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Bad reactions

Martin Kennedy

Monday, 3 February 2014 11:27am

Geneticists at Otago's Carney Centre for Pharmacogenomics are looking at how genetic make-up may contribute to adverse reactions to drugs.

Almost a third of New Zealand hospital patients have some kind of adverse reaction to drugs and for about one in 20 people the reaction is serious or deadly. These reactions come at an often substantial cost to both patients and the health system.

It is becoming increasingly acknowledged that a person's genetic make-up can have a significant effect on whether they react to medication.

Geneticist Professor Martin Kennedy, director of the University of Otago, Christchurch's Carney Centre for Pharmacogenomics, is one of the country's leading experts in this rapidly developing area of medicine.

"We don't have to look very hard to find patients who have suffered various nasty adverse reactions on different drugs. Quite a large proportion of these are due to differences in genetic make-up and it may be that genetic screening prior to drug treatment would have prevented them," Kennedy says.

"The pace of advance in DNA analysis means it is now feasible to consider applying one test that will screen all genes relevant to adverse drug reactions.

"The pace of advance in DNA analysis means it is now feasible to consider applying one test that will screen all genes relevant to adverse drug reactions."

"We are interested in exploring how this might translate into the New Zealand health-care setting. Can it improve drug safety and reduce costs overall? In what situations would it be best applied?

"Most drug reactions are quite specific – so even if you are fine with some drugs, you won't know until you take a particular drug whether you are allergic to it, or whether it may cause some other kind of adverse drug reaction.

"We are focusing on finding and studying people who have had a serious adverse reaction and then trying to work out if the cause is genetic – and we have had some successes at this.

"We have established a project called UDRUGS to study the genetic factors that predispose people to adverse drug reactions. UDRUGS allows us to collect patient DNA samples and apply modern genetic techniques to clarify the underlying causes of severe adverse drug reactions for selected patients."

A cornerstone of this work has been the establishment of a DNA biobank of patients who have had serious reactions to drugs and is linked to their clinical records.
Kennedy has formed collaborations with international groups working in the same field so he and his team can both contribute to and benefit from the findings of these larger projects.

The UDRUGS project – in which PhD student Eng Wee Chua has played a key role – is currently focused on two liver enzymes CYP2D6 and CYP2C19. Together these act on many therapeutic drugs including those used to treat depression, heart disease, blood pressure, cancer, pain and many other serious conditions. The genes for these enzymes show a wide range of variation in the population and up to 10 per cent of people lack these enzymes altogether.

Kennedy now aims to extend the UDRUGS project to develop and apply genetic knowledge in strategies to prevent adverse drug reactions in New Zealand patients.

A mystery solved

A newly-discovered genetic phenomenon is the subject of a cutting-edge project by Professor Martin Kennedy.

Most people recognise DNA as the distinctive twin spirals of the double helix.

In 2013, Cambridge University scientists announced they had found evidence of a "quadruple helix" in living human cells. The structures appeared at different places in the DNA during growth and division of the cells. Other work has shown these structures to be important for turning genes on and off, and for the process of copying DNA whenever cells divide. This is relevant to cancer and many other diseases.

"G-quadruplexes seem to be under the radar of many geneticists at the moment, but are rapidly becoming a very important area of discovery which will change our views on how genes affect human development and disease."

Kennedy and his group discovered a novel effect of these G-quadruplexes when they were studying a gene called MEST. Humans have two copies of most genes, but whenever they tried to "amplify" a small part of the MEST gene to study it, one copy of the gene always remained invisible.

"Almost nothing could help us identify the missing copy, but we knew it had to exist."

After years of detective work, the "invisible gene" was unveiled.

"MEST is an unusual gene in that the copy each of us inherits from our mother is chemically modified and 'switched off'. Only the copy we get from Dad works.

"Not many of our genes behave in this way and we call this memory of parental origin 'genomic imprinting'. All the imprinted genes are important in disease and human development."

The mystery proved to be due to the formation of G-quadruplex structures combined with the natural chemical modification of the mother's DNA. Together these things make the DNA extremely difficult to amplify, so Mum's DNA is always the "invisible gene", he says.

These results sound a warning to clinical diagnostic laboratories and research groups because these "vanishing genes" are unexpected and can be quite misleading.

This work also suggests the novel idea that G-quadruplexes may have wider roles in the mysterious process of genomic imprinting.

"G-quadruplexes seem to be under the radar of many geneticists at the moment, but are rapidly becoming a very important area of discovery which will change our views on how genes affect human development and disease."