Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families
Authors: Hippich Markus , Beyerlein Andreas , Hagopian William A. , Krischer Jeffrey P. , Vehik Kendra , Knoop Jan , Winker Christiane , Toppari Jorma , Lernmark Åke , Rewers Marian J. , Steck Andrea K. , She Jin-Xiong , Akolkar Beena , Robertson Catherine C. , Onengut-Gumuscu Suna , Rich Stephen S. , Bonifacio Ezio , Ziegler Anette-G. ,   Teddy Study Group, Rewers Marian , Bautista Kimberly , Baxter Judith , Felipe-Morales Daniel , Driscoll Kimberly , Frohnert Brigitte I. , Gallant Marisa , Gesualdo Patricia , Hoffman Michelle , Karban Rachel , Liu Edwin , Norris Jill , Samper-Imaz Adela , Steck Andrea , Waugh Kathleen , Wright Hali , Toppari Jorma , Simell Olli G. , Adamsson Annika , Ahonen Suvi , Hyöty Heikki , Ilonen Jorma , Koreasalo Mirva , Kurppa Kalle , Latva-aho Tiina , Lönnrot Maria , Mattila Markus , Mäntymäki Elina , Multasuo Katja , Niininen Tina , Niinistö Sari , Nyblom Mia , Ollikainen Paula , Rajala Petra , Rautanen Jenna , Riikonen Anne , Romo Minna , Ruohonen Suvi , Rönkä Juulia , Vainionpää Sini , Varjonen Eeva , Veijola Riitta , Virtanen Suvi M. , Vähä-Mäkilä Mari , Åkerlund Mari , Lindfors Katri , She Jin-Xiong , Schatz Desmond , Hopkins Diane , Steed Leigh , Bryant Jennifer , Adams Janey , Silvis Katherine , Haller Michael , Gardiner Melissa , McIndoe Richard , Sharma Ashok , Anderson Stephen W. , Jacobsen Laura , Marks John , Towe P.D. , Ziegler Anette G. , Beyerlein Andreas , Bonifacio Ezio , Gavrisan Anita , Gezginci Cigdem , Heublein Anja , Hummel Michael , Hummel Sandra , Knopff Annette , Koch Charlotte , Koletzko Sibylle , Ramminger Claudia , Roth Roswith , Scholz Marlon , Stock Joanna , Warncke Katharina , Wendel Lorena , Winkler Christiane , Lernmark Åke , Agardh Daniel , Andrén Aronsson Carin , Ask Maria , Bremer Jenny , Carlsson Ulla-Marie , Cilio Corrado , Ericson- Hallström Emelie , Fors Annika , Fransson Lina , Johansen Fredrik , Jonsdottir Berglind , Jovic Silvija , Elding Larsson Helena , Lindström Marielle , Lundgren Markus , Månsson-Martinez Maria , Markan Maria , Melin Jessica , Mestan Zeliha , Nilsson Caroline , Ottoson Karin , Rahmati Kobra , Ramelius Anita , Salami Falastin , Sibthorpe Sara , Sjöberg Anette , Sjöberg Birgitta , Törn Carina , Wallin Anne , Wimar Åsa , Åberg Sofie , Hagopian William A. , Killian Michael , Cowen Crouch Claire , Skidmore Jennifer , Akramoff Ashley , Banjanin Jana , Chavoshi Masumeh , Dunson Kayleen , Hervey Rachel , Lyons Rachel , Meyer Arlene , Mulenga Denise , Radtke Jared , Schmitt Davey , Schwabe Julie , Zink Sarah , Becker Dorothy , Franciscus Margaret , Dalmagro-Elias Smith MaryEllen , Daftary Ashi , Klein Mary Beth , Yates Chrystal , Krischer Jeffrey P. , Austin-Gonzalez Sarah , Avendano Maryouri , Baethke Sandra , Brown Rasheedah , Burkhardt Brant , Butterworth Martha , Clasen Joanna , Cuthbertson David , Eberhard Christopher , Fiske Steven , Garcia Dena , Garmeson Jennifer , Gowda Veena , Heyman Kathleen , Hsiao Belinda , Perez Laras Francisco , Lee Hye-Seung , Liu Shu , Liu Xiang , Lynch Kristian , Maguire Colleen , Malloy Jamie , McCarthy Cristina , Merrell Aubrie , Meulemans Steven , Parikh Hemang , Quigley Ryan , Remedios Cassandra , Shaffer Chris , Smith Laura , Smith Susan , Sulman Noah , Tamura Roy , Uusitalo Ulla , Vehik Kendra , Vijayakandipan Ponni , Wood Keith , Yang Jimin , Abbondondolo Michael , Ballard Lori , Hadley David , McLeod Wendy , Akolkar Beena , Bourcier Kasia , Briese Thomas , Bennett Johnson Suzanne , Triplett Eric , Yu Liping , Miao Dongmei , Bingley Polly , Williams Alistair , Chandler Kyla , Ball Olivia , Kelland Ilana , Grace Sian , Gillard Ben , Hagopian William , Chavoshi Masumeh , Radtke Jared , Schwabe Julie , Erlich Henry , Mack Steven J. , Fear Anna Lisa , Rich Stephen S. , Chen Wei-Min , Onengut-Gumuscu Suna , Farber Emily , Roche Pickin Rebecca , Davis Jonathan , Davis Jordan , Gallo Dan , Bonnie Jessica , Campolieto Paul , Ke Sandra , Mulholland Niveen 
Published: January 2019

The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes–associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6–3.02]) and for diabetes (HR 2.92 [95% CI 2.05–4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata.