6 October 2009

Gene change could make common asthma drug less effective and increase asthma attacks

The most common asthma reliever may increase the risk of attacks in a subgroup of young sufferers, new research has discovered.

A study by the Brighton & Sussex Medical School (BSMS) and the University of Dundee found a gene change meant children and youths may not fully benefit from Salbutamol, the most popular inhaler medicine prescribed today, if it is taken frequently. A million UK children have asthma and over one hundred thousand carry this gene change.

The authors of the study emphasise that children and young adults with asthma should continue to use their inhalers as indicated by their doctor. The work does not alter current consensus guidelines for the treatment of asthma. It points towards the need for further research in this area of study.

The research, led by Professor Somnath Mukhopadhyay at BSMS and Professor Colin Palmer at Dundee, found that a specific change, called the Arg16 variant, in the gene that makes the body molecule that binds Salbutamol, may cause the medicine to be less effective as a reliever when used frequently (at least once a day).

Their research showed that while most patients taking Salbutamol had their asthma well under control, those carrying the Arg16 variant and using their inhaler daily, were at a 30 per cent greater risk of asthma attacks compared to those with the more usual form of the gene. Furthermore, those with a double copy of the Arg16 gene, 13 per cent of the population, were twice as likely not to respond to the drug.

Asthma attacks are a common cause of hospital admissions and visits to GPs, and are a major contributor to the health service cost burden. Researchers said it was possible that the presence of this gene change in young people with asthma and who were taking Salbutamol frequently could be worsening their health and driving up healthcare costs.

They said alternative medicines that act through biological pathways not involving the Arg16 variant body molecule currently were available but, they said, more research was needed to determine whether they relieved symptoms better and reduced asthma attack risks in genetically-susceptible patients.

And more research was needed to determine if genetic testing for the Arg16 variant should be used in deciding routine asthma prescribing.

The researchers said this could be a step along the path to personalised medicine where genetic information on individual patients may lead to more effective use of drugs.

Professor Mukhopadhyay said: 'Do not stop using your inhaler or change the way you use the inhalers. Salbutamol via the blue inhaler is effective ‘reliever’ treatment in most children but it is common experience among doctors that a proportion of children do not seem to respond to this medicine as well as others.'

'Some of these children could progress to develop asthma attacks with wheeze and cough that leads to days off school, visits to GPs, courses of oral steroids, and often, hospital admissions, despite the use of concurrent controller medication.'

'Our study shows that common gene changes may predict the children with asthma who will have a worsening of symptoms with this commonly used medicine. We need to find out if alternative reliever medication will provide better asthma control in these children. Our work does not alter current consensus guidelines for the treatment of asthma.It points towards the need for further research in this area.'

Professor Palmer said: 'Salbutamol and Salmeterol are extremely effective drugs in the management of asthma, however it is known that they work better in some children more than others. This study gives us a better understanding as to who is at risk of poor asthma control using these drugs, however this information is not useful if we do not have a better treatment for these children. We now need to determine if other medications might be more effective in the children with the Arg16 variant.'

'This study is just scratching the surface of the use genetic information in the development of personalised medicine, and the pace at which genetic technology is developing is staggering. It is now possible to assess an individual’s entire genome for variants that determine response to drugs. However a rigorous phase of testing will be required before these tests make it to routine clinical practise'

Notes to editors:
The team studied 1,182 children and adolescents with asthma in Tayside, Scotland and is now extending some of its work. A new study has been set up in Brighton, Eastbourne, Worthing and Haywards Heath, where the team has already recruited over 200 children with asthma.

The new research from Dundee and Brighton ties this increased risk to a specific genetic status, known as the Arg/Arg-16 genetic status. Prof Lipworth of the Asthma and Allergy Research Group, Dundee had already identified in a previous paper that the same gene was responsible in adult asthmatics for making the airways more twitchy when exposed to regular salmeterol, and another similar drug called formoterol, even in patients taking a steroid inhaler at the same time. Salbutamolis part of a group of drugs known as beta-agonists, and is widely prescribed within the NHS to patients with asthma who have breakthrough symptoms, often despite the use of ‘controller’ medicine like inhaled steroids. While this drug is meant to be taken as a “reliever” medicine, many children use this drug at least once a day, and it is in these children that the Arg16 variant is associated with poorer asthma control.

One of the ‘controller’ medicines called Salmeterol works through the same body molecule as Salbutamol, and the researchers found a similar increase in asthma attacks in children with this gene change using Salmeterol.

Researchers said this supported the findings with the more commonly used Salbutamol but also highlighted risks of treatment failure in the smaller numbers of Arg-16 carriers who are on regular treatment with the long-acting controller Salmeterol.

The study suggests the importance of monitoring patients who are started on Salbutamolto check if the medicine is working. If asthma is still poorly controlled onSalbutamol as reliever and there is no other obvious contributory cause, then alternatives to Salbutamol, rather than additional treatments, may need to be considered. There are a number of other drugs working through a different body molecule that may be useful as an alternative treatments in these individuals.

The study and its follow-up has been supported by the children with asthma and their families in Tayside, Scotland and Sussex, England, and by their general practitioners.

The University of Dundee is internationally recognised for excellence in life sciences and medical research with particular expertise in cancer, diabetes and tropical diseases. The University has both a 5* rated medical school and College of Life Sciences, with research expanding from 'the cell to the clinic to the community'. See www.dundee.ac.uk for further details.

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