'Goldilocks' gene could determine best treatment for TB patients

February 03, 2012

Tuberculosis patients may receive treatments in the future according to what version they have of a single 'Goldilocks' gene

'Goldilocks' gene could determine best treatment for TB patients Tuberculosis patients may receive treatments in the future according to what version they have of a single 'Goldilocks' gene, says an international research team from Oxford University, King's College London, Vietnam and the USA.

This is one of the first examples in infectious disease of where an individual's genetic profile can determine which drug will work best for them - the idea of personalised medicine that is gradually becoming familiar in cancer medicine.

The scientists found that people generate an immune response to tuberculosis that is 'too much', 'too little' or 'just right', according to what versions they have of the LTA4H gene.

The findings indicate that patients are likely to benefit from different drug treatments depending on their LTA4H gene profile.

Furthermore, the researchers show that steroids used as part of the standard treatment for the most severe form of tuberculosis, TB meningitis, only benefit some patients.

The results of the study, part-funded by the Wellcome Trust, are published in the journal Cell.

Tuberculosis is a major cause of death worldwide, with an estimated 9.4 million cases and 1.7 million deaths in 2009. The disease is caused by Mycobacterium tuberculosis bacteria and differs according to where the infection takes hold. Most TB affects the lungs, but around 40% of cases involve disease elsewhere. In perhaps 1% of cases, TB affects the brain. This form of the disease, TB meningitis, is the most serious. It is hard to diagnose and treat, and even with treatment it is often fatal.

The standard treatment for TB meningitis involves a range of antibiotics to try and kill the bacteria, and the steroid dexamethasone to dampen inflammation - the body's response to tuberculosis infection that can be almost as much of a problem.

The new study combines work in zebrafish at the University of Washington, Seattle to identify genes and biological pathways involved in the immune response to TB, with clinical research work in collaboration with Pham Ngoc Thach Hospital, the Hospital for Tropical Diseases and the Oxford University Clinical Research Unit in Vietnam.

The scientists identified a gene in zebrafish associated with susceptibility to tuberculosis, which controlled the balance of the inflammatory response. Variations in the DNA code in this gene could alter different biological pathways, leading either to too much inflammation or too little. Both too much and too little inflammation were problems, allowing the tuberculosis bacteria to thrive and multiply.

The researchers showed that blocking the appropriate biological pathway with drugs could restore just the right level of inflammatory response.

The researchers based in Vietnam then went back to samples from a previous clinical trial in over 500 patients with TB meningitis. They showed changes at a single position in the human LTA4H gene were associated with treatment response.

Only those having LTA4H genes that led to too much inflammation benefitted from the use of the steroid dexamethasone.

There is some suggestion that the steroid could have an adverse effect for those whose LTA4H genes already lead them to have a reduced inflammatory response, though the result is not statistically significant.

'It's like a "Goldilocks" gene. Depending on what versions of the LTA4H gene you have inherited, you could see an inflammatory response to tuberculosis that is "too much", "too little", or "just right",' explains Dr Sarah Dunstan Head of Human Genetics of Oxford University Vietnam. 'You are likely to benefit most from a treatment tailored to your own genes.'

Dr Guy Thwaites of King's College London and who lead the clinical study in Vietnam on a Wellcome Trust Fellowship says: 'This is a fundamental discovery. It is now possible to think about the use of simple but rapid genetic tests to determine how people will respond to tuberculosis infection and whether they would benefit from steroids.'

'The findings could apply much more widely than just in TB meningitis, or other forms of tuberculosis,' adds Dr Thwaites. 'Since the inflammation pathways governed by the LTA4H gene are central to many infections, there could be implications for many diseases.'

'This study highlights the power of really good clinical research supported through Wellcome Trust Fellowships and linked with some of the very best scientists in the world in Vietnam and the USA, which can bring immediate benefits to patients and also point the way to develop better, more targeted drugs to treat people with tuberculosis in the future,' says Professor Jeremy Farrar who leads the Oxford University Clinical Research Unit in Vietnam. 'The idea that a patient's genes can determine what treatment they will benefit from is pretty novel outside of cancer. Nothing like this has been seen before in infectious disease. Now we need to see if we can use this to help patients with this devastating disease'

