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

369 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

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MHC Class I Genes
HLA-A Antigens
HLA-B Antigens
Major Histocompatibility Complex
Type 1 Diabetes Mellitus
MHC Class II Genes
Alleles
HLA-DRB1 Chains
Chromosomes, Human, Pair 6
Disease Susceptibility
Human Genome
Genetic Predisposition to Disease
Sample Size
Genes
Odds Ratio

ASJC Scopus subject areas

  • General

Cite this

Nejentsev, S., Howson, J. M. M., Walker, N. M., Szeszko, J., Field, S. F., Stevens, H. E., ... 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

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.; Cardon, Lon R.; Craddock, Nick; Deloukas, Panos; Duncanson, Audrey; Kwiatkowski, Dominic P.; McCarthy, Mark I.; Ouwehand, Willem H.; Samani, Nilesh J.; Donnelly, Peter; Barrett, Jeffrey C.; Davison, Dan; Easton, Doug; Evans, David; Leung, Hin Tak; Marchini, Jonathan L.; Morris, Andrew P.; Spencer, Chris C.A.; Tobin, Martin D.; 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.; Taylor, Niall C.; Walters, Graham R.; Watkins, Nicholas A.; Winzer, Thilo; 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; O'Donovan, Michael C.; Owen, Michael J.; Collier, David A.; Elkin, Amanda; Farmer, Anne; Williamson, Richard; McGuffin, Peter; Young, Allan H.; Ferrier, I. Nicol; 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.; Dixon, Richard J.; Mangino, Massimo; Stevens, Suzanne; Thompson, John R.; 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; Mohiuddin, M. Khalid; Todhunter, Catherine E.; Mansfield, John C.; Tariq, Ahmad; Cummings, Fraser R.; Jewell, Derek P.; Webster, John; Brown, Morris J.; Lathrop, G. Mark; Connell, John; Dominiczak, Anna; Braga Marcano, 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; Dunger, David B.; Widmer, Barry; 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; 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; Rockett, Kirk A.; 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; Cardin, Niall J.; Ferreira, Teresa; Pereira-Gale, Joanne; Hallgrimsdóttir, Ingeleif B.; Howie, Bryan N.; Su, Zhan; Yik, Ying Teo; Vukcevic, Damjan; Bentley, David; Compston, Alistair.

In: Nature, Vol. 450, No. 7171, 06.12.2007, p. 887-892.

