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Professor Gregory Peterson MPS, is Deputy Dean
(Research), Faculty of Health and Co-Director, Health
Services Innovation Tasmania, University of Tasmania
and a community pharmacist.
There is enormous variability between individuals in the therapeutic
response to many drugs.
One source of this variability is differing
pharmacokinetic handling of drugs or
tissue sensitivities (pharmacodynamics)
that are genetically determined.
Given that the elderly are the greatest
users of medication, our expanding
knowledge of pharmacogenomics
should have the potential to benefit
older individuals the most. Some of the
much touted possible benefits of the
application of pharmacogenomics are
now starting to make their way into
practice, although others are still lacking
a robust evidence base.
A clinically important pharmacogenomics
paper, particularly to Asian patients, was
recently published in the British Medical
Journal. Ko and colleagues evaluated the
use of prospective genotyping for human
leucocyte antigen (HLA) to identify
Taiwanese individuals at risk of severe
cutaneous adverse reactions (SCARs)
induced by allopurinol, before they
tested positive for HLA-B*58:01 (19.6%,
n=571) were advised to avoid allopurinol,
and were referred to an alternate drug
treatment or advised to continue with
their pre-study treatment. Patients
who tested negative (80.4%, n=2339)
were given allopurinol. Patients were
interviewed once a week for two months
to monitor symptoms. SCARs did not
develop in any of the patients receiving
allopurinol who screened negative for
HLA-B*58:01. Using historical incidence as
a comparator, the researchers expected to
see seven cases of SCARs but found none;
a highly significant difference. It was
concluded that prospective screening of
the HLA-B*58:01 allele, coupled with an
alternative drug treatment for carriers,
significantly decreased the incidence of
allopurinol-induced SCARs in Taiwanese
As pointed out by Li Wan Po in an
accompanying editorial,5 the results are
not generalisable enough to prompt
routine genetic testing for all patients
needing treatment with allopurinol.
The patients were all Han Chinese
from Taiwan, a population with a high
prevalence of the HLA-B*58:01 allele
(about 10%). This allele frequency
is low in white populations (<1%).
More importantly, even in other Asian
populations, the strength of association
between allele and reaction is weaker.
Almost all carriers of HLA-B*58:01 (about
98%) do not develop SCARs, and in
some ethnic groups (including white
populations), many patients with the
adverse effect do not carry the risk allele.
Other well-known examples of the
association between HLA genotype
and adverse drug reactions include
hypersensitivity to abacavir with the
HLA-B*57:01 allele and carbamazepine-
induced Stevens-Johnson syndrome
and/or toxic epidermal necrolysis with
the HLA-B*15:02 allele.
Two other areas with significant, but
less well established, pharmacogenomic
potential for elderly patients will now
be discussed – using genotyping to
predict the (i) therapeutic response to
acetylcholinesterase inhibitor therapy in
patients with Alzheimer’s disease and (ii)
risk of myopathy related to statin therapy.
Alzheimer’s disease (AD) is the most
common cause of dementia affecting
older people and is associated with the
loss of cholinergic neurons in parts of the
brain.8,9 The strongest genetic risk factor
for sporadic AD is carriage of the epsilon
4 (E4) allele of the apolipoprotein E (APOE)
APOE is a multifunctional protein
playing a key role in the metabolism of
cholesterol and triglycerides, and in tissue
repair and inflammation.
10 The E4 allele is
associated with hypercholesterolaemia and
an increased risk of late-onset (>65 years)
Alzheimer’s disease, while the E2 allele
is associated with the opposite effect.
The APOE E4 allele is associated with
lower activity of choline acetyltransferase
(synthesising acetylcholine) in the
hippocampus and temporal lobes, and
higher acetylcholinesterase activity,
theoretically leading to less residual
cholinergic function in the brain.
The E4 carrier status is found in 65% of
AD cases despite being present in less
than 20% of the general population.
Heterozygotes have a three-fold increased
risk of AD, whereas homozygotes have
an eight-times increased risk of AD,
which may even be as high as 12-fold.
However, homozygosity for APOE E4 does
not guarantee the development of AD.
Thus, APOE E4 testing is not routinely
recommended, even for those with a
family history of AD.
The loss of cholinergic transmission is
assumed to be a principal cause of the
Pharmacogenomics: a role in managing
Alzheimer’s disease and in the use of statins?
BY PROFESSOR GREGORY PETERSON MPS
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