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Pharmacogenomics for General Practitioners:
Time for clinical application
Contributed by Dr Patrick Gladding
Pharmacogenomics tests are not yet available to general practice. The purpose of the following
article is to inform primary care clinicians about the existence of such tests and to generate discussion about what role,
if any, they may play in future medical practice. - Professor Murray Tilyard, Editor-in-chief, Best Practice Journal
Most medical practitioners will be aware of the variable nature of medication response. Until recently prescribing the
correct medicine, at the correct dose, to the right patient has largely been empirical. Skilled prescribers take into
account age, body weight and other co-morbidities when making a treatment choice. However, there are many other important
factors that can be considered, such as genetics.
Pharmacogenomic testing will soon be available to GPs and encompasses what has previously been out of reach, the molecular
dimension of patient care. The exciting promise of genomics and other molecular technologies is to make medicine more
predictive, preventative and personalised.
What is pharmacogenomics?
The field of pharmacogenomics has existed for several decades, however, its clinical application has been limited by
a number of factors. Although good science and clinical data exists to support the use of the technology, there are barriers
to its implementation. These include cost, availability, speed of turnaround in results, education and opposition from
industry. Since the completion of the human genome project in 2003, the cost of genotyping has reduced exponentially.
Alongside this, there has been an explosion in the methods to perform genotyping and sequencing. A complete genome is
not necessary to make important clinical decisions - single individual genetic variants (also known as single nucleotide
polymorphisms, “SNPs”) can be useful tests in isolation. The cost of testing SNPs has now dropped to under
$200 and each test needs to be performed only once in an individual’s lifetime.
Pharmacogenomic testing generally involves the testing of a number of SNPs within key genes that encode for metabolic
pathways, transporter systems or drug targets. Alterations in SNPs may alter the function of an enzyme or protein to make
it more or less active, contributing to the phenotype or physical characteristics of an individual. It is important to
understand that the genotype does not always correlate perfectly with the phenotype.
Considerations for healthcare professionals
As personalised medicine enters primary care, it will be important for it to be understandable and relevant to both
the patient and practitioner. Unfamiliar data for general practitioners will be potentially confusing. For a SNP test
to be worthwhile, it has to provide a result that is able to be actioned and also must provide additional benefit compared
to current management strategies.
Pharmacogenomic tests fall into two categories (though some may provide information on both):
- Predictive tests that are actionable and change treatment. These tests provide information about a patient’s
response or non-response to a medication.
Examples of this include:
- Warfarin - genetic information combined with clinical information provides an accurate maintenance dose estimate
(within 0.5 mg). In the future those at high risk for bleeding may be prescribed dabigatran.1
- Clopidogrel - provides the ability to identify non-responders who are at higher risk for stent thrombosis and death.
Non-responders can be given alternative treatments when they become available in New Zealand.2
- Prognostic tests that assess risk.
Examples of this include:
- Simvastatin - provides a relative risk for the development of myopathy on 80 mg of simvastatin. Homozygotes are
at a sixteen times higher risk of myopathy.3
- Abacavir - provides a risk for developing Stevens-Johnson syndrome.4,5
- Carbamazepine - provides a risk for developing Stevens-Johnson syndrome in Asian people.6
Two considerations for the prescriber about pharmacogenomic testing are:
- What is the likelihood of the adverse event?
In the instance of statin myopathy the clinical trial event rate is uncommon and testing every patient may
not be cost-effective.
- How common is the genetic variant in the population I am testing?
In some populations genetic variants that code non-response are more prevalent, meaning that testing may
be more cost-effective.
Ethics and privacy
Genetic testing may be viewed as discriminatory by some groups. This concern is well founded as employers and insurance
companies have shown an interest in using genetic information to assess prospective employees and load policies. General
practitioners need to be aware that entering genetic information into patient’s clinical notes may allow them to
be viewed by third parties. Also, a non-functioning or deficient enzyme could quite easily be considered a label of a “deficient
Other concerns with genetic testing include racial ancestry and paternity. Rare variants that are common in some ethnic
groups may be used as a surrogate for race. Presence or absence of a variant may imply paternity. Discussing genetic results
with patients can be fraught with problems and genetic counselling is advised for any genetic test that has the potential
for significant psychological impact to an individual and their family. Genetic testing of an individual, in effect, is
also indirectly testing family members.
