable diversity of pathways, variation types, and mechanisms have been found to be relevant pharmacogenetic factors. Today, pharmacogenetics is becoming more important in pharmacology for target validation, lead optimization, and understanding of idiosyncratic toxicity. This unit provides an overview of the history of pharmacogenetics and current research applications in drug discovery, as well as a discussion of research quality issues relevant for human subjects research in the pharmacogenetics laboratory. Curr. Protoc. Hum. Genet. 60:9.19.1-9.19.23. © 2009 by John Wiley & Sons, Inc.
Keywords: pharmacogenetics; genotype-phenotype correlations; drug discovery; toxicogenomics; drug development
Figures
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Figure 9.19.1Pharmacogenetic pathways. The three major categories of genes relate to pharmacokinetics, pharmacology, and physiology. Example pathway types within each category are shown. -
Figure 9.19.2In Factor V Leiden (F5.0001), a single-nucleotide polymorphism (SNP), in which a guanosine (G) is changed to an adenosine (A), results in a change from arginine (R) to glutamine (Q). This variation alters protein-protein interactions and predisposes carriers to deep-vein thrombosis. The line drawing above the sequence shows the position in the protein. -
Figure 9.19.3A simple tandem repeat (STR) polymorphism in 5-lipoxygenase (ALOX5) that modulates gene expression and response to some antiasthma drugs. -
Figure 9.19.4Cytochrome P450 2D6 gene (CYP2D6) deletion and amplification events that affect the pharmacokinetics of various drugs. The dashed lines delineate regions that are deleted/inserted between alleles. Abbreviations: PM, poor metabolism phenotype; UM, ultrarapid metabolism phenotype. -
Figure 9.19.5Complex polymorphism of the dopamine D4 receptor gene (DRD4). Each pattern represents a distinct form of a 48-nucleotide repeat sequence. -
Figure 9.19.6Haplotypes of thiopurine methyltransferase that affect the safety and efficacy of thiopurine drugs. Two SNPs in TPMT (460G>A and 719A>G) independently lead to amino acid changes that destroy enzyme function. These variants of the wild type (TMPT*1) may be found together on the same chromosome (TMPT*3A) or the 460G>A (TMPT*3B) and 719A>G (TMPT*3C) variants may be found on separate chromosomes. Individuals with two copies of any of these variants lack the enzyme and cannot tolerate typical doses of certain drugs that are normally metabolized by TPMT. The status of an individual heterozygous for both SNPs cannot be determined by simple genotyping. Abbreviation: PM, poor metabolism. -
Figure 9.19.7Epigenetic alteration of O6-methylguanosine DNA methyltransferase (MGMT) that correlates with response rates to the anticancer alkylating agent carmustine. Methylation of cytosine residues in the promoter region of the MGMT gene blocks transcription and limits gene expression (bottom). Lack of MGMT expression, which occurs in ~30% of gliomas, correlates with response to the antitumor agent carmustine. -
Figure 9.19.8Pharmacogenetic effects in context of the central dogma of molecular biology. -
Figure 9.19.9Common alleles of cytochrome P450 2D6 gene (CYP2D6) lead to four broad classes of activity toward substrates of that enzyme. Alleles: CYP2D6*5, complete gene deletion; CYP2D6*3 and *6, nucleotide changes or insertions in the open reading frame; CYP2D6*4, disruption of RNA splicing; CYP2D6*10 and *17, variants that lead to alterations in substrate affinity, catalytic rate, or substrate specificity; CYP2D6*41, lowered expression due to a promoter variant. Phenotypes: EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolism; UM, ultrarapid metabolism. More than 30 rare alleles that lead to the PM phenotype are also known. -
Figure 9.19.10Alleles of cytochrome P450 3A5 that alter RNA splicing, such that only about 1/3 of individuals express functional enzyme. CYP3A5*3 is a common SNP in which a cryptic splice acceptor site is created in the intron, leading to RNA containing a “junk” exon (diagonal stripes) and producing no active protein. CYP3A6*6 is produced by a similar mechanism and is found predominantly in African populations. It has the same functional consequences as CYP3A5*3. Arrow indicates approximate position of the cryptic splice site. Boxes not drawn to scale. -
Figure 9.19.11Qualitative relationship between dose and relative influence of cytochrome P450 3A5 genotype on human pharmacokinetics (ERMBT = erythromycin breath test). -
Figure 9.19.12Response to isoproterenol-induced venodilation in individuals homozygous for different 2-adrenoceptor alleles. Maximal dilation in response to isoproterenol was measured in hand veins that were previously constricted using phenylephrine. NS, no significant difference from acute dose. -
Figure 9.19.13Variants of protein tyrosine phosphatase 1B, a potential therapeutic target for type 2 diabetes. The top line represents exons as boxes along the PTPN1 gene. The middle line represents the transcribed mRNA and the location of the G insertion in the 3ยข-untranslated region. The G insertion results in increased mRNA stability and higher expression. PTP1B protein containing the P387L change is shown at the bottom of the figure. In a Danish study (Echwald et al., -
Figure 9.19.14Pharmacogenetic clinical trial designs: (A) screened, (B) selected, (C) stratified. -
Figure 9.19.15Pharmacogenetic-based dose selection for drug development.
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| Vulliamy, T., Beutler, E., and Luzzatto, L. 1993. Variants of glucose-6-phosphate dehydrgenase are due to missense mutations spread throughout the coding region of the gene. Hum. Mutat. 2:159-167. | |
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| Wong, M., Balleine, R.L., Collins, M., Liddle, C., Clarke, C.L., and Gurney, H. 2004. CYP3A5 genotype and midazolam clearance in Australian patients receiving chemotherapy. Clin. Pharm. Ther. 75:529-538. | |
| Xie, R., Knuth, D., Tan, L., Polasek, E., Hong, C., Teillol-Foo, M., et al. 2003. Fexofenidine and midazolam disposition in relation to genetic polymorphisms of CYP3A, PXR and P-glycoprotein. Clin. Pharm. Ther. 73:P19. | |
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| Yue, Q., Svensson, J.-O., Alm, C., Sjoqvist, F., and Sawe, J. 1989. Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. Br. J. Clin. Pharmacol. 28:639-645. | |
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| Zheng, H., Webber, S., Zeevi, A., Schuetz, E., Zhang, J., Bowman, P., Boyle, G., Law, Y., Miller, S., Lamba, J., and Burckart, G.J. 2003. Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am. J. Transplant. 3:477-483. | |
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| Internet Resources | |
| http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi db=OMIM | |
| The Online Mendelian Inheritance in Man (OMIM) Web site. An annotated database containing information about genes and genetic variants. From the OMIM entry for a gene, it is possible to link to most other major Internet resources on that gene. This is the best place from which to gather gene-centric information. | |
| http://www.pharmgkb.org | |
| PharmGKB, a database of candidate gene polymorphisms maintained via the NIH Pharmacogenetics Research Network (PRN). This group comprises investigators who are funded by a targeted NIGMS grant program. The site includes information about genes studied by PRN investigators, upcoming scientific meetings and the individual PRN centers. | |
| http://www.gentest.com/human_p450_database/index.html | |
| The human cytochrome P450 metabolism database (Rendic, | |
| http://www.imm.ki.se/CYPalleles | |
| Homepage of the Human Cytochrome P450 Allele Nomenclature Committee. This is an up-to-date catalog of known sequence variants of human cytochromes P450. Unfortunately, it does not include allele frequency, and lists rare alleles, even those that have been observed only once. | |
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