Overview of Pharmacogenetics

David A. Katz1

1 Abbott Laboratories, Abbott Park, Illinois
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 6.10
DOI:  10.1002/0471141755.ph0610s36
Online Posting Date:  March, 2007
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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 to human subjects research in the pharmacogenetics laboratory.

Keywords: pharmacogenetics; genotype‐phenotype correlations; drug discovery; toxicogenomics; drug development

     
 
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Table of Contents

  • The Diversity of Pharmacogenetics
  • Applications in Drug Discovery
  • Applications in Drug Development
  • A Final Word: Technologies
  • Literature Cited
  • Figures
  • Tables
     
 
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Materials

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Figures

  •   FigureFigure 6.10.1 Pharmacogenetic pathways. Example pathway types within each category are shown.
  •   FigureFigure 6.10.2 A single nucleotide polymorphism (SNP) yields Factor V Leiden ( F5.0001). The change of a guanosine (G) in the wild type (wt) 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 amino acid position in the protein.
  •   FigureFigure 6.10.3 A simple tandem repeat (STR) polymorphism in 5‐lipoxygenase ( ALOX5) that modulates gene expression and response to some antiasthma drugs.
  •   FigureFigure 6.10.4 Cytochrome 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; wt, wild type; UM, ultrarapid metabolism phenotype.
  •   FigureFigure 6.10.5 Complex polymorphism of the dopamine D4 receptor gene ( DRD4). Each pattern represents a distinct form of a 48‐nucleotide repeat sequence.
  •   FigureFigure 6.10.6 Haplotypes of thiopurine methyltransferase that affect the safety and efficacy of thiopurine drugs. Two SNPs in TPMT independently lead to amino acid changes that destroy enzyme function. The SNPs may be found together on the same chromosome ( TPMT*3A with variants 460G>A and 719A>G) or separately on different chromosomes ( TPMT*3B with the variant 460G>A, or TPMT*3C with the variant 719A>G) 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. It is necessary to determine the individual's haplotypes to choose an appropriate dose, but the status of an individual heterozygous for both SNPs cannot be determined by simple genotyping. Abbreviation: PM, poor metabolism.
  •   FigureFigure 6.10.7 Epigenetic 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 of the enzyme that degrades carmustine (bottom). Lack of MGMT expression, which occurs in ∼30% of gliomas, correlates with a positive response to the antitumor agent carmustine.
  •   FigureFigure 6.10.8 Pharmacogenetic effects in context of the central dogma of molecular biology.
  •   FigureFigure 6.10.9 Common alleles of the 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, alterations in substrate affinity, catalytic rate, or substrate specificity; CYP2D6*41, lowered expression. 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.
  •   FigureFigure 6.10.10 Alleles of the cytochrome P450 3A5 gene ( CYP3A5) alter RNA splicing, such that only about 1/3 of individuals express functional enzyme. The CYP3A5*3 allele has 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 functions by a similar mechanism and is found predominantly in African populations. It has the same consequences as CYP3A5*3. Arrow indicates the approximate position of the cryptic splice site. Boxes not drawn to scale.
  •   FigureFigure 6.10.11 Qualitative relationship between drug dose and relative influence of cytochrome P450 3A5 genotype on human pharmacokinetics (ERMBT = erythromycin breath test; administration of a tracer dose of erythromycin to quantitate CYP3A activity).
  •   FigureFigure 6.10.12 Response to isoproterenol‐induced venodilation in individuals homozygous for different β2‐adrenoceptor ( BAR2) alleles. Maximal dilation in response to either acute or chronic dosing with isoproterenol was measured in hand veins that were previously constricted using phenylephrine. NS, no significant difference from acute dose.
  •   FigureFigure 6.10.13 Variants 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 3′‐untranslated region. The G insertion results in increased mRNA stability and higher expression. PTP1B protein containing the P387L variant is shown at the bottom of the figure. In a Danish study (Echwald et al., ), this variant was frequently found in diabetics. However, the molecular consequences of this variant have not been established.
  •   FigureFigure 6.10.14 Pharmacogenetic clinical trial designs: (A) screened, (B) selected, (C) stratified.
  •   FigureFigure 6.10.15 Pharmacogenetic‐based dose selection for drug development.

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Internet Resources
   http://www.ich.org/
  Good clinical practice regulations promulgated by the International Committee for Harmonization.
   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. This information is also published on a regular basis in Pharmacological Reviews.
   http://www.nccls.org
  The Clinical and Laboratory Standards Institute (CLIS, formerly NCCLS) homepage. This group is a globally recognized, voluntary consensus standards‐developing organization that enhances the value of medical testing within the healthcare community through the development and dissemination of standards, guidelines, and best practices. Guidance documents for laboratory quality may be purchased via their website.
   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.
   http://www.gpoaccess.gov/cfr/index.html
  Access to U.S. federal regulations related to drug development, diagnostic development, and diagnostic manufacturing.
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