teaser
Philippa Brice
PhD
PHG Foundation
Cambridge
UK
The Human Genome Project (HGP), officially completed in 2003, paved the way for a new generation of large-scale projects to investigate how variations in genome sequence influence health (see Resources). Most diseases, as well as individual responses to drugs, foods and other external agents, are the product of a complex interplay of multiple genetic and environmental factors. The genetic contribution to variability in drug response has been proposed to range from around 20% to as much as 95% for certain drugs.(1)
While it has become increasingly possible to identify rare mutations that cause “genetic” diseases such as cystic fibrosis or haemophilia, it is much harder to pinpoint the polymorphisms that influence multifactorial traits such as drug responses and conditions like diabetes or heart disease. Polymorphisms are “normal” genetic variants, typically changes of single bases known as single nucleotide polymorphisms (SNPs). Haplotypes − combinations of closely linked SNPs − describe patterns of common genetic variation between individuals. The International Haplotype Map Project is a collaborative effort to catalogue the most useful SNPs in genomes from different human populations, allowing researchers to link genetic variants with specific traits and responses (see Resources). Cancer is in many respects a form of genetic disease, in that loss of normal regulation of cellular growth and replication is driven by the accumulation of certain mutations within a normal cell. The Cancer Genome Project, another important initiative, is mapping the genes and mutations involved in different cancers (see Resources).
Ultimately, these and other postgenomic research efforts will yield new insight into the labyrinthine function of the human genome in health and disease, and this emerging knowledge will have a huge clinical impact. What, then, will the implications be for hospital pharmacy practice? Although realising the full potential of the HGP will take many years – probably much longer than a working lifetime – applications are already appearing and many have significance for pharmacists, notably in the area of pharmacogenomics.(2)
Pharmacogenomics, the way in which multiple inherited genetic variants across the genome influence drug metabolism and response, has two broad areas of application. The first is drug development, where drug companies are routinely using knowledge of which metabolic pathways and drug targets are subject to significant genetic variation to streamline drug pipelines, excluding candidates likely to risk reduced efficacy or increased toxicity. Genomic research is also suggesting new drug targets, as understanding of disease mechanisms deepens.
The second application is tailoring treatments to individual patients. Personalised medicine is one of the ultimate goals of postgenomic research; proponents envision a world where clinicians routinely use genetic analysis to select the optimum type and dose of therapeutic for each patient, maximising efficacy and preventing adverse drug responses. While this sort of scenario remains firmly in the future, some aspects of personalised medicine are beginning to emerge.
Pharmacogenetic testing is already a reality for a few medicines where isolated genetic polymorphisms are known to have a significant effect on drug disposition or action. For example, variants in the TPMT gene are known to reduce thiopurine methyltransferase activity; individuals with reduced activity require lower doses of thiopurine drugs to avoid haematological toxicity.(3–5)
However, even currently available pre-prescription genetic testing is rarely used; it can only be justified where drugs are sufficiently costly, or the potential adverse reactions severe. The prime example of this is cancer, a disease serious enough to merit the use of relatively toxic medication, where the potential impact of non-efficacy or major side-effects on prognosis and quality of life is significant. Rising rates of cancer diagnosis across Europe are expected to strain healthcare systems, so cost-efficacy will become increasingly important.(6) A new generation of therapeutic agents for cancer is specifically targeting tumour cells by exploiting their unique genetic characteristics, increasing efficacy and minimising toxicity; genetic testing of tumour samples is an essential prerequisite to the use of targeted biologics such as trastuzumab (Herceptin®) and imatinib (Glivec®). Similar agents are likely to emerge soon as understanding of the distinct genetic profiles of different types and subtypes of cancer increases. Hospital pharmacists are therefore likely to encounter pharmacogenetic testing before their counterparts in the community, and especially in oncology.
A development worth watching is the use of high-density DNA-chip or microarray technology, which exploits the capacity of single strands of complementary DNA sequences to bind specifically to each other (see Figure 1). Sample DNA is fluorescently labelled and passed over a regular array of between several hundred and many thousands of short (known) DNA sequences on a solid platform; complementary sequences bind, and the position and amount present can be determined by the position and intensity of each fluorescent signal. Microarrays lend themselves to high-throughput analysis and are being used increasingly by hospital genetics laboratories to interrogate DNA samples for the presence of mutations or to determine cancer gene expression profiles for diagnosis and prognosis.
[[HPE33_fig1_26USE]]
Roche’s Amplichip® CYP450 test uses the same approach to analyse which common variations in the CYP2D6 and CYP2C19 genes for cytochrome P450 enzymes are present and classifies subjects as poor, intermediate, extensive or ultra-rapid metabolisers on this basis, with correspondingly adjusted recommended drug doses.(7)
The currently high cost of this particular pharmacogenetic test, coupled with the relatively low cost of many prescription drugs metabolised via the relevant CYP450 enzymes (eg, antidepressants, beta blockers, etc), limits clinical use.
However, similar tests based on simultaneous analysis of multiple genetic variants could enter future practice, especially as array costs fall. Similarly, microarrays may be used to analyse tumours prior to the use of genetically targeted therapeutics or to predict the best choice of drug based on genetic features of the tumour.8
As researchers begin to dissect the complex interactions between genetic and environmental factors, disease and therapeutics, the key message for pharmacists is the increasing need for awareness of the importance of genomics in health and the development of novel genome-based diagnostics, therapeutics and vaccines.
Basic genomic literacy will become essential for the current generation of hospital pharmacists as their role expands to encompass the handling of new (and for hospitals with research programmes, experimental) agents.
References
1. Evans WE, McLeod HL. Pharmacogenomics: drug disposition, drug targets and side-effects. N Engl J Med 2003;348:538-49.
2. O’Shaughnessy KM. HapMap,
pharmacogenomics, and the goal of personalized prescribing. Br J Clin Pharmacol 2006;61(6):783-6.
3. Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997;126:608-14.
4. Otterness D, Szumlanski C, Lennard L, et al. Human thiopurine methyltransferase pharmacogenetics.
Clin Pharmacol Ther 1997;62:60-73.
5. Evans WE, Hon YY, Bomgaars L, et al.
Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients
intolerant to mercaptopurine or azathioprine.
J Clin Oncol 2001;19:2293-301.
6. Ferlay J, Autier P, Boniol M et al. Estimates of the cancer incidence and mortality in Europe in 2006.
Ann Oncol 2007;18(3):581-92.
7. Jain KK. Applications of AmpliChip CYP450.
Mol Diagn 2005;9(3):119-27.
8. Brennan DJ, O’Brien SL, Fagan A et al.
Application of DNA microarray technology in determining breast cancer prognosis and therapeutic response. Expert Opin Biol Ther 2005;5(8):1069-83.
Resources
DNA from the Beginning.
An animated primer on the basics of DNA, genes and heredity
W: www.dnaftb.org
Focus on Pharmacogenetics.
A collection of freely available reviews and perspectives from the Nature Publishing Group, 2004
W: www.nature.com/reviews/focus/pgx/index.html
PHG Foundation.
An independent charity working to achieve the responsible and evidence-based application of biomedical science for health
W: www.phgfoundation.org
Human Genome Project
W: www.ornl.gov/sci/techresources/Human_Genome/home.shtml
International Haplotype Mapping Project
W: www.hapmap.org
Cancer Genome Project
W: www.sanger.ac.uk/genetics/CGP