Research output: Contribution to journalArticle

Nejentsev, S, Howson, JMM, Walker, NM, Szeszko, J, Field, SF, Stevens, HE, Reynolds, P, Hardy, M, King, E, Masters, J, Hulme, J, Maier, LM, Smyth, D, Bailey, R, Cooper, JD, Ribas, G, Campbell, RD, Clayton, DG, Todd, JA, Burton, PR, Cardon, LR, Craddock, N, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Samani, NJ, Donnelly, P, Barrett, JC, Davison, D, Easton, D, Evans, D, Leung, HT, Marchini, JL, Morris, AP, Spencer, CCA, Tobin, MD, Attwood, AP, Boorman, JP, Cant, B, Everson, U, Hussey, JM, Jolley, JD, Knight, AS, Koch, K, Meech, E, Nutland, S, Prowse, CV, Taylor, NC, Walters, GR, Watkins, NA, Winzer, T, Jones, RW, McArdle, WL, Ring, SM, Strachan, DP, Pembrey, M, Breen, G, St Clair, D, Caesar, S, Gordon-Smith, K, Jones, L, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Holmans, PA, Jones, IR, Kirov, G, Moskvina, V, Nikolov, I, O'Donovan, MC, Owen, MJ, Collier, DA, Elkin, A, Farmer, A, Williamson, R, McGuffin, P, Young, AH, Ferrier, IN, Ball, SG, Balmforth, AJ, Barrett, JH, Bishop, DT, Iles, MM, Maqbool, A, Yuldasheva, N, Hall, AS, Braund, PS, Dixon, RJ, Mangino, M, Stevens, S, Thompson, JR, Bredin, F, Tremelling, M, Parkes, M, Drummond, H, Lees, CW, Nimmo, ER, Satsangi, J, Fisher, SA, Forbes, A, Lewis, CM, Onnie, CM, Prescott, NJ, Sanderson, J, Mathew, CG, Barbour, J, Mohiuddin, MK, Todhunter, CE, Mansfield, JC, Tariq, A, Cummings, FR, Jewell, DP, Webster, J, Brown, MJ, Lathrop, GM, Connell, J, Dominiczak, A, Braga Marcano, CA, Burke, B, Dobson, R, Gungadoo, J, Lee, KL, Munroe, PB, Newhouse, SJ, Onipinla, A, Wallace, C, Xue, M, Caulfield, M, Farrall, M, Barton, A, Bruce, IN, Donovan, H, Eyre, S, Gilbert, PD, Hider, SL, Hinks, AM, John, SL, Potter, C, Silman, AJ, Symmons, DPM, Thomson, W, Worthington, J, Dunger, DB, Widmer, B, Frayling, TM, Freathy, RM, Lango, H, Perry, JRB, Shields, BM, Weedon, MN, Hattersley, AT, Hitman, GA, Walker, M, Elliott, KS, Groves, CJ, Lindgren, CM, Rayner, NW, Timpson, NJ, Zeggini, E, Newport, M, Sirugo, G, Lyons, E, Vannberg, F, Hill, AVS, Bradbury, LA, Farrar, C, Pointon, JJ, Wordsworth, P, Brown, MA, Franklyn, JA, Heward, JM, Simmonds, MJ, Gough, SCL, Seal, S, Stratton, MR, Rahman, N, Ban, M, Goris, A, Sawcer, SJ, Compston, A, Conway, D, Jallow, M, Rockett, KA, Bryan, C, Bumpstead, SJ, Chaney, A, Downes, K, Ghori, J, Gwilliam, R, Hunt, SE, Inouye, M, Keniry, A, King, E, McGinnis, R, Potter, S, Ravindrarajah, R, Whittaker, P, Withers, D, Cardin, NJ, Ferreira, T, Pereira-Gale, J, Hallgrimsdóttir, IB, Howie, BN, Su, Z, Yik, YT, Vukcevic, D, Bentley, D & Compston, A 2007, 'Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A', Nature, vol. 450, no. 7171, pp. 887-892. https://doi.org/10.1038/nature06406
Nejentsev S, Howson JMM, Walker NM, Szeszko J, Field SF, Stevens HE et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature. 2007 Dec 6;450(7171):887-892. https://doi.org/10.1038/nature06406
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. ; Cardon, Lon R. ; Craddock, Nick ; Deloukas, Panos ; Duncanson, Audrey ; Kwiatkowski, Dominic P. ; McCarthy, Mark I. ; Ouwehand, Willem H. ; Samani, Nilesh J. ; Donnelly, Peter ; Barrett, Jeffrey C. ; Davison, Dan ; Easton, Doug ; Evans, David ; Leung, Hin Tak ; Marchini, Jonathan L. ; Morris, Andrew P. ; Spencer, Chris C.A. ; Tobin, Martin D. ; 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. ; Taylor, Niall C. ; Walters, Graham R. ; Watkins, Nicholas A. ; Winzer, Thilo ; 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 ; O'Donovan, Michael C. ; Owen, Michael J. ; Collier, David A. ; Elkin, Amanda ; Farmer, Anne ; Williamson, Richard ; McGuffin, Peter ; Young, Allan H. ; Ferrier, I. Nicol ; 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. ; Dixon, Richard J. ; Mangino, Massimo ; Stevens, Suzanne ; Thompson, John R. ; 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 ; Mohiuddin, M. Khalid ; Todhunter, Catherine E. ; Mansfield, John C. ; Tariq, Ahmad ; Cummings, Fraser R. ; Jewell, Derek P. ; Webster, John ; Brown, Morris J. ; Lathrop, G. Mark ; Connell, John ; Dominiczak, Anna ; Braga Marcano, 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 ; Dunger, David B. ; Widmer, Barry ; 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 ; 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 ; Rockett, Kirk A. ; 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 ; Cardin, Niall J. ; Ferreira, Teresa ; Pereira-Gale, Joanne ; Hallgrimsdóttir, Ingeleif B. ; Howie, Bryan N. ; Su, Zhan ; Yik, Ying Teo ; Vukcevic, Damjan ; Bentley, David ; Compston, Alistair. / Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. In: Nature. 2007 ; Vol. 450, No. 7171. pp. 887-892.
@article{93f76816aa5f4e89bd75978e360a9bd2,
title = "Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A",
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.",
author = "Sergey Nejentsev and Howson, {Joanna M.M.} and Walker, {Neil M.} and Jeffrey Szeszko and Field, {Sarah F.} and Stevens, {Helen E.} and Pamela Reynolds and Matthew Hardy and Erna King and Jennifer Masters and John Hulme and Maier, {Lisa M.} and Deborah Smyth and Rebecca Bailey and Cooper, {Jason D.} and Gloria Ribas and Campbell, {R. Duncan} and Clayton, {David G.} and Todd, {John A.} and Burton, {Paul R.} and Cardon, {Lon R.} and Nick Craddock and Panos Deloukas and Audrey Duncanson and Kwiatkowski, {Dominic P.} and McCarthy, {Mark I.} and Ouwehand, {Willem H.} and Samani, {Nilesh J.} and Peter Donnelly and Barrett, {Jeffrey C.} and Dan Davison and Doug Easton and David Evans and Leung, {Hin Tak} and Marchini, {Jonathan L.} and Morris, {Andrew P.} and Spencer, {Chris C.A.} and Tobin, {Martin D.} and Attwood, {Antony P.} and Boorman, {James P.} and Barbara Cant and Ursula Everson and Hussey, {Judith M.} and Jolley, {Jennifer D.} and Knight, {Alexandra S.} and Kerstin Koch and Elizabeth Meech and Sarah Nutland and Prowse, {Christopher V.} and Taylor, {Niall C.} and Walters, {Graham R.} and Watkins, {Nicholas A.} and Thilo Winzer and Jones, {Richard W.} and McArdle, {Wendy L.} and Ring, {Susan M.} and Strachan, {David P.} and Marcus Pembrey and Gerome Breen and {St Clair}, David and Sian Caesar and Katherine Gordon-Smith and Lisa Jones and Christine Fraser and Green, {Elaine K.} and Detelina Grozeva and Hamshere, {Marian L.} and Holmans, {Peter A.} and Jones, {Ian R.} and George Kirov and Valentina Moskvina and Ivan Nikolov and O'Donovan, {Michael C.} and Owen, {Michael J.} and Collier, {David A.} and Amanda Elkin and Anne Farmer and Richard Williamson and Peter McGuffin and Young, {Allan H.} and Ferrier, {I. Nicol} and Ball, {Stephen G.} and Balmforth, {Anthony J.} and Barrett, {Jennifer H.} and Bishop, {D. Timothy} and Iles, {Mark M.} and Azhar Maqbool and Nadira Yuldasheva and Hall, {Alistair S.} and Braund, {Peter S.} and Dixon, {Richard J.} and Massimo Mangino and Suzanne Stevens and Thompson, {John R.} and Francesca Bredin and Mark Tremelling and Miles Parkes and Hazel Drummond and Lees, {Charles W.} and Nimmo, {Elaine R.} and Jack Satsangi and Fisher, {Sheila A.} and Alastair Forbes and Lewis, {Cathryn M.} and Onnie, {Clive M.} and Prescott, {Natalie J.} and Jeremy Sanderson and Mathew, {Christopher G.} and Jamie Barbour and Mohiuddin, {M. Khalid} and Todhunter, {Catherine E.} and Mansfield, {John C.} and Ahmad Tariq and Cummings, {Fraser R.} and Jewell, {Derek P.} and John Webster and Brown, {Morris J.} and Lathrop, {G. Mark} and John Connell and Anna Dominiczak and {Braga Marcano}, {Carolina A.} and Beverley Burke and Richard Dobson and Johannie Gungadoo and Lee, {Kate L.} and Munroe, {Patricia B.} and Newhouse, {Stephen J.} and Abiodun Onipinla and Chris Wallace and Mingzhan Xue and Mark Caulfield and Martin Farrall and Anne Barton and Bruce, {Ian N.} and Hannah Donovan and Steve Eyre and Gilbert, {Paul D.} and Hider, {Samantha L.} and Hinks, {Anne M.} and John, {Sally L.} and Catherine Potter and Silman, {Alan J.} and Symmons, {Deborah P.M.} and Wendy Thomson and Jane Worthington and Dunger, {David B.} and Barry Widmer and Frayling, {Timothy M.} and Freathy, {Rachel M.} and Hana Lango and Perry, {John R.B.} and Shields, {Beverley M.} and Weedon, {Michael N.} and Hattersley, {Andrew T.} and Hitman, {Graham A.} and Mark Walker and Elliott, {Kate S.} and Groves, {Christopher J.} and Lindgren, {Cecilia M.} and Rayner, {Nigel W.} and Timpson, {Nicholas J.} and Eleftheria Zeggini and Melanie Newport and Giorgio Sirugo and Emily Lyons and Fredrik Vannberg and Hill, {Adrian V.S.} and Bradbury, {Linda A.} and Claire Farrar and Pointon, {Jennifer J.} and Paul Wordsworth and Brown, {Matthew A.} and Franklyn, {Jayne A.} and Heward, {Joanne M.} and Simmonds, {Matthew J.} and Gough, {Stephen C.L.} and Sheila Seal and Stratton, {Michael R.} and Nazneen Rahman and Maria Ban and An Goris and Sawcer, {Stephen J.} and Alastair Compston and David Conway and Muminatou Jallow and Rockett, {Kirk A.} and Claire Bryan and Bumpstead, {Suzannah J.} and Amy Chaney and Kate Downes and Jilur Ghori and Rhian Gwilliam and Hunt, {Sarah E.} and Michael Inouye and Andrew Keniry and Emma King and Ralph McGinnis and Simon Potter and Rathi Ravindrarajah and Pamela Whittaker and David Withers and Cardin, {Niall J.} and Teresa Ferreira and Joanne Pereira-Gale and Hallgrimsd{\'o}ttir, {Ingeleif B.} and Howie, {Bryan N.} and Zhan Su and Yik, {Ying Teo} and Damjan Vukcevic and David Bentley and Alistair Compston",
year = "2007",
month = "12",
day = "6",
doi = "10.1038/nature06406",
language = "English",
volume = "450",
pages = "887--892",
journal = "Nature",
issn = "0028-0836",
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}

