PMID- 28941965 OWN - NLM STAT- MEDLINE DCOM- 20190408 LR - 20240422 IS - 1095-9157 (Electronic) IS - 0896-8411 (Print) IS - 0896-8411 (Linking) VI - 86 DP - 2018 Jan TI - Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident beta-cell autoantibodies. PG - 93-103 LID - S0896-8411(17)30558-9 [pii] LID - 10.1016/j.jaut.2017.09.005 [doi] AB - beta-cell autoantibodies against insulin (IAA), GAD65 (GADA) and IA-2 (IA-2A) precede onset of childhood type 1 diabetes (T1D). Incidence of the first appearing beta-cell autoantibodies peaks at a young age and is patterned by T1D-associated genes, suggesting an early environmental influence. Here, we tested if gestational infections and interactions with child's human leukocyte antigen (HLA) and non-HLA genes affected the appearance of the first beta-cell autoantibody. Singletons of mothers without diabetes (n = 7472) with T1D-associated HLA-DR-DQ genotypes were prospectively followed quarterly through the first 4 years of life, then semiannually until age 6 years, using standardized autoantibody analyses. Maternal infections during pregnancy were assessed via questionnaire 3-4.5 months post-delivery. Polymorphisms in twelve non-HLA genes associated with the first appearing beta-cell autoantibodies were included in a Cox regression analysis. IAA predominated as the first appearing beta-cell autoantibody in younger children (n = 226, median age at seroconversion 1.8 years) and GADA (n = 212; 3.2 years) in children aged >/=2 years. Gestational infections were not associated with the first appearing beta-cell autoantibodies overall. However, gestational respiratory infections (G-RI) showed a consistent protective influence on IAA (HR 0.64, 95% CI 0.45-0.91) among CTLA4-(AG, GG) children (G-RI*CTLA4 interaction, p = 0.002). The predominant associations of HLA-DR-DQ 4-8/8-4 with IAA and HLA-DR-DQ 3-2/3-2 with GADA were not observed if a G-RI was reported (G-RI*HLA-DR-DQ interaction, p = 0.03). The role of G-RI may depend on offspring HLA and CTLA-4 alleles and supports a bidirectional trigger for IAA or GADA as a first appearing beta-cell autoantibody in early life. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Lynch, Kristian F AU - Lynch KF AD - Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. Electronic address: Kristian.Lynch@epi.usf.edu. FAU - Lee, Hye-Seung AU - Lee HS AD - Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. FAU - Torn, Carina AU - Torn C AD - Department of Clinical Sciences Malmo, Lund University/CRC, Skane University Hospital SUS, Malmo, Sweden. FAU - Vehik, Kendra AU - Vehik K AD - Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. FAU - Krischer, Jeffrey P AU - Krischer JP AD - Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. FAU - Larsson, Helena Elding AU - Larsson HE AD - Department of Clinical Sciences Malmo, Lund University/CRC, Skane University Hospital SUS, Malmo, Sweden. FAU - Haller, Michael J AU - Haller MJ AD - Department of Pediatrics, University of Florida Gainesville, Gainesville, FL, USA. FAU - Hagopian, William A AU - Hagopian WA AD - Pacific Northwest Diabetes Research Institute, Seattle, WA, USA. FAU - Rewers, Marian J AU - Rewers MJ AD - Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA. FAU - She, Jin-Xiong AU - She JX AD - Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. FAU - Simell, Olli G AU - Simell OG AD - Department of Pediatrics, Turku University Hospital, Turku, Finland. FAU - Toppari, Jorma AU - Toppari J AD - Department of Pediatrics, Turku University Hospital, Turku, Finland; Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland. FAU - Ziegler, Anette-G AU - Ziegler AG AD - Institute of Diabetes