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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, Nicholas John, 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, Grozeva, Detelina, Hamshere, Marian Lindsay, Holmans, Peter Alan, Jones, Ian Richard, Kirov, George, Escott-Price, Valentina, Nikolov, Ivan, O'Donovan, Michael Conlon, Owen, Michael John, Craddock, Nicholas John, 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. and Worthington, Jane 2007. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450 (7171) , pp. 887-892. 10.1038/nature06406

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > R Medicine (General)
Publisher: Nature Publishing Group
ISSN: 0028-0836
Last Modified: 13 Apr 2019 03:01
URI: http://orca.cf.ac.uk/id/eprint/82847

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