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BIBTEX RIS

HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

2015; National Academy of Sciences; Volume: 112; Issue: 52 Linguagem: Inglês

10.1073/pnas.1520779112

1091-6490

Michael J. Ombrello, Elaine F. Remmers, Ioanna Tachmazidou, Alexei A. Grom, Dirk Foell, Johannes‐Peter Haas, Alberto Martini, Marco Gattorno, Seza Özen, Sampath Prahalad, Andrew Zeft, John F. Bohnsack, Elizabeth Mellins, Norman T. Ilowite, Ricardo Russo, Cláudio Arnaldo Len, Maria Odete Esteves Hilário, Sheila Oliveira, Rae S. M. Yeung, Alan Rosenberg, Lucy R. Wedderburn, Jordi Antón, Tobias Schwarz, Anne Hinks, Yelda Bilginer, Jane Park, Joanna Cobb, Colleen Satorius, Buhm Han, Elizabeth Baskin, Sara Signa, Richard H. Duerr, J ACHKAR, M. Ilyas Kamboh, Kenneth M. Kaufman, Leah C. Kottyan, Dalila Pinto, Stephen W. Scherer, Marta E. Alarcón‐Riquelme, Elisa Docampo, Xavier Estivill, Ahmet Gül, Paul I. W. de Bakker, Soumya Raychaudhuri, Carl D. Langefeld, Susan D. Thompson, Eleftheria Zeggini, Wendy Thomson, Daniel L. Kastner, Patricia Woo, J ACHKAR, Marta E. Alarcón‐Riquelme, Roger C. Allen, Jordi Antón, Elizabeth Baskin, Stefan Berg, Bianca Bica, Yelda Bilginer, John F. Bohnsack, André Cavalcanti, Jeffrey Chaitow, Joanna Cobb, Rubin Cuttica, Paul I. W. de Bakker, Elisa Docampo, Richard H. Duerr, Justine A. Ellis, Xavier Estivill, Terri H. Finkel, Dirk Foell, Marco Gattorno, Alexei A. Grom, Ahmet Gül, Johannes‐Peter Haas, Hákon Hákonarson, Buhm Han, Maria Odete Esteves Hilário, Anne Hinks, Norman T. Ilowite, M. Ilyas Kamboh, Daniel L. Kastner, Kenneth M. Kaufman, Leah C. Kottyan, Carl Langefeld, Cláudio Arnaldo Len, Alberto Martini, Elizabeth Mellins, Kirstin Minden, Kevin Murray, Sheila Knupp Feitosa de Oliveira, Michael J. Ombrello, Seza Özen, Jane Park, Dalila Pinto, Sampath Prahalad, Pierre Quartier, Soumya Raychaudhuri, Elaine F. Remmers, Alan Rosenberg, Ricardo Russo, Colleen Satorius, Stephen W. Scherer, Rayfel Schneider, Tobias Schwarz, Davinder Singh-Gerwal, Ioanna Tachmazidou, Susan D. Thompson, Wendy Thomson, Lucy R. Wedderburn, Patricia Woo, Nico Wulffraat, Rae SM Yeung, Andrew Zeft, Eleftheria Zeggini, Mario Abinum, A. L. Bell, Alan Craft, Esther Crawley, Joel David, Helen Foster, Janet Gardener-Medwin, Jane Griffin, Ann Hall, Michael E. Hall, Ariane L. Herrick, P. Hollingworth, Lennox Holt, Stan Jones, G. Pountain, Clive Ryder, Tauny Southwood, I M Stewart, H Venning, Lucy R. Wedderburn, Patricia Woo, Sue Wyatt, Eileen Baildam, Nick Bishop, Lynsey Brown, Joanne Buckley, Alice Chieng, Roberto Carrasco, Joanna Cobb, Lucy Cook, Joyce Davidson, Annette Duggan, Michael Eltringham, Helen Foster, Elizabeth Friel, Mark Friswell, Janet Gardner‐Medwin, Paul Gilbert, V. C. Gould, Kelly Hadfield, Kimme L Hyrich, J. E. Jones, Sham Lal, M.-L. J. Lay, Gabrielle Lloyd, Olivia Lloyd, Carol Lydon, N Makengo, Ann McGovern, Alexandra Meijer, Nicola Mills-Wierda, Theresa Moorcroft, Vicki Price, Liang Qiao, Kay Riding, Ji-Yeon Sim, Tauny Southwood, Wendy Thomson, Maureen Todd, Susan Tremble, Katharine Venter, Debbie Wade, Peter Ward, Sharon Watson, Gwen Webster, Lucy R. Wedderburn, Jadranka Zelenovic, James Birmingham, Melissa E. Elder, Beth S. Gottlieb, Normal T. Ilowite, Lisa F. Imundo, Yukiko Kimura, Yuliya Lokhnygina, Michael L. Miller, Diana Milojevic, Kathleen M. O’Neil, Marilynn Punaro, Kristi Prather, Natasha M. Ruth, Christy Sandborg, Laura E. Schanberg, David D. Sherry, Nora G. Singer, Steven J. Spalding, Stacey E. Tarvin, James Verbsky, Carol A. Wallace, Lawrence Zemel, Katrin Burkle, Joanna Cobb, Angela Etheridge, Paul Gilbert, Anne Hinks, Shashivadan P. Hirani, Laura Kassoumeri, Sham Lal, Laura Melville, Halima Moncrieffe, Kathleen Mulligan, Jordi Antón, Fiona Patrick, Tauny Southwood, Wendy Thomson, Simona Ursu, Lucy R. Wedderburn, Pamela Whitworth, Patricia Woo, Adam Baxter‐Jones, Susanne M. Benseler, Gilles Boire, David A. Cabral, Bonnie Cameron, Sarah Campillo, Gaëlle Chédeville, Anne-Laure Chetaille, Paul Dancey, Ciarán M. Duffy, Karen Watanabe Duffy, Janet Ellsworth, Brian M. Feldman, Michele Gibbon, Chantal Guillet, Jaime Guzmán, Kristin Houghton, Adam M. Huber, Roman Juřenčák, Bianca Lang, Ronald M. Laxer, Lynn Maenz, Loren A. Matheson, Kiem Oen, Ross E. Petty, Suzanne Ramsey, Elham Rezaei, Alan Rosenberg, Johannes Roth, Rayfel Schneider, Rosie Scuccimarri, Earl D. Silverman, Lynn Spiegel, Elizabeth Stringer, Shirley M. L. Tse, Lori B. Tucker, Stuart E. Turvey, Rae SM Yeung,

Reproductive System and Pregnancy

Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 × 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.