David Hadley1, William Hagopian2, Edwin Liu3, Jin-Xiong She4, Olli Simell5, Beena Akolkar6, Anette-G Ziegler7, Marian Rewers8, Jeffrey P Krischer9, Wei-Min Chen10, Suna Onengut-Gumuscu10, Teodorica L Bugawan11, Stephen S Rich10, Henry Erlich12, Daniel Agardh13. 1. 1] Division of Population Health Sciences and Education, St. George's, University of London, London, UK [2] TransMed Systems, Pleasanton, California, USA. 2. Pacific Northwest Diabetes Research Institute, Seattle, Washington, USA. 3. 1] Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA [2] Barbara Davis Center, University of Colorado Denver, Aurora, Colorado, USA. 4. Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, Georgia, USA. 5. Department of Pediatrics, University of Turku, Turku, Finland. 6. DDEMD, NIDDK, Bethesda, Maryland, USA. 7. 1] Institute of Diabetes Research, Helmholtz Zentrum Mìnchen, Oberschleissheim, Germany [2] Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich, Germany [3] Forschergruppe Diabetes e.V., Neuherberg, Germany. 8. Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA. 9. Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA. 10. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. 11. Department of Human Genetics, Roche Molecular Systems, Alameda, California, USA. 12. Children's Hospital of Oakland Research Institute, Oakland, California, USA. 13. 1] Pediatric Epidemiology Center, University of South Florida, Tampa, Florida, USA [2] Department of Clinical Sciences, Lund University, Malmo, Sweden.
Abstract
OBJECTIVES: Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1*05:01-DQB1*02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1*03:01-DQB1*03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B, -DRB3, -DRB4, -DPA1, and -DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex. RESULTS: After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1*04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1*04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013). CONCLUSIONS: HLA-DPB1*04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.
OBJECTIVES: Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1*05:01-DQB1*02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1*03:01-DQB1*03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B, -DRB3, -DRB4, -DPA1, and -DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex. RESULTS: After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1*04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1*04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013). CONCLUSIONS: HLA-DPB1*04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.
Authors: Richard Ahn; Yuan Chun Ding; Joseph Murray; Alessio Fasano; Peter H R Green; Susan L Neuhausen; Chad Garner Journal: PLoS One Date: 2012-05-17 Impact factor: 3.240
Authors: Gosia Trynka; Karen A Hunt; Nicholas A Bockett; Jihane Romanos; Vanisha Mistry; Agata Szperl; Sjoerd F Bakker; Maria Teresa Bardella; Leena Bhaw-Rosun; Gemma Castillejo; Emilio G de la Concha; Rodrigo Coutinho de Almeida; Kerith-Rae M Dias; Cleo C van Diemen; Patrick C A Dubois; Richard H Duerr; Sarah Edkins; Lude Franke; Karin Fransen; Javier Gutierrez; Graham A R Heap; Barbara Hrdlickova; Sarah Hunt; Leticia Plaza Izurieta; Valentina Izzo; Leo A B Joosten; Cordelia Langford; Maria Cristina Mazzilli; Charles A Mein; Vandana Midah; Mitja Mitrovic; Barbara Mora; Marinita Morelli; Sarah Nutland; Concepción Núñez; Suna Onengut-Gumuscu; Kerra Pearce; Mathieu Platteel; Isabel Polanco; Simon Potter; Carmen Ribes-Koninckx; Isis Ricaño-Ponce; Stephen S Rich; Anna Rybak; José Luis Santiago; Sabyasachi Senapati; Ajit Sood; Hania Szajewska; Riccardo Troncone; Jezabel Varadé; Chris Wallace; Victorien M Wolters; Alexandra Zhernakova; B K Thelma; Bozena Cukrowska; Elena Urcelay; Jose Ramon Bilbao; M Luisa Mearin; Donatella Barisani; Jeffrey C Barrett; Vincent Plagnol; Panos Deloukas; Cisca Wijmenga; David A van Heel Journal: Nat Genet Date: 2011-11-06 Impact factor: 38.330
Authors: Edwin Liu; Hye-Seung Lee; Carin A Aronsson; William A Hagopian; Sibylle Koletzko; Marian J Rewers; George S Eisenbarth; Polly J Bingley; Ezio Bonifacio; Ville Simell; Daniel Agardh Journal: N Engl J Med Date: 2014-07-03 Impact factor: 176.079
Authors: Kendra Vehik; Steven W Fiske; Chad A Logan; Daniel Agardh; Corrado M Cilio; William Hagopian; Olli Simell; Merja Roivainen; Jin-Xiong She; Thomas Briese; Sami Oikarinen; Heikki Hyoty; Anette-G Ziegler; Marian Rewers; Ake Lernmark; Beena Akolkar; Jeffrey P Krischer; Brant R Burkhardt Journal: Diabetes Metab Res Rev Date: 2013-10 Impact factor: 8.128
Authors: Xiaoming Jia; Buhm Han; Suna Onengut-Gumuscu; Wei-Min Chen; Patrick J Concannon; Stephen S Rich; Soumya Raychaudhuri; Paul I W de Bakker Journal: PLoS One Date: 2013-06-06 Impact factor: 3.240
Authors: Jihane Romanos; Anna Rosén; Vinod Kumar; Gosia Trynka; Lude Franke; Agata Szperl; Javier Gutierrez-Achury; Cleo C van Diemen; Roan Kanninga; Soesma A Jankipersadsing; Andrea Steck; Georges Eisenbarth; David A van Heel; Bozena Cukrowska; Valentina Bruno; Maria Cristina Mazzilli; Concepcion Núñez; Jose Ramon Bilbao; M Luisa Mearin; Donatella Barisani; Marian Rewers; Jill M Norris; Anneli Ivarsson; H Marieke Boezen; Edwin Liu; Cisca Wijmenga Journal: Gut Date: 2013-05-23 Impact factor: 23.059
Authors: Amanda K Cartee; Lisa A Owens; Brian D Lahr; Barbara P Yawn; Joseph A Murray; Yogish C Kudva Journal: Mayo Clin Proc Date: 2016-08 Impact factor: 7.616
Authors: William Hagopian; Hye-Seung Lee; Edwin Liu; Marian Rewers; Jin-Xiong She; Anette-G Ziegler; Åke Lernmark; Jorma Toppari; Stephen S Rich; Jeffrey P Krischer; Henry Erlich; Beena Akolkar; Daniel Agardh Journal: Pediatrics Date: 2017-10-10 Impact factor: 9.703
Authors: Ashok Sharma; Xiang Liu; David Hadley; William Hagopian; Edwin Liu; Wei-Min Chen; Suna Onengut-Gumuscu; Ville Simell; Marian Rewers; Anette-G Ziegler; Åke Lernmark; Olli Simell; Jorma Toppari; Jeffrey P Krischer; Beena Akolkar; Stephen S Rich; Daniel Agardh; Jin-Xiong She Journal: PLoS One Date: 2016-03-25 Impact factor: 3.752