A therapy tailored to individuals’ genes has transformed the treatment of a
chronic disease, in a ground-breaking advance for personalised medicine.
Hundreds of diabetes sufferers in Britain were able to switch from insulin
injections to cheaper, more effective drugs after a simple test showed that
they had a particular genetic form of the disorder.
The test, which is available on the NHS, could benefit up to 20,000 with the
condition, many of whom are wrongly told that they have type 1 diabetes, and
save the NHS at least £30,000 over each patient’s lifetime. A second genetic
test could identify another 30,000 people with a mild form of diabetes, who
often require no treatment at all.
The success of the test highlights the growing potential of pharmacogenetics –
the new medical science of diagnosing diseases with reference to a person’s
genetic profile, allowing for much more effective therapy. Scientists
believe that within the next decade this approach will be applied to the
treatment of other chronic conditions such as heart disease and type 2
diabetes.
At present, doctors generally select from a few possible treatments according
to their clinical judgment, but it can be difficult to predict which drugs
will be effective for a particular patient and which will cause unpleasant
or dangerous side-effects.
As genetic factors often influence a patient’s response to therapy, DNA tests
should allow a more targeted approach. Patients could be matched to drugs
that are most likely to work, and steered away from those that may cause
complications.
Scientists have already started research into how genes affect a patient’s
response to statins – the cholesterol-lowering drugs taken by about three
million people in Britain – and pharmacogenetics has also improved the
treatment of some cancers, with doctors now giving patients whose tumours
have a certain genetic makeup drugs such as Herceptin.
Andrew Hattersley, Professor of Molecular Medicine at Peninsula Medical School
in Exeter, who led the research, said: “If past evidence-based medicine was
about what was best on average for patients, then the next step will be what
is best for individual patients, by classifying their conditions more
precisely. Having seen how successful it can be, it makes it worth trying to
make the effort to define diseases better with genetic insights.”
The advance follows the discovery of a gene called HNF1-alpha, which when
mutated causes an unusual form of diabetes known as maturity-onset diabetes
of the young (Mody).
Diabetes is usually split into two classes. Type 1 typically starts in
childhood or adolescence, and involves the destruction of the insulin-making
beta cells in the pancreas. Sufferers must inject themselves with insulin,
usually daily, to control blood sugar levels.
The other kind, type 2, generally begins in adulthood, and is often related to
obesity. It is treated with drugs and/ or diet and exercise.
People with Mody are regularly misdiagnosed with type 1 diabetes, because the
condition usually manifests itself in adolescence or early adulthood, and
sufferers are not usually overweight. The condition, however, responds
poorly to insulin therapy and many sufferers struggle to control their blood
sugar.
A simple genetic test, costing £380 and available on the NHS, can determine
whether a diabetic has the HNF1 -alpha mutation. If a patient tests
positive, he or she can stop injecting insulin and instead take low doses of
sulphonylureas – cheap, generic tablets that have few sideeffects and are
usually used to control type 2 diabetes.
“The test has completely changed the treatment of these patients,” Professor
Hattersley said. “What it means on an individual level is phenomenal. Not
only can you stop insulin injections completely, but you get much better
blood glucose control.”
This genetic diagnosis also saves the NHS money. Insulin costs more than
sulponylurea therapy and switching saves £30,000 over the patient’s
lifetime, even before the benefits of better health are taken into account.
So far, Professor Hattersley’s clinic and another centre in Edinburgh have
diagnosed Mody in about 700 patients, but the number of people with the
mutation in Britain is an estimated 20,000. Most have been misdiagnosed and
are injecting insulin, but would achieve much better results if they have
the genetic test.
“These patients are often not recognised,” Professor Hattersley said. “They
sit in diabetes clinics all over the world being treated as type 1
diabetics, but that diagnosis is wrong.
“We need to teach clinicians how to recognise this, to get it into main-stream
practice to stop the misdiagnosis. It is so new that few centres do the
tests. It is starting the idea of individualised medicine. It is simply a
more sophisticated diagnosis – these are not patients with type 1 diabetes,
the diagnosis is wrong, and they should be treated in a different way.”