TY - JOUR

T1 - Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

AU - Nejentsev, Sergey

AU - Howson, Joanna M.M.

AU - Walker, Neil M.

AU - Szeszko, Jeffrey

AU - Field, Sarah F.

AU - Stevens, Helen E.

AU - Reynolds, Pamela

AU - Hardy, Matthew

AU - King, Erna

AU - Masters, Jennifer

AU - Hulme, John

AU - Maier, Lisa M.

AU - Smyth, Deborah

AU - Bailey, Rebecca

AU - Cooper, Jason D.

AU - Ribas, Gloria

AU - Campbell, R. Duncan

AU - Clayton, David G.

AU - Todd, John A.

AU - Burton, Paul R.

AU - Cardon, Lon R.

AU - Craddock, Nick

AU - Deloukas, Panos

AU - Duncanson, Audrey

AU - Kwiatkowski, Dominic P.

AU - McCarthy, Mark I.

AU - Ouwehand, Willem H.

AU - Samani, Nilesh J.

AU - Donnelly, Peter

AU - Barrett, Jeffrey C.

AU - Davison, Dan

AU - Easton, Doug

AU - Evans, David

AU - Leung, Hin Tak

AU - Marchini, Jonathan L.

AU - Morris, Andrew P.

AU - Spencer, Chris C.A.

AU - Tobin, Martin D.

AU - Attwood, Antony P.

AU - Boorman, James P.

AU - Cant, Barbara

AU - Everson, Ursula

AU - Hussey, Judith M.

AU - Jolley, Jennifer D.

AU - Knight, Alexandra S.

AU - Koch, Kerstin

AU - Meech, Elizabeth

AU - Nutland, Sarah

AU - Prowse, Christopher V.

AU - Taylor, Niall C.

AU - Walters, Graham R.

AU - Watkins, Nicholas A.

AU - Winzer, Thilo

AU - Jones, Richard W.

AU - McArdle, Wendy L.

AU - Ring, Susan M.

AU - Strachan, David P.

AU - Pembrey, Marcus

AU - Breen, Gerome

AU - St Clair, David

AU - Caesar, Sian

AU - Gordon-Smith, Katherine

AU - Jones, Lisa

AU - Fraser, Christine

AU - Green, Elaine K.

AU - Grozeva, Detelina

AU - Hamshere, Marian L.

AU - Holmans, Peter A.

AU - Jones, Ian R.

AU - Kirov, George

AU - Moskvina, Valentina

AU - Nikolov, Ivan

AU - O'Donovan, Michael C.

AU - Owen, Michael J.

AU - Collier, David A.

AU - Elkin, Amanda

AU - Farmer, Anne

AU - Williamson, Richard

AU - McGuffin, Peter

AU - Young, Allan H.

AU - Ferrier, I. Nicol

AU - Ball, Stephen G.

AU - Balmforth, Anthony J.

AU - Barrett, Jennifer H.

AU - Bishop, D. Timothy

AU - Iles, Mark M.

AU - Maqbool, Azhar

AU - Yuldasheva, Nadira

AU - Hall, Alistair S.

