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Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Nejentsev, Sergey; Howson, Joanna M. M.; Walker, Neil M.; Szeszko, Jeffrey; Field, Sarah F.; Stevens, Helen E.; Reynolds, Pamela; Hardy, Matthew; King, Erna; Masters, Jennifer; Hulme, John; Maier, Lisa M.; Smyth, Deborah; Bailey, Rebecca; Cooper, Jason D.; Ribas, Gloria; Campbell, R. Duncan; Clayton, David G.; Todd, John A.; Burton, Paul R.; Clayton, David G.; Cardon, Lon R.; Craddock, Nick; Deloukas, Panos; Duncanson, Audrey; Kwiatkowski, Dominic P.; McCarthy, Mark I.; Ouwehand, Willem H.; Samani, Nilesh J.; Todd, John A.; Donnelly, Peter; Barrett, Jeffrey C.; Burton, Paul R.; Davison, Dan; Donnelly, Peter; Easton, Doug; Evans, David; Leung, Hin-Tak; Marchini, Jonathan L.; Morris, Andrew P.; Spencer, Chris C. A.; Tobin, Martin D.; Cardon, Lon R.; Clayton, David G.; Attwood, Antony P.; Boorman, James P.; Cant, Barbara; Everson, Ursula; Hussey, Judith M.; Jolley, Jennifer D.; Knight, Alexandra S.; Koch, Kerstin; Meech, Elizabeth; Nutland, Sarah; Prowse, Christopher V.; Stevens, Helen E.; Taylor, Niall C.; Walters, Graham R.; Walker, Neil M.; Watkins, Nicholas A.; Winzer, Thilo; Todd, John A.; Ouwehand, Willem H.; Jones, Richard W.; McArdle, Wendy L.; Ring, Susan M.; Strachan, David P.; Pembrey, Marcus; Breen, Gerome; St Clair , David; Caesar, Sian; Gordon-Smith, Katherine; Jones, Lisa; Fraser, Christine; Green, Elaine K.; Grozeva, Detelina; Hamshere, Marian L.; Holmans, Peter A.; Jones, Ian R.; Kirov, George; Moskvina, Valentina; Nikolov, Ivan; Oâ Donovan, Michael C.; Owen, Michael J.; Craddock, Nick; Collier, David A.; Elkin, Amanda; Farmer, Anne; Williamson, Richard; McGuffin, Peter; Young, Allan H.; Nicol Ferrier, I.; Ball, Stephen G.; Balmforth, Anthony J.; Barrett, Jennifer H.; Bishop, D. Timothy; Iles, Mark M.; Maqbool, Azhar; Yuldasheva, Nadira; Hall, Alistair S.; Braund, Peter S.; Burton, Paul R.; Dixon, Richard J.; Mangino, Massimo; Stevens, Suzanne; Tobin, Martin D.; Thompson, John R.; Samani, Nilesh J.; Bredin, Francesca; Tremelling, Mark; Parkes, Miles; Drummond, Hazel; Lees, Charles W.; Nimmo, Elaine R.; Satsangi, Jack; Fisher, Sheila A.; Forbes, Alastair; Lewis, Cathryn M.; Onnie, Clive M.; Prescott, Natalie J.; Sanderson, Jeremy; Mathew, Christopher G.; Barbour, Jamie; Khalid Mohiuddin, M.; Todhunter, Catherine E.; Mansfield, John C.; Ahmad, Tariq; Cummings, Fraser R.; Jewell, Derek P.; Webster, John; Brown, Morris J.; Clayton, David G.; Lathrop, G. Mark; Connell, John; Dominiczak, Anna; Samani, Nilesh J.; Braga, Carolina A.; Burke, Beverley; Dobson, Richard; Gungadoo, Johannie; Lee, Kate L.; Munroe, Patricia B.; Newhouse, Stephen J.; Onipinla, Abiodun; Wallace, Chris; Xue, Mingzhan; Caulfield, Mark; Farrall, Martin; Barton, Anne; Bruce, Ian N.; Donovan, Hannah; Eyre, Steve; Gilbert, Paul D.; Hider, Samantha L.; Hinks, Anne M.; John, Sally L.; Potter, Catherine; Silman, Alan J.; Symmons, Deborah P. M.; Thomson, Wendy; Worthington, Jane; Clayton, David G.; Dunger, David B.; Nutland, Sarah; Stevens, Helen E.; Walker, Neil M.; Widmer, Barry; Todd, John A.; Frayling, Timothy M.; Freathy, Rachel M.; Lango, Hana; Perry, John R. B.; Shields, Beverley M.; Weedon, Michael N.; Hattersley, Andrew T.; Hitman, Graham A.; Walker, Mark; Elliott, Kate S.; Groves, Christopher J.; Lindgren, Cecilia M.; Rayner, Nigel W.; Timpson, Nicholas J.; Zeggini, Eleftheria; McCarthy, Mark I.; Newport, Melanie; Sirugo, Giorgio; Lyons, Emily; Vannberg, Fredrik; Hill, Adrian V. S.; Bradbury, Linda A.; Farrar, Claire; Pointon, Jennifer J.; Wordsworth, Paul; Brown, Matthew A.; Franklyn, Jayne A.; Heward, Joanne M.; Simmonds, Matthew J.; Gough, Stephen C. L.; Seal, Sheila; Stratton, Michael R.; Rahman, Nazneen; Ban, Maria; Goris, An; Sawcer, Stephen J.; Compston, Alastair; Conway, David; Jallow, Muminatou; Newport, Melanie; Sirugo, Giorgio; Rockett, Kirk