Research, Helmholtz Zentrum Munchen, Neuherberg, Germany; Klinikum rechts der Isar, Technische Universitat Munchen, Neuherberg, Germany; Forschergruppe Diabetes e.V., Neuherberg, Germany. FAU - Akolkar, Beena AU - Akolkar B AD - National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD, USA. FAU - Hyoty, Heikki AU - Hyoty H AD - Department of Virology, Faculty of Medicine and Lifesciences, University of Tampere, Tampere, Finland; Fimlab Laboratories, Pirkannmaa Hospital District, Tampere, Finland. FAU - Bonifacio, Ezio AU - Bonifacio E AD - Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany. FAU - Lernmark, Ake AU - Lernmark A AD - Department of Clinical Sciences Malmo, Lund University/CRC, Skane University Hospital SUS, Malmo, Sweden. CN - TEDDY Study Group LA - eng GR - U01 DK063821/DK/NIDDK NIH HHS/United States GR - UC4 DK063863/DK/NIDDK NIH HHS/United States GR - HHSN267200700014C/DK/NIDDK NIH HHS/United States GR - U01 DK063861/DK/NIDDK NIH HHS/United States GR - UL1 TR001427/TR/NCATS NIH HHS/United States GR - U01 DK063790/DK/NIDDK NIH HHS/United States GR - UL1 TR001082/TR/NCATS NIH HHS/United States GR - P30 DK017047/DK/NIDDK NIH HHS/United States GR - UL1 TR000064/TR/NCATS NIH HHS/United States GR - U01 DK063836/DK/NIDDK NIH HHS/United States GR - U01 DK063829/DK/NIDDK NIH HHS/United States GR - U01 DK063865/DK/NIDDK NIH HHS/United States GR - UC4 DK095300/DK/NIDDK NIH HHS/United States GR - UC4 DK063861/DK/NIDDK NIH HHS/United States GR - UC4 DK063829/DK/NIDDK NIH HHS/United States GR - UC4 DK063821/DK/NIDDK NIH HHS/United States GR - UC4 DK117483/DK/NIDDK NIH HHS/United States GR - UC4 DK063836/DK/NIDDK NIH HHS/United States GR - UC4 DK112243/DK/NIDDK NIH HHS/United States GR - UC4 DK063865/DK/NIDDK NIH HHS/United States GR - U01 DK063863/DK/NIDDK NIH HHS/United States GR - UC4 DK106955/DK/NIDDK NIH HHS/United States GR - UC4 DK100238/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20170921 PL - England TA - J Autoimmun JT - Journal of autoimmunity JID - 8812164 RN - 0 (Autoantibodies) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (HLA-DQ Antigens) RN - 0 (HLA-DR Antigens) RN - 0 (Insulin) RN - EC 3.1.3.48 (PTPRN protein, human) RN - EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 8) RN - EC 4.1.1.15 (Glutamate Decarboxylase) RN - EC 4.1.1.15 (glutamate decarboxylase 2) SB - IM MH - Autoantibodies/metabolism MH - CTLA-4 Antigen/*metabolism MH - Female MH - Gestational Age MH - Glutamate Decarboxylase/immunology MH - HLA-DQ Antigens/genetics/metabolism MH - HLA-DR Antigens/genetics/metabolism MH - Humans MH - Infant MH - Insulin/immunology MH - Insulin-Secreting Cells/*immunology MH - Male MH - Polymorphism, Genetic MH - Pregnancy MH - Prenatal Exposure Delayed Effects/epidemiology/*immunology MH - Receptor-Like Protein Tyrosine Phosphatases, Class 8/immunology MH - Respiratory Tract Infections/epidemiology/*immunology PMC - PMC5747989 MID - NIHMS907744 OTO - NOTNLM OT - Autoimmune diabetes OT - Autoimmunity OT - Glutamic acid decarboxylase OT - HLA OT - IA-2 OT - Insulin OT - Type 1 diabetes OT - beta-cell autoantibodies COIS- Conflicts of interest The authors declare no conflict of interest. EDAT- 2017/09/25 06:00 MHDA- 2019/04/09 06:00 PMCR- 2019/01/01 CRDT- 2017/09/25 06:00 PHST- 2017/08/13 00:00 [received] PHST- 2017/09/06 00:00 [revised] PHST- 2017/09/11 00:00 [accepted] PHST- 2017/09/25 06:00 [pubmed] PHST- 2019/04/09 06:00 [medline] PHST- 2017/09/25 06:00 [entrez] PHST- 2019/01/01 00:00 [pmc-release] AID - S0896-8411(17)30558-9 [pii] AID - 10.1016/j.jaut.2017.09.005 [doi] PST - ppublish SO - J Autoimmun. 2018 Jan;86:93-103. doi: 10.1016/j.jaut.2017.09.005. Epub 2017 Sep 21.