Complement gene variants in relation to autoantibodies to beta cell specific antigens and type 1 diabetes in the TEDDY Study
Authors: Törn Carina , Liu Xiang , Hagopian William , Lernmark Åke , Simell Olli , Rewers Marian , Ziegler Anette-G , Schatz Desmond , Akolkar Beena , Onengut-Gumuscu Suna , Chen Wei-Min , Toppari Jorma , Mykkänen Juha , Ilonen Jorma , Rich Stephen S. , She Jin-Xiong , Sharma Ashok , Steck Andrea , Krischer Jeffrey ,   The TEDDY Study Group, Abbondondolo Michael , Adams Janey , Adamsson Annika , Agardh Daniel , Anderson Stephen W. , Aronsson Carin Andrén , Ask Maria , Austin-Gonzalez Sarah , Ayres Stephen , Baethke Sandra , Bautista Kimberly , Baxter Judith , Becker Dorothy , Bedoy Ruth , Bennet Rasmus , Johnson Suzanne Bennett , Beyerlein Andreas , Bonifacio Ezio , Bourcier Kasia , Bremer Jenny , Briese Thomas , Brown Rasheedah , Burkhardt Brant , Butterworth Martha , Carlsson Ulla-Marie , Cilio Corrado , Clasen Joanna , Crouch Claire Cowen , Cuthbertson David , Daftary Ashi , Dalmagro-Elias MaryEllen , Dunson Kayleen , Eberhard Christopher , Larsson Helena Elding , Ericsson-Hallström Emelie , Felipe-Morales Daniel , Fiske Steven , Foghis Gabriella , Foterek Kristina , Fransiscus Margaret , Fransson Lina , Frohnert Brigitte I. , Garcia Dena , Gard Thomas , Gardiner Melissa , Garmeson Jennifer , Gerardsson Joanna , Gesualdo Patricia , Gowda Veena , Haller Michael , Hansen Monica , Hansson Gertie , Harmby Cecilia , Hervey Rachel , Heyman Kathleen , Hoffman Michelle , Hopkins Diane , Hummel Michael , Hummel Sandra , Hyberg Susanne , Hyöty Heikki , Johansen Fredrik , Johnson Corbin , Jokipuu Sanna , Jonasdottir Berglind , Kallio Tiina , Karban Rachel , Kersting Mathilde , Killian Michael , Klein Beth , Knip Mikael , Knopff Annette , Koivu Annika , Koletzko Sibylle , Koreasalo Mirva , Kurppa Kalle , Kähönen Miia , Lee Hye-Seung , Forss Sigrid Lenrick , Liu Edwin , Liu Shu , Lundgren Markus , Lynch Kristian , Lyons Rachel , Lönnrot Maria , Malloy Jamie , Markan Maria , McCarthy Cristina , McIndoe Richard , McLeod Wendy , Melin Jessica , Mestan Zeliha , Meulemans Steven , Meyer Arlene , Mulenga Denise , Multasuo Katja , Månsson-Martinez Maria , Mäntimäki Elina , Niinien Tiina , Norris Jill , Nyblom Mia , Peplow Claudia , Laras Francisco Perez , Rahmati Kobra , Rajala Petra , Ramelius Anita , Rautanen Jenna , Riikonen Anne , Robinson Richard , Romo Minna , Rosenquist Anna , Roth Roswith , Salami Falastin , Samper-Imaz Adela , Scott Elisabeth , Shaffer Chris , Sibthorpe Sara , Silvis Katherine , Simell Satu , Simell Ville , Sjöberg Maija , Sjöberg Birgitta , Skidmore Jennifer , Smith Laura , Smith Susan , Stabbert Joshua , Steed Leigh , Stenius Aino , Stock Joanna , Strauss Elisabeth , Sulman Noah , Swartling Ulrica , Särmä Maria , Tamura Roy , Tarr Alexander , Amboh Evelyn Tekum , Thomas Jamie , Triplett Eric , Trulsson Erika , Uland Morgan , Uusitalo Ulla , Vainionpää Sini , Wallin Anne , Varionen Eeva , Warncke Katharina , Waugh Kathleen , Vehik Kendra , Veijola Riitta , Vijayakandipan Ponni , Williams Joshua , Willis John , Wimar Åsa , Winkler Christiane , Virtanen Suvi M. , Wood Keith , Wright Hali , Vähä-Mäkilä Mari , Yang Jimin , Yates Chrystal , Åberg Sofie , Åkerlund Mari 
Published: June 2016

A total of 15 SNPs within complement genes and present on the ImmunoChip were analyzed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A total of 5474 subjects were followed from three months of age until islet autoimmunity (IA: n = 413) and the subsequent onset of type 1 diabetes (n = 115) for a median of 73 months (IQR 54–91). Three SNPs within ITGAM were nominally associated (p < 0.05) with IA: rs1143678 [Hazard ratio; HR 0.80; 95% CI 0.66–0.98; p = 0.032], rs1143683 [HR 0.80; 95% CI 0.65–0.98; p = 0.030] and rs4597342 [HR 1.16; 95% CI 1.01–1.32; p = 0.041]. When type 1 diabetes was the outcome, in DR3/4 subjects, there was nominal significance for two SNPs: rs17615 in CD21 [HR 1.52; 95% CI 1.05–2.20; p = 0.025] and rs4844573 in C4BPA [HR 0.63; 95% CI 0.43–0.92; p = 0.017]. Among DR4/4 subjects, rs2230199 in C3 was significantly associated [HR 3.20; 95% CI 1.75–5.85; p = 0.0002, uncorrected] a significance that withstood Bonferroni correction since it was less than 0.000833 (0.05/60) in the HLA-specific analyses. SNPs within the complement genes may contribute to IA, the first step to type 1 diabetes, with at least one SNP in C3 significantly associated with clinically diagnosed type 1 diabetes.