Title |
Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A
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Published in |
Nature, November 2007
|
DOI | 10.1038/nature06406 |
Pubmed ID | |
Authors |
Paul R. Burton, David G. Clayton, Lon R. Cardon, Nick Craddock, Panos Deloukas, Audrey Duncanson, Dominic P. Kwiatkowski, Mark I. McCarthy, Willem H. Ouwehand, Nilesh J. Samani, John A. Todd, Peter Donnelly, Jeffrey C. Barrett, Paul R. Burton, Dan Davison, Peter Donnelly, Doug Easton, David Evans, Hin-Tak Leung, Jonathan L. Marchini, Andrew P. Morris, Chris C. A. Spencer, Martin D. Tobin, Lon R. Cardon, David G. Clayton, Antony P. Attwood, James P. Boorman, Barbara Cant, Ursula Everson, Judith M. Hussey, Jennifer D. Jolley, Alexandra S. Knight, Kerstin Koch, Elizabeth Meech, Sarah Nutland, Christopher V. Prowse, Helen E. Stevens, Niall C. Taylor, Graham R. Walters, Neil M. Walker, Nicholas A. Watkins, Thilo Winzer, John A. Todd, Willem H. Ouwehand, Richard W. Jones, Wendy L. McArdle, Susan M. Ring, David P. Strachan, Marcus Pembrey, Gerome Breen, David St Clair, Sian Caesar, Katherine Gordon-Smith, Lisa Jones, Christine Fraser, Elaine K. Green, Detelina Grozeva, Marian L. Hamshere, Peter A. Holmans, Ian R. Jones, George Kirov, Valentina Moskvina, Ivan Nikolov, Michael C. O’Donovan, Michael J. Owen, Nick Craddock, David A. Collier, Amanda Elkin, Anne Farmer, Richard Williamson, Peter McGuffin, Allan H. Young, I. Nicol Ferrier, Stephen G. Ball, Anthony J. Balmforth, Jennifer H. Barrett, D. Timothy Bishop, Mark M. Iles, Azhar Maqbool, Nadira Yuldasheva, Alistair S. Hall, Peter S. Braund, Paul R. Burton, Richard J. Dixon, Massimo Mangino, Suzanne Stevens, Martin D. Tobin, John R. Thompson, Nilesh J. Samani, Francesca Bredin, Mark Tremelling, Miles Parkes, Hazel Drummond, Charles W. Lees, Elaine R. Nimmo, Jack Satsangi, Sheila A. Fisher, Alastair Forbes, Cathryn M. Lewis, Clive M. Onnie, Natalie J. Prescott, Jeremy Sanderson, Christopher G. Mathew, Jamie Barbour, M. Khalid Mohiuddin, Catherine E. Todhunter, John C. Mansfield, Tariq Ahmad, Fraser R. Cummings, Derek P. Jewell, John Webster, Morris J. Brown, David G. Clayton, G. Mark Lathrop, John Connell, Anna Dominiczak, Nilesh J. Samani, Carolina A. Braga, Beverley Burke, Richard Dobson, Johannie Gungadoo, Kate L. Lee, Patricia B. Munroe, Stephen J. Newhouse, Abiodun Onipinla, Chris Wallace, Mingzhan Xue, Mark Caulfield, Martin Farrall, Anne Barton, Ian N. Bruce, Hannah Donovan, Steve Eyre, Paul D. Gilbert, Samantha L. Hider, Anne M. Hinks, Sally L. John, Catherine Potter, Alan J. Silman, Deborah P. M. Symmons, Wendy Thomson, Jane Worthington, David G. Clayton, David B. Dunger, Sarah Nutland, Helen E. Stevens, Neil M. Walker, Barry Widmer, John A. Todd, Timothy M. Frayling, Rachel M. Freathy, Hana Lango, John R. B. Perry, Beverley M. Shields, Michael N. Weedon, Andrew T. Hattersley, Graham A. Hitman, Mark Walker, Kate S. Elliott, Christopher J. Groves, Cecilia M. Lindgren, Nigel W. Rayner, Nicholas J. Timpson, Eleftheria Zeggini, Mark I. McCarthy, Melanie Newport, Giorgio Sirugo, Emily Lyons, Fredrik Vannberg, Adrian V. S. Hill, Linda A. Bradbury, Claire Farrar, Jennifer J. Pointon, Paul Wordsworth, Matthew A. Brown, Jayne A. Franklyn, Joanne M. Heward, Matthew J. Simmonds, Stephen C. L. Gough, Sheila Seal, Michael R. Stratton, Nazneen Rahman, Maria Ban, An Goris, Stephen J. Sawcer, Alastair Compston, David Conway, Muminatou Jallow, Melanie Newport, Giorgio Sirugo, Kirk A. Rockett, Dominic P. Kwiatkowski, Claire Bryan, Suzannah J. Bumpstead, Amy Chaney, Kate Downes, Jilur Ghori, Rhian Gwilliam, Sarah E. Hunt, Michael Inouye, Andrew Keniry, Emma King, Ralph McGinnis, Simon Potter, Rathi Ravindrarajah, Pamela Whittaker, David Withers, Panos Deloukas, Hin-Tak Leung, Sarah Nutland, Helen E. Stevens, Neil M. Walker, John A. Todd, Doug Easton, David G. Clayton, Paul R. Burton, Martin D. Tobin, Jeffrey C. Barrett, David Evans, Andrew P. Morris, Lon R. Cardon, Niall J. Cardin, Dan Davison, Teresa Ferreira, Joanne Pereira-Gale, Ingeleif B. Hallgrimsdóttir, Bryan N. Howie, Jonathan L. Marchini, Chris C. A. Spencer, Zhan Su, Yik Ying Teo, Damjan Vukcevic, Peter Donnelly, David Bentley, Matthew A. Brown, Lon R. Cardon, Mark Caulfield, David G. Clayton, Alistair Compston, Nick Craddock, Panos Deloukas, Peter Donnelly, Martin Farrall, Stephen C. L. Gough, Alistair S. Hall, Andrew T. Hattersley, Adrian V. S. Hill, Dominic P. Kwiatkowski, Christopher G. Mathew, Mark I. McCarthy, Willem H. Ouwehand, Miles Parkes, Marcus Pembrey, Nazneen Rahman, Nilesh J. Samani, Michael R. Stratton, John A. Todd, Jane Worthington |
Abstract |
The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. |
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Other | 2 | <1% |
Unknown | 333 | 94% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 86 | 24% |
Student > Ph. D. Student | 63 | 18% |
Student > Bachelor | 37 | 10% |
Professor | 31 | 9% |
Student > Master | 29 | 8% |
Other | 61 | 17% |
Unknown | 49 | 14% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 113 | 32% |
Medicine and Dentistry | 72 | 20% |
Biochemistry, Genetics and Molecular Biology | 54 | 15% |
Immunology and Microbiology | 14 | 4% |
Computer Science | 7 | 2% |
Other | 37 | 10% |
Unknown | 59 | 17% |