A.; Kwiatkowski, Dominic P.; Bryan, Claire; Bumpstead, Suzannah J.; Chaney, Amy; Downes, Kate; Ghori, Jilur; Gwilliam, Rhian; Hunt, Sarah E.; Inouye, Michael; Keniry, Andrew; King, Emma; McGinnis, Ralph; Potter, Simon; Ravindrarajah, Rathi; Whittaker, Pamela; Withers, David; Deloukas, Panos; Leung, Hin-Tak; Nutland, Sarah; Stevens, Helen E.; Walker, Neil M.; Todd, John A.; Easton, Doug; Clayton, David G.; Burton, Paul R.; Tobin, Martin D.; Barrett, Jeffrey C.; Evans, David; Morris, Andrew P.; Cardon, Lon R.; Cardin, Niall J.; Davison, Dan; Ferreira, Teresa; Pereira-Gale, Joanne; Hallgrimsdóttir, Ingeleif B.; Howie, Bryan N.; Marchini, Jonathan L.; Spencer, Chris C. A.; Su, Zhan; Ying Teo, Yik; Vukcevic, Damjan; Donnelly , Peter; Bentley, David; Brown, Matthew A.; Cardon, Lon R.; Caulfield, Mark; Clayton, David G.; Compston, Alistair; Craddock, Nick; Deloukas, Panos; Donnelly, Peter; Farrall, Martin; Gough, Stephen C. L.; Hall, Alistair S.; Hattersley, Andrew T.; Hill, Adrian V. S.; Kwiatkowski, Dominic P.; Mathew, Christopher G.; McCarthy, Mark I.; Ouwehand, Willem H.; Parkes, Miles; Pembrey, Marcus; Rahman, Nazneen; Samani, Nilesh J.; Stratton, Michael R.; Todd, John A.; Worthington, Jane; The Wellcome Trust Case Control Consortium; Management committee; Analysis committee; UK blood services and University of Cambridge controls; 1958 birth cohort controls; Bipolar disorder; Coronary artery disease; Crohnâ s disease; Hypertension; Rheumatoid arthritis; The Biologics in RA Genetics and Genomics Study Syndicate (BRAGGS) Steering Committee; Type 1 diabetes; Type 2 diabetes; Tuberculosis; Ankylosing spondylitis; Autoimmune thyroid disease; Breast cancer; Breast Cancer Susceptibility Collaboration (UK); Multiple sclerosis; Gambian controls; DNA, genotyping, data QC and informatics; Statistics; Primary investigators; Nejentsev, Sergey; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Howson, Joanna M. M.; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Walker, Neil M.; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Szeszko, Jeffrey; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Field, Sarah F.; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Stevens, Helen E.; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Reynolds, Pamela; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Hardy, Matthew; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; King, Erna; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Masters, Jennifer; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Hulme, John; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Maier, Lisa M.; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Smyth, Deborah; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Bailey, Rebecca; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Cooper, Jason D.; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Ribas, Gloria; MRC Rosalind Franklin Centre for Genomics Research, Hinxton, Cambridge, CB10 1SB, UK; Campbell, R. Duncan; MRC Rosalind Franklin Centre for Genomics Research, Hinxton, Cambridge, CB10 1SB, UK; Department of Physiology Anatomy and Genetics, University of Oxford, OX1 3QX, UK; Clayton, David G.; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK; Todd, John A.; Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK
Журнал: Nature
Дата: 2007

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Аннотация:

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 1â 3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the regionâ 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 methodsâ recursive partitioning and regressionâ to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratiosâ >1.5; Pcombined = 2.01â Ã â 10<sup>-19</sup> and 2.35â Ã â 10<sup>-13</sup>, 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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