As the HNF1-alpha mutation is dominant, sufferers generally have a parent and
other relatives with the same disorder. Such family histories can be used to
work out who should have the test, but only a small fraction of carriers
have been identified so far in Britain.
In the longer term, pharmacogenetics has great potential to improve treatment
of type 2 diabetes and heart disease. This will be harder because these
chronic conditions are not caused by single genes, but tend to be influenced
by common genetic variants that combine to increase individuals’ risk.
Professor Hattersley said that it was already clear to clinicians that type 2
diabetes was not a single disease, any more than cancer. “I would love a
future where we no longer talk about type 2 diabetes,” he said. “My feeling
is my clinics are already like that, but I can’t classify it. I believe that
will be a reality in the next decade or so.
“There will come a time when we remember when we used type 2 diabetes for all
the diabetes we didn’t know the cause of, and then laugh.”
Heart disease research is also starting to follow the pharmacogenetic route.
In April the Wellcome Trust announced that it would fund an investigation,
led by Colin Palmer, at the University of Dundee, into the genetic factors
that affect people’s response to statins.Although statins are generally
considered to be safe, they occasionally cause a muscle-wasting condition
called rhabdomyolysis, which can lead to heart failure. This risk may be
linked to genetics, and if Dr Palmer finds any of the variations that are
responsible, it would be possible to test patients so that those at high
risk of a dangerous reaction to statins are not prescribed them.
Map of our well-being
— Working draft of the map of the human genome – our genetic makeup – released
in 2000
— Francis S. Collins, director of the National Human Genome Research
Institute, announces in 2001 that the “instruction book” on the human genome
is ready to be used for medical discoveries
— Also in 2001, Novartis launches Glivec as a genetically targeted drug
to treat leukaemia without harming healthy cells. A similar drug to treat
breast cancer, Herceptin, launched in 2006
— In 2007 online personal genotyping becomes available. For £500, deCODE
in Iceland and 23andMe in the US calculate a person’s risk of 20 diseases,
such as Alzheimer’s and heart attacks
Sources: Times database, University of Virginia
Case study: ‘It was only after the test I realised how ill I had been’
Dan Humphries, 20, is in the middle of his first-year exams at Bristol
University, where he is studying veterinary science. He plays football and
cycles regularly, and spent a gap year working on a dairy farm.
Three years ago, all this seemed impossible: Mr Humphries, from Shawbury,
Shropshire, was then an extremely sick teenager. At 16, he began to feel
constantly thirsty, and type 1 diabetes was diagnosed. Yet the insulin he
was prescribed made no difference to his condition, which was deteriorating
rapidly.
He suffered regular blackouts, often without warning, and was often too sick
to go to college. “I don’t remember the period well because I spent a lot of
it unconscious,” he said. “I could only go to college intermittently and had
to stop football — I was on the floor after ten minutes.”
His mother, Mary, 47, had also had diabetes diagnosed, a few months before her
son, and she knew that it ran in her family. As a nurse, she knew about the
possibility of Mody, and along with the family’s GP tried for months to
persuade a consultant endocrinologist to refer her son for genetic testing,
without success.
“The consultant was adamant that Dan was too old for Mody, it had to be type
1,” Mrs Humphries said. “I pleaded with him for about eight months. In the
end, I found out about the Exeter clinic on the internet and went to them
behind the consultant’s back.”
The genetic test was positive for the HNF1-alpha gene: he stopped injecting
insulin and began low doses of glicalazide, a sulphonylurea drug.
“I cannot explain how fantastic it was,” he said. “The difference in one day
was absolutely stunning. I went out cycling for 20 miles and my bloods were
absolutely perfect. It was only then, after the test and switching
treatment, that I understood how ill I had been beforehand.”
He returned to college, where he got straight As in his A levels and has yet
to have any serious setbacks on his new treatment regimen.
This is an excellent article. You have mentioned "....
A second genetic test could identify another 30,000 people with a mild form of diabetes, who often require no treatment at all. ..". It seem to have dropped from the story. Would you care to name the test and also the group.
A Herath, Abingdon, UK