Joint press release issued by the Wellcome Trust and the Juvenile Diabetes Research Foundation

Scientists identify genetic variation in 'molecular brake' for immune system that increases risk of three serious common diseases

The Human Genome Project has helped scientists identify an inherited fault associated with diseases affecting more than 1 million people in the UK. Researchers have found a variation in a 'master regulator' of the immune system associated with an increased risk of developing type 1 (early onset) diabetes, Graves disease and autoimmune hypothyroidism.

The gene variant or factors on the same genetic pathway that it controls, are potential therapeutic targets in many people with these immune disorders as the variant is found in a majority of these individuals.

Researchers at the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation laboratory in Cambridge, led by Professor John Todd and Professor Linda Wicker in collaboration with Dr Stephen Gough of the University of Birmingham, have identified subtle variations in the sequence of a gene called CTLA-4 (cytotoxic T lymphocyte antigen 4) which when present are associated with an increased risk of developing these autoimmune diseases. The findings are published on Wednesday 30 April 2003 in an online version of Nature.

The CTLA-4 variation is present in 50 per cent of the population. CTLA-4 is a vital regulator of the immune system, and applies a "molecular brake" to stop it running out of control and causing autoimmune or other disorders. Autoimmune disorders affect around 5 per cent of the population; they occur when the immune system turns on itself and attacks the body's normal cells rather than performing its normal surveillance and attack of invading organisms, or infected or abnormal cells.

The researchers carried out genetic studies in hundreds of families and found that a small region of the human genome on chromosome 2 was home to at least three genes associated with the immune response, which made them good candidates for contributing to the autoimmune diseases. They also knew that in a mouse model of type 1 diabetes, susceptibility to the disease was associated with the same three genes on an equivalent region of the mouse genome, on chromosome 1.

The genes in the human chromosome 2q33 region were analysed for single nucleotide polymorphisms (SNPs), small genetic variations. Their analysis showed that in a particular region of CTLA-4, certain SNP variants increased susceptibility to the three autoimmune diseases by influencing the levels at which the gene is active. The result was confirmed in the mouse model of type 1 diabetes. The researchers believe that these SNPs are likely to be one of many variations in the human genome that govern susceptibility to type I diabetes, Graves'disease and autoimmune hypothyroidism.

Only about ten genetic associations in common diseases have been convincingly established, and CTLA4 can now be added to this list. This is thought to be the first time such a complete and systematic approach to fine gene mapping has been taken, with results mirrored in a mouse model.

Professor John Todd said: "The study shows that the human genome project can provide important biological information about common chronic diseases. By using these approaches much more can be learned in the future about the basic, inherited causes of disease. These results support the idea that autoimmune diseases are due to a failure of the controls that prevent the immune system attacking the body's own tissues."

Professor Linda Wicker said: "CTLA-4, or the genes on the same pathway, are potential targets for therapy, as the gene variant is found in a majority of those who are susceptible to autoimmune disease."

There is no immediate benefit from this discovery to those affected by these diseases, in terms of diagnosis or treatment. "The search for the genetic and other causes of autoimmune diseases will take some time but it is an essential part of future attempts to safely divert the immune response away from disease in those who are at risk," said Professor Todd. "A more near-term problem is the rejection of transplanted pancreatic islets into type 1 diabetics. An understanding of the pathways of the immune system that destroy the insulin-producing islets in this disorder might help develop new ways of preventing the destruction of transplants," he added.

Although they commonly cluster in the same families, autoimmune disorders are classic examples of complex diseases - those in which multiple genes and environmental factors interact. The role of environment is also crucial in the development of type I diabetes - if one of a pair of twins has type I diabetes, there is only a 30-50 per cent chance the other child will be affected.

In the case of type 1 diabetes, the insulin producing beta cells in the pancreas are destroyed by an autoimmune response. It strikes children suddenly, makes them insulin-dependent for life and carries the constant threat of long term complications. People with type 1 diabetes must test their blood glucose several times a day and are dependent on multiple daily insulin injections - just to stay alive. However, insulin is an imperfect treatment and does not guarantee protection against complications, which include blindness, kidney disease, limb amputations and heart disease.

Graves' disease affects 1 in 200 individuals in the western world and results from the presence of antibody molecules that stimulate and attack the thyroid gland, causing growth of the gland and overproduction of thyroid hormone. Among the symptoms are tiredness, weight loss and heart palpitations. It occurs around eight times more frequently in women than men. Graves'disease may have its onset after stress, viral infection or pregnancy. Autoimmune hypothyroidism (a cause of an underactive thyroid) results from immune system cells inappropriately attacking the thyroid gland.

Further information

Professor John Todd
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory
Tel: 01223 762101
E-mail: john.todd@cimr.cam.ac.uk
Mobile: 07786 540003

Professor Linda Wicker
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory
Tel: 01233 762816
E-mail: linda.wicker@cimr.cam.ac.uk

Dr Shaun Griffin
Wellcome Trust Media Office:
Tel: 020 7611 8612
Mobile: 07710 307059
E-mail: s.griffin@wellcome.ac.uk

Ruth Best
Juvenile Diabetes Research Foundation
Tel: 020 7713 2030
Mobile: 07939 557438
E-mail: rbest@jdrf.org.uk

Notes to Editors:

1. A case study with type 1 diabetes is available. Please contact Ruth Best for details.

2. The Advance Online Publication (AOP) is available at www.nature.com on 30 April at 19:00 London time / 1400 US Eastern time. The paper's digital object identifier (DOI) is 10.1038/nature01621. It will appear in print at a later date.

3. The Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory (DIL) was established in 2000 with grants from the two charities of some £20 million.

4. The Wellcome Trust is an independent research-funding charity, established under the will of Sir Henry Wellcome in 1936. It is funded from a private endowment which is managed with long-term stability and growth in mind. The Trust's mission is to foster and promote research with the aim of improving human and animal health. Website: www.wellcome.ac.uk

5. Juvenile Diabetes Research Foundation International (JDRF) is dedicated to finding a cure for diabetes and its complications through the support of research. Founded in 1970 by the parents of children with type 1 (juvenile) diabetes, JDRF is the world's leading nonprofit, nongovernmental funder of diabetes research and has, since inception, provided more than £400 million to diabetes research worldwide. Website: www.jdrf.org.uk

6. For more information on the Juvenile Diabetes Research Foundation /Wellcome Trust Diabetes and Inflammation Laboratory visit: www-gene.cimr.cam.ac.uk/todd/