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

Sergey Nejentsev, Joanna M.M. Howson*, Neil M. Walker, Jeffrey Szeszko, Sarah F. Field, Helen E. Stevens, Pamela Reynolds, Matthew Hardy, Erna King, Jennifer Masters, John Hulme, Lisa M. Maier, Deborah Smyth, Rebecca Bailey, Jason D. Cooper, Gloria Ribas, R. Duncan Campbell, David G. Clayton, John A. Todd, Paul R. BurtonLon R. Cardon, Nick Craddock, Panos Deloukas, Audrey Duncanson, Dominic P. Kwiatkowski, Mark I. McCarthy, Willem H. Ouwehand, Nilesh J. Samani, Peter Donnelly, Jeffrey C. Barrett, Dan Davison, Doug Easton, David Evans, Hin Tak Leung, Jonathan L. Marchini, Andrew P. Morris, Chris C.A. Spencer, Martin D. Tobin, 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, Niall C. Taylor, Graham R. Walters, Nicholas A. Watkins, Thilo Winzer, 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, 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, Richard J. Dixon, Massimo Mangino, Suzanne Stevens, John R. Thompson, 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, Ahmad Tariq, Fraser R. Cummings, Derek P. Jewell, John Webster, Morris J. Brown, G. Mark Lathrop, John Connell, Anna Dominiczak, Carolina A. Braga Marcano, 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 B. Dunger, Barry Widmer, 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, 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, Kirk A. Rockett, 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, Niall J. Cardin, Teresa Ferreira, Joanne Pereira-Gale, Ingeleif B. Hallgrimsdóttir, Bryan N. Howie, Zhan Su, Ying Teo Yik, Damjan Vukcevic, David Bentley, Alistair Compston

*Corresponding author for this work

Research output: Contribution to journalArticle

376 Citations (Scopus)

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; Pcombined = 2.01 × 10-19 and 2.35 × 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.

Original languageEnglish
Pages (from-to)887-892
Number of pages6
JournalNature
Volume450
Issue number7171
DOIs
Publication statusPublished - 6 Dec 2007

Fingerprint Dive into the research topics of 'Localization of type 1 diabetes susceptibility to the MHC class I genes <i>HLA-B</i> and <i>HLA-A</i>'. Together they form a unique fingerprint.

  • Cite this

    Nejentsev, S., Howson, J. M. M., Walker, N. M., Szeszko, J., Field, S. F., Stevens, H. E., Reynolds, P., Hardy, M., King, E., Masters, J., Hulme, J., Maier, L. M., Smyth, D., Bailey, R., Cooper, J. D., Ribas, G., Campbell, R. D., Clayton, D. G., Todd, J. A., ... Compston, A. (2007). Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature, 450(7171), 887-892. https://doi.org/10.1038/nature06406