A full-day symposium on September 13, chaired by Professor Paul Nicholls (Welsh school of pharmacy), reflected current interest in genetic factors in drug therapy
Genetic abnormalities were first recognised in 1900, when Sir Archibald Garrod,
in a lecture at the Royal College of Physicians of London, reported variations
in urinary constituents, Professor DAVID PRICE EVANS (Riyadh, Saudi Arabia)
told the symposium. In 1908, Garrod had published his book ‘Inborn errors
of metabolism’.
Highlights of the subsequent 50 years had included the first inter-ethnic investigations
by Padnick, taste polymorphism by Fox and Noller and a recognition of the biological
significance of genetic polymorphism by Ford.
The latter half of the 20th century had seen major advances in the field, both
from the drug metabolism perspective, where Tecwyn Williams and Roger Williams
had stimulated wide ranging ideas, and in the recognition of the functions and
variety of the P450 enzymes — now renamed the CYP enzymes. It had led to
a variety of definitions of pharmacogenetics, the study of variability in drug
response due to heredity, and pharmacogenomics, the science underpinning the
genetic basis for individual variations in response to therapeutic agents.
The Human Genome Project, which had just issued the first comprehensive map
of the human genome, had been a major stimulus to the whole pharmacogenetics
field and was providing the basis for definitive statements on genetic polymorphisms.
Professor Evans commented on some specific studies in bladder, bronchial and
colorectal cancers, where there were some clear associations with particular
CYP enzyme profiles, but where the authors of the studies still suggested caution
in interpretation. This was an active area of research and was likely to be
of immense value in ensuring that patients received “tailored” medications
in the future.
Occupational and environmental health seemed to be a major area for exploitation
where guidance to the public on risks such as those associated with smoking
would be more clearly defined, although not necessarily understood or acted
upon. Much data on Gulf war syndrome had led to possible mechanisms for the
clinical observations but there was still intense debate in this area.
CYP enzymes
Reviewing the CYP drug metabolising enzymes, Professor PHILIP ROUTLEDGE (Cardiff)
made a strong case for the association of particular CYP enzymes and patient
responses to cardiovascular medicine, notably the warfarin range of anticoagulants.
He stressed the small therapeutic window of drugs such as warfarin and noted
that the particular profile of metabolic enzymes could have marked clinical
consequences. Patients who metabolised warfarin slowly were potentially at risk
in trauma situations when a severe bleeding episode could occur.
Polymorphism of drug receptors
Professor IAN HALL (Nottingham) used asthma genetics to comment on the polymorphisms
of drug receptors. He suggested that opportunities existed for candidate genes
related to airway remodelling, to variations in the cells of the immune system
and in the genes responsible for therapeutic responses. It had been shown that
on average one in 600 bases varied in gene areas of the genome and one in 300
in non-gene areas.
It was important to have strict criteria for functional changes, association
with relevant clinical endpoints or on prevalence in the general population
before definitive statements on polymorphisms could be made.
Interestingly, the number of single nucleotide polymorphisms (SNPs) varied with
airway receptors from 16 for the B2 adrenoceptor to none for the M3 muscarinic
receptor, with much current research ongoing into phosphodiesterase IV enzyme.
Drazen had suggested that there were polymorphisms in the 5-lipoxygenase enzyme
where if there was reduced activity there was a much-reduced clinical response
to FLAP (5-lipoxygenase activator protein) inhibitors.
In one example of a monocyte receptor (CCR5), a polymorphism that had probably
arisen in Scandinavia some 5,000 years ago appeared to give an implied selection
advantage. This had been confirmed in a recent study in Aberdeen. Such studies
were key in the translation of pharmacogenetic research into general medicine.
They could help in determining reduced risk for asthma and variation in medicine
targets and they would help in therapeutic interpretation.
Childhood leukaemias
Speaking on childhood leukaemias, Professor WILLIAM EVANS (Memphis, United States)
said that there two clear population curves when methotrexate and mercaptopurine
were used as therapeutic agents. The variation was more than 30-fold in incidence
of adverse reactions despite matching for age and surface area. He noted that
adverse drug reactions (ADRs) were the fourth leading cause of hospitalisation
and the fifth leading cause of mortality in the US.
The use of new protocols to select out non-responders and ADR potential had
increased cure response rates from 5 per cent in 1962 to 80 per cent in 1998,
although all medications had been available since 1979 (etoposide 1983). Better
management was the key — notably for mercaptopurine, which had been approved
for use in 1953.
At least nine genetic subgroups had been defined, and the younger population
showed a higher proportion of treatable patients. These variations also had
an ethnic basis. This had been published in the general medical literature rather
than the cancer literature to increase awareness of the power of such research.
The advent of DNA “chips” to analyse patients before initiating therapy
would allow the selection of disease genotypes and so improve clinical outcomes.
Pharmacogenetics in prophylaxis
Professor KLAUS LINDPAINTNER (Roche, Switzerland) described the use of pharmacogenetics
in the move from intervention therapy towards prophylaxis for many diseases.
He reflected that the association of trauma with the ApoE genotype increased
the risk of Alzheimer’s disease 10-fold, and that even a high exposure
to boxing increased the risk four times.
Towards the end of the 20th century the drive in medicine had been towards better
imaging techniques for diagnosis but in his view the new growth would come in
the use of novel and more informative in vitro diagnostic tools. The drivers
of medical progress would be differential diagnosis where clinical acumen was
key and risk assessment where classical epidemiology would be the primary contributor.
Genetic information would help both components.
In the short term, pharmacogenetics would help to limit ADRs and increase efficacy
while in the medium term genetic epidemiology would allow specific subgroups
to be targeted. If no disease association could be found then non-selective
therapy could be tried. In the long term genetics would inform the selection
of new drug targets.
Turning to the potential abuse of genetic information, Professor Lindpaintner
said that the widespread fear was not matched by concerns over other medical
information, but the current drive to increase confidentiality could limit the
wider use of data for both individual patients and medicine in general. This
did mean that there was an absolute need for dialogue on these societal concerns
and a legal framework to address them. The key was to always use the highest
standards in data acquisition and utility and ensure transparency at all times.
He concluded with Sir William Osler’s statement in ‘The principles
and practice of medicine’ (1892) that “if it were not for the great
variability among individuals medicine might as well be a science and not an
art”, a quotation that had been used widely throughout the symposium and
was particularly apt for this topic. — Contributed.