The future of personalised medicine
It is clear that the future of medicine is heading in the direction of personalised risk and treatment decisions. Historically
the practice of medicine has largely focused on the physical (or phenotypic) manifestations of disease. However, many
diseases begin at earlier stages that may not be apparent to most modern methods of diagnosis. These disease stages are
sometimes detectable using molecular methods of diagnosis. Pharmacogenomics is the first in a number of scientific fields
that is emerging as clinically valuable. The goal for these fields is to improve on the efficiency of current medical
practice, rather than add to their cost. An example of this is a recently developed molecular stool-based test for bowel
cancer screening (sensitivity 85%, specificity 90%). This test potentially may increase adherence to screening programmess
and reduce negative colonoscopies.7 In addition, genomic medicine is revealing highly targeted therapies, such
as a new melanoma treatment produced by the company Plexxikon.
Cost is an important consideration when reviewing all of these new technologies. Making medicine more efficient by identifying
high risk individuals using genomics, and applying non-invasive molecular screening tools, should lead to reduced cost,
which is currently consumed by procedures and specialists applying healthcare that is not widely accessible. A smaller
market for the pharmaceutical industry is unattractive and drugs developed for a few may unfortunately cost a lot, putting
them out of reach for patients in New Zealand. General practitioners are likely to be at the very forefront of personalised
medicine which seeks to provide a more global and holistic approach to healthcare.
Current and future personalised medicine tests available in New Zealand
Notes: Other genetic tests of note include TPMT for azathioprine, KRAS for cetuximab and BRAF for
melanoma treatment (see Phase III study from Plexxikon). Pharmacogenetic testing for SSRIs and tamoxifen are also emerging
areas. Clopidogrel and warfarin tests have proven cost-effectiveness.
||Utility and Accuracy
|Stool-based molecular diagnostic test
||Detects the presence of bowel cancer and adenomatous polyps
||Higher uptake of screening
Improved specificity compared to faecal occult blood test
||Predicts success of monotherapy to antihypertensive treatment (chlorthalidone
||Avoids cycling through therapy and may reduce number of pills needed
|Urine-based molecular diagnostic test
||Pacific Edge Biotechnology Ltd
||Detects the presence of bladder cancer
||Screening tool for bladder cancer, allows early diagnosis and treatment
|Clopidogrel pharmacogenetic test
||Predicts risk of adverse events and efficacy
||Prompts treatment increase or change in treatment to reduce stent thrombosis
|Statin pharmacogenetic test
||Predicts myopathy risk
||Improved adherence to treatment
|Warfarin pharmacogenetic test
||Dose prediction and bleeding risk
||Reduced bleeding events
|ACE inhibitor pharmacogenetic test
||Prediction for ACE inhibitor-related cough
||Prevents ACE cough, patients could possibly switch to ARB treatment
This article was contributed by Dr Patrick Gladding, Cardiology Imaging Fellow, Cleveland Clinic,
Competing interests: Dr Gladding has a patent pending on clopidogrel pharmacogenomics with treatment
strategies and is the founder of a non-profit translational research company.
- Epstein RS, Moyer TP, Aubert RE, et al. Warfarin genotyping reduces hospitalisation rates results from the MM-WES
(Medco-Mayo Warfarin Effectiveness study). J Am Coll Cardiol 2010;55(25):2804-12.
- Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among
patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 2010;304(16):1821-30.
- Vladutiu GD, Isackson PJ. SLCO1B1 variants and statin-induced myopathy. N Engl J Med 2009;360(3):304.
- Kauf TL, Farkouh RA, Earnshaw SR, et al. Economic efficiency of genetic screening to inform the use of abacavir sulfate
in the treatment of HIV. Pharmacoeconomics 2010;28(11):1025-39.
- Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions
to abacavir. Lancet 2002;359(9312):1121-2.
- Ferrell PB, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis:
US FDA recommendations. Pharmacogenomics 2008;9(10):1543-6.
- Diehl F, Schmidt K, Durkee KH, et al. Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer
patients. Gastroenterology 2008;135(2):489-98.
- Turner S, Schwartz G, Chapman A, et al. Plasma renin activity predicts blood pressure responses to β-blocker and
thiazide diuretic as monotherapy and add-on therapy for hypertension. Am J Hypertens 2010;23(9):1014-22.