King's College London

---

---

	The White Plague: Tuberculosis, Man and Society by Jean Dubos (Author)
	Tuberculosis and Nontuberculous Mycobacterial Infections by David Schlossberg (Editor) Here's an up-to-date 4th Edition of the resource that discusses tuberculosis at a time when major outbreaks and drug-resistant strains of the disease are making headlines.
	The Forgotten Plague: How the Battle Against Tuberculosis Was Won - And Lost by Frank Ryan (Author) Ryan, a physician, offers a history of the cure for tuberculosis, including accounts of the people and scientists involved. The final chapter spells out a renewed threat in the congruence of AIDS and tuberculosis.
	Invincible Microbe: Tuberculosis and the Never-Ending Search for a Cure by Jim Murphy (Author), Alison Blank (Author) This is the story of a killer that has been striking people down for thousands of years: tuberculosis. After centuries of ineffective treatments, the microorganism that causes TB was identified, and the cure was thought to be within reach—but drug-resistant varieties continue to plague and panic the human race. The “biography” of this deadly germ, an account of the diagnosis, treatment, and “cure” of the disease over time, and the social history of an illness that could strike anywhere but was most prevalent among the poor are woven together in an engrossing, carefully researched narrative. Bibliography, source notes, index.
	Tuberculosis: A Comprehensive Clinical Reference, 1e by H. Simon Schaaf MBChB(Stellenbosch) MMed Paed(Stellenbosch) DCM(Stellenbosch) MD Paed(Stellenbosch) (Editor), Alimuddin Zumla BSc.MBChB.MSc.PhD.FRCP(Lond).FRCP(Edin).FRCPath(UK) (Editor) This book provides all the vital information you need to know about tuberculosis, especially in the face of drug-resistant strains of the disease. Coverage includes which patient populations face an elevated risk of infection, as well as which therapies are appropriate and how to correctly monitor ongoing treatment so that patients are cured. Properly administer screening tests, interpret their results, and identify manifestations of the disease, with authoritative guidance from expert clinicians from around the world.Discusses screening tests for tuberculosis so you can interpret their results and identify not only common manifestations of the disease, but also those that are comparatively rare-such as tuberculosis in pregnant women. Covers all clinical aspects of tuberculosis in...
	Captain of Death: The Story of Tuberculosis by Thomas M. Daniel (Author) The dramatic story of tuberculosis is told here in a straightforward and accessible style. It presents the stories of persons connected with the disease, either as victims, or as those who made contributions to our knowledge of it; in addition to these personal accounts, the book unfolds the history and explains the pathogenesis of TB. The re-emergence of tuberculosis as a major American public health hazard has focused much attention on this ancient disease. This book offers a comprehensive account of the disease from prehistoric times through to the present day, detailing the attempts to eradicate it completely. Its four separate sections (the spread of tuberculosis; its infectious nature; susceptibility to it; and methods of treatment) are linked through the device of presenting...
	A Child of Sanitariums: A Memoir of Tuberculosis Survival and Lifelong Disability by Gloria Paris (Author) This dramatic memoir recounts one woman's experience with skeletal tuberculosis, which she contracted at the age of five in the 1930s. It recounts her next nine years living in tuberculosis sanatoriums where she underwent many treatments for the disease and was finally released when she was 14. Despite her subsequent disablement, she went on to marry and have three children, work as a micro-biologist, perform as a comedienne, and serve as an advocate for minority groups. By turns deeply affecting and hilarious, this memoir provides a glimpse into a still-dangerous disease and is a testament to the power of human perseverance and hope.
	The Return of the White Plague: Global Poverty and the "New" Tuberculosis by Matthew Gandy (Editor), Alimuddin Zumla (Editor) A global health catastrophe threatens to undermine all efforts to eradicate poverty and human suffering.The dramatic increase since the 1980s in the global prevalence of tuberculosis, a disease destined as recently as thirty years ago for complete eradication, is a story of medical failure. A pandemic whose geography defies simple categorization, it ranges from schools in the UK to prisons in Russia, from refugee camps in central Africa to affluent suburbs in North America. The 'new' tuberculosis is derived from a combination of different developments such as collapsing health-care services, shifting patterns of poverty and inequality, the spread of HIV, and the emergence of virulent drug-resistant strains. This collection provides an international survey of current thought on the spread...
	Tuberculosis TUBERCULOSIS Last updated 2/25/2012 Table of Contents - Background, Statistics, Epidemiology - Method of Spread - Pathophysiology - History - Risk factors - Differential Diagnosis - Physical Exam - Workup - Treatment - More to come
	Prof. Koch's Method to Cure Tuberculosis Popularly Treated by Max Birnbaum (Author) Prof. Koch's Method to Cure Tuberculosis Popularly Treated is presented here in a high quality paperback edition. This popular classic work by Max Birnbaum is in the English language, and may not include graphics or images from the original edition. If you enjoy the works of Max Birnbaum then we highly recommend this publication for your book collection.