Objective Higher gluten intake, frequent gastrointestinal infections and adenovirus, enterovirus, rotavirus and reovirus have been proposed as environmental triggers for coeliac disease. However, it is not known whether an interaction exists between the ingested gluten amount and viral exposures in the development of coeliac disease. This study investigated whether distinct viral exposures alone or together with gluten increase the risk of coeliac disease autoimmunity (CDA) in genetically predisposed children.
Design The Environmental Determinants of Diabetes in the Young study prospectively followed children carrying the HLA risk haplotypes DQ2 and/or DQ8 and constructed a nested case–control design. From this design, 83 CDA case–control pairs were identified. Median age of CDA was 31 months. Stool samples collected monthly up to the age of 2 years were analysed for virome composition by Illumina next-generation sequencing followed by comprehensive computational virus profiling.
Results The cumulative number of stool enteroviral exposures between 1 and 2 years of age was associated with an increased risk for CDA. In addition, there was a significant interaction between cumulative stool enteroviral exposures and gluten consumption. The risk conferred by stool enteroviruses was increased in cases reporting higher gluten intake.
Conclusions Frequent exposure to enterovirus between 1 and 2 years of age was associated with increased risk of CDA. The increased risk conferred by the interaction between enteroviruses and higher gluten intake indicate a cumulative effect of these factors in the development of CDA.
- coeliac disease
- small bowel
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KL and JL contributed equally.
Collaborators Aaron Barbour; Kimberly Bautista; Judith Baxter; Daniel Felipe-Morales; Kimberly Driscoll; Brigitte I Frohnert; Marisa Stahl; Patricia Gesualdo; Michelle Hoffman; Rachel Karban; Jill Norris; Stesha Peacock; Hanan Shorrosh; Andrea Steck; Megan Stern; Erica Villegas; Kathleen Waugh; Olli G Simell; Annika Adamsson; Suvi Ahonen; Mari Åkerlund; Leena Hakola; Anne Hekkala; Henna Holappa; Anni Ikonen; Jorma Ilonen; Sinikka Jäminki; Sanna Jokipuu; Leena Karlsson; Jukka Kero; Miia Kähönen; Mikael Knip; Minna-Liisa Koivikko; Merja Koskinen; Mirva Koreasalo; Jarita Kytölä; Tiina Latva-aho; Maria Lönnrot; Elina Mäntymäki; Markus Mattila; Maija Miettinen; Katja Multasuo; Teija Mykkänen; Tiina Niininen; Sari Niinistö; Mia Nyblom; Sami Oikarinen; Paula Ollikainen; Zhian Othmani; Sirpa Pohjola; Petra Rajala; Jenna Rautanen; Anne Riikonen; Eija Riski; Miia Pekkola; Minna Romo; Satu Ruohonen; Satu Simell; Maija Sjöberg; Aino Stenius; Päivi Tossavainen; Mari Vähä-Mäkilä; Sini Vainionpää; Eeva Varjonen; Riitta Veijola; Irene Viinikangas; Suvi M Virtanen; Jin-Xiong She; Desmond Schatz; Diane Hopkins; Leigh Steed; Jennifer Bryant; Katherine Silvis; Michael Haller; Melissa Gardiner; Richard McIndoe; Ashok Sharma; Stephen W Anderson; Laura Jacobsen; John Marks; Ezio Bonifacio; Anita Gavrisan; Cigdem Gezginci; Anja Heublein; Verena Hoffmann; Sandra Hummel; Andrea Keimer; Annette Knopff; Charlotte Koch; Claudia Ramminger; Roswith Roth; Marlon Scholz; Joanna Stock; Katharina Warncke; Lorena Wendel; Christiane Winkler; Åke Lernmark; Carin Andrén Aronsson; Maria Ask; Rasmus Bennet; Corrado Cilio; Helene Engqvist; Emelie Ericson-Hallström; Annika Fors; Lina Fransson; Thomas Gard; Monika Hansen; Hanna Jisser; Fredrik Johansen; Berglind Jonsdottir; Silvija Jovic; Helena Elding Larsson; Marielle Lindström; Markus Lundgren; Marlena Maziarz; Maria Månsson-Martinez; Maria Markan; Jessica Melin; Zeliha Mestan; Caroline Nilsson; Karin