AU - Braund, Peter S.

AU - Dixon, Richard J.

AU - Mangino, Massimo

AU - Stevens, Suzanne

AU - Thompson, John R.

AU - Bredin, Francesca

AU - Tremelling, Mark

AU - Parkes, Miles

AU - Drummond, Hazel

AU - Lees, Charles W.

AU - Nimmo, Elaine R.

AU - Satsangi, Jack

AU - Fisher, Sheila A.

AU - Forbes, Alastair

AU - Lewis, Cathryn M.

AU - Onnie, Clive M.

AU - Prescott, Natalie J.

AU - Sanderson, Jeremy

AU - Mathew, Christopher G.

AU - Barbour, Jamie

AU - Mohiuddin, M. Khalid

AU - Todhunter, Catherine E.

AU - Mansfield, John C.

AU - Tariq, Ahmad

AU - Cummings, Fraser R.

AU - Jewell, Derek P.

AU - Webster, John

AU - Brown, Morris J.

AU - Lathrop, G. Mark

AU - Connell, John

AU - Dominiczak, Anna

AU - Braga Marcano, Carolina A.

AU - Burke, Beverley

AU - Dobson, Richard

AU - Gungadoo, Johannie

AU - Lee, Kate L.

AU - Munroe, Patricia B.

AU - Newhouse, Stephen J.

AU - Onipinla, Abiodun

AU - Wallace, Chris

AU - Xue, Mingzhan

AU - Caulfield, Mark

AU - Farrall, Martin

AU - Barton, Anne

AU - Bruce, Ian N.

AU - Donovan, Hannah

AU - Eyre, Steve

AU - Gilbert, Paul D.

AU - Hider, Samantha L.

AU - Hinks, Anne M.

AU - John, Sally L.

AU - Potter, Catherine

AU - Silman, Alan J.

AU - Symmons, Deborah P.M.

AU - Thomson, Wendy

AU - Worthington, Jane

AU - Dunger, David B.

AU - Widmer, Barry

AU - Frayling, Timothy M.

AU - Freathy, Rachel M.

AU - Lango, Hana

AU - Perry, John R.B.

AU - Shields, Beverley M.

AU - Weedon, Michael N.

AU - Hattersley, Andrew T.

AU - Hitman, Graham A.

AU - Walker, Mark

AU - Elliott, Kate S.

AU - Groves, Christopher J.

AU - Lindgren, Cecilia M.

AU - Rayner, Nigel W.

AU - Timpson, Nicholas J.

AU - Zeggini, Eleftheria

AU - Newport, Melanie

AU - Sirugo, Giorgio

AU - Lyons, Emily

AU - Vannberg, Fredrik

AU - Hill, Adrian V.S.

AU - Bradbury, Linda A.

AU - Farrar, Claire

AU - Pointon, Jennifer J.

AU - Wordsworth, Paul

AU - Brown, Matthew A.

AU - Franklyn, Jayne A.

AU - Heward, Joanne M.

AU - Simmonds, Matthew J.

AU - Gough, Stephen C.L.

AU - Seal, Sheila

AU - Stratton, Michael R.

AU - Rahman, Nazneen

AU - Ban, Maria

AU - Goris, An

AU - Sawcer, Stephen J.

AU - Compston, Alastair

AU - Conway, David

AU - Jallow, Muminatou

AU - Rockett, Kirk A.

AU - Bryan, Claire

AU - Bumpstead, Suzannah J.

AU - Chaney, Amy

AU - Downes, Kate

AU - Ghori, Jilur

AU - Gwilliam, Rhian

AU - Hunt, Sarah E.

AU - Inouye, Michael

AU - Keniry, Andrew

AU - King, Emma

AU - McGinnis, Ralph

AU - Potter, Simon

AU - Ravindrarajah, Rathi

AU - Whittaker, Pamela

AU - Withers, David

AU - Cardin, Niall J.

AU - Ferreira, Teresa

AU - Pereira-Gale, Joanne

AU - Hallgrimsdóttir, Ingeleif B.

AU - Howie, Bryan N.

AU - Su, Zhan

AU - Yik, Ying Teo

AU - Vukcevic, Damjan

AU - Bentley, David

AU - Compston, Alistair

PY - 2007/12/6

Y1 - 2007/12/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=36849012027&partnerID=8YFLogxK

U2 - 10.1038/nature06406

DO - 10.1038/nature06406

M3 - Article

AN - SCOPUS:36849012027

VL - 450

SP - 887

EP - 892

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7171

ER -