Molecular Tags to catch Common Killers
Leading causes of disability and death worldwide are today a step closer to being identified thanks to a new map of a vital region of the human genome, the Major Histocompatibility Complex (MHC). An international consortium has developed a detailed map of common variation in the MHC, a region that contains genes linked to common diseases such as diabetes and multiple sclerosis, as well as bestowing protection from pathogens and being vital in transplant medicine.
The new map of variation is the finest that can be produced with current technology and in a pilot study the team have shown it can be used to identify variants that predispose to two diseases. The MHC map will help researchers to pinpoint genes involved in many more conditions.
The extended MHC is a region of around 8,000,000 bases on chromosome 6 that contains over 250 genes that code for proteins. As well as being one of the most gene-dense regions of our genome, it is one of the most variable – our immune system and its ability to fight a host of invaders rely on variation in products of the MHC.
“This was one of the reasons to focus on the region but also the most challenging part of the project. No existing project had the power or depth to uncover and map the variation in the MHC. This is the definitive map that will drive the discovery of genes associated with a host of common diseases.
“This resource can be expected to stand for many years to come.”
Dr Stephan Beck Project Leader at the Wellcome Trust Sanger Institute, where one-half of the mapping was carried out
Studies over many years have shown that combinations of variants, called haplotypes, in the MHC can predispose to diseases as diverse as multiple sclerosis, rheumatoid arthritis, coeliac disease and diabetes, while other variants can help to protect against infections such as malaria, TB and AIDS (see Table below). Associations between genes and disease have been extremely difficult to pinpoint because the high level of individual variation means that it is very difficult to find sequence variants common to many or all of the affected people.
In the new study, published online in Nature Genetics on Sunday 24 September, the large amount of common variation is simplified by selecting a reduced set of ‘tag’ variants that can act as surrogates for most of the variants in the region. This reduced set provides a cost-effective resource to investigate disease association in greater detail and with more efficiency.
“The project is complementary to HapMap in which we mapped common human variation across the whole genome but focused to provide a refined and definitive resource for this critical region. We are already using the MHC map in our work with the Wellcome Trust Case-Control Consortium to find genes involved in eleven common diseases, but also in fine mapping studies such as the search for genes implicated in Type 1 diabetes and the cancer of the nasopharynx.
“We knew this critical region would need special attention and these efforts are already paying off.”
Dr Panos Deloukas Project Leader at the Wellcome Trust Sanger Institute
The MHC map places a marker approximately every 1500 bases. Mining this comprehensive collection of common variation in detailed studies has allowed the team to select the tag SNPs, which are up to fivefold more efficient. To test the tag approach, the team examined whether previously discovered risk haplotypes in two diseases – coeliac diseases and systemic lupus erythematosis – could be identified using the new MHC map. The results were remarkable, with sensitivity and specificity both 97 per cent or greater for common HLA alleles (e.g. HLA-A, B and C), confirming the map’s value in screening for new genes implicated in disease.
Conventionally, finding risk-associated haplotypes within this region must be carried out using a process known as HLA typing: this new study found that SNPs can be used instead, in a much simpler assay, saving time and expense. The authors caution that the map cannot be used for all variants and that conventional HLA typing must continue for those alleles that are rarer than 5 per cent. However, it does promise to capture most of the more common variants that affect the largest numbers of people.
“The new map of the MHC is an example of how cutting-edge research could help patients by enriching our understanding of this vital region influencing transplantation treatments, and the outcome of a number of diseases. More importantly, these results might provide a cost-effective, complementary approach to matching donors and patients. More work must be done to investigate the possibilities of applying this knowledge to the development of new diagnostic tools.”
Professor Marcela Contreras MD FRCPath FRCPEdin FRCP, Professor of Transfusion Medicine, RFUCHMS, National Director of Diagnostics, Development & Research at the National Blood Service
This remarkable, detailed study will tell us much about common disease and, it is hoped, will speed progress to new benefits in healthcare.
Examples of diseases associated with genes in the extended MHC
| Autoimmunity | Other immune disorders | Infections | Other diseases | Hypersensitivity |
|---|---|---|---|---|
| Ankylosing spondylitis | Behcet’s disease | AIDS progression | Cervical cancer | Abacavir (HIV) |
| Graves disease | Coeliac disease | Kaposi’s sarcoma | Gastric cancer | Allopurinol (gouty arthritis) |
| Multiple sclerosis | Crohn’s disease | Leprosy/Tuberculosis | Hepatitis B virus non-response to vaccine | Carbamazepine (anticonvulsant, epilepsy) |
| Myasthenia gravis | Psoriasis | Lyme disease | Hepatitis C virus sustained response to therapy | Pollen-induced allergic rhinitis |
| Pemphigus vulgaris | Malaria | Hypertrophic cardiomyopathy | ||
| Rheumatoid arthritis | SARS | Nasopharyngeal carcinoma | ||
| Type 1 diabetes |
More information
Participating Centres
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA
- Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114-2790, USA
- Department of Statistics, University of Oxford, Oxford, UK
- Wellcome Trust Sanger Institute, Hinxton, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. Complex Genetics Section, Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands
- Laboratory of Genomic Diversity, SAIC-Frederick, Inc. and National Cancer Institute, Frederick, Maryland, USA
- Illumina, Inc., San Diego, California, USA
- Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA
- Brigham and Women’s Hospital, Department of Neurology, Boston, Massachusetts, USA
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
- Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Hills Road, Cambridge, UK
- Imperial College of London, London, UK
- Université de Montréal, Department of Medicine, Montréal, Québec, Canada
- Montréal Heart Institute, Montréal, Québec, Canada
Websites
- Publication (doi: 10.1038/ng1885)
- Laboratory in Genetics and Genomic Medicine in Inflammation, the Montreal Heart Institute – http://www.inflammgen.org/
- Wellcome Trust Case-Control Consortium – http://www.wtccc.org.uk/
- Type 1 diabetes – http://www.t1dgc.org/home.cfm
- HapMap Project – http://www.hapmap.org/
Publications:
Selected websites
The Wellcome Trust Sanger Institute
The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.
The Wellcome Trust and Its Founder
The Wellcome Trust is the most diverse biomedical research charity in the world, spending about £450 million every year both in the UK and internationally to support and promote research that will improve the health of humans and animals. The Trust was established under the will of Sir Henry Wellcome, and is funded from a private endowment, which is managed with long-term stability and growth in mind.