Ottosson; Kobra Rahmati; Anita Ramelius; Falastin Salami; Anette Sjöberg; Birgitta Sjöberg; Malin Svensson; Carina Törn; Anne Wallin; Åsa Wimar; Sofie Åberg; Michael Killian; Claire Cowen Crouch; Jennifer Skidmore; Masumeh Chavoshi; Rachel Hervey; Rachel Lyons; Arlene Meyer; Denise Mulenga; Jared Radtke; Matei Romancik; Davey Schmitt; Sarah Zink; Dorothy Becker; Margaret Franciscus; MaryEllen Dalmagro-Elias Smith; Ashi Daftary; Mary Beth Klein; Chrystal Yates; Sarah Austin-Gonzalez; Maryouri Avendano; Sandra Baethke; Rasheedah Brown; Brant Burkhardt; Martha Butterworth; Joanna Clasen; David Cuthbertson; Stephen Dankyi; Christopher Eberhard; Steven Fiske; Jennifer Garmeson; Veena Gowda; Kathleen Heyman; Belinda Hsiao; Christina Karges; Francisco Perez Laras; Qian Li; Shu Liu; Xiang Liu; Kristian Lynch; Colleen Maguire; Jamie Malloy; Cristina McCarthy; Aubrie Merrell; Hemang Parikh; Ryan Quigley; Cassandra Remedios; Chris Shaffer; Laura Smith; Susan Smith; Noah Sulman; Roy Tamura; Dena Tewey; Michael Toth; Ulla Uusitalo; Kendra Vehik; Ponni Vijayakandipan; Keith Wood; Jimin Yang; Michael Abbondondolo; Lori Ballard; David Hadley; Wendy McLeod; Steven Meulemans; Liping Yu; Dongmei Miao; Polly Bingley; Alistair Williams; Kyla Chandler; Olivia Ball; Ilana Kelland; Sian Grace; Masumeh Chavoshi; Jared Radtke; Sarah Zink; Nadim J Ajami; Matthew C Ross; Jacqueline L O’Brien; Diane S Hutchinson; Daniel P Smith; Matthew C Wong; Xianjun Tian; Tulin Ayvaz; Auriole Tamegnon; Nguyen Truong; Hannah Moreno; Lauren Riley; Eduardo Moreno; Tonya Bauch; Lenka Kusic; Ginger Metcalf; Donna Muzny; HarshaVArdhan Doddapaneni; Richard Gibbs; Sandra Ke; Niveen Mulholland; Kasia Bourcier; Thomas Briese; Suzanne Bennett Johnson; Eric Triplett.
Contributors Study concept and design: JL, HH, REL, MN, KK, EL, SK, MR, WH, JT, AGZ, BA, JPK, JFP, KL, DA; administrative, technical and material support: WH, JT, BA, JPK; acquisition, analysis and interpretation of the data: JL, HSL, HH, REL, MN, KK, EL, SK, WH, JT, AGZ, BA, JPK, JFP, KL, DA; statistical analysis: JL, HSL, MN, JPK, JFP; drafting of the manuscript: JL, HH, KL, DA; obtaining funding: MR, WH, JT, AGZ, BA, JPK; study supervision: HH, MR, WH, JT, AGZ, BA, JPK, DA. All authors have participated in the critical revision of the manuscript for important intellectual content.
Funding The TEDDY Study was funded by grants U01 DK63829, U01 6 DK63861, U01 DK63821, U01 42 DK63865, U01 DK63863, U01 DK63836, 7 U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 43 DK63821, UC4 8 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, and 44 UC4 DK106955, UC4 DK112243, UC4 DK117483, and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of 2 Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health 3 and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), 4 Centers for Disease Control and Prevention (CDC) and JDRF. This work supported in part by the 5 NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 6 TR000064) and the University of Colorado (UL1 TR001082).
Competing interests HH is a shareholder and chairman of the board of Vactech Ltd, which develops vaccines against picornaviruses.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement De-identified datasets generated and analysed during the current study will be made available by request from the NIDDK Central Repository at https://www.niddkrepository.org/studies/teddy. The TEDDY metagenomics next-generation sequencing (NGS) data that support the findings of this study will be available by request from NCBI’s database of Genotypes and Phenotypes (dbGaP) with the primary accession code phs001442.
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