PMID- 26513234 OWN - NLM STAT- MEDLINE DCOM- 20160819 LR - 20220410 IS - 1476-5470 (Electronic) IS - 1466-4879 (Print) IS - 1466-4879 (Linking) VI - 16 IP - 8 DP - 2015 Dec TI - Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies. PG - 541-51 LID - 10.1038/gene.2015.43 [doi] AB - The possible interrelations between human leukocyte antigen (HLA)-DQ, non-HLA single-nucleotide polymorphisms (SNPs) and islet autoantibodies were investigated at clinical onset in 1-34-year-old type 1 diabetes (T1D) patients (n=305) and controls (n=203). Among the non-HLA SNPs reported by the Type 1 Diabetes Genetics Consortium, 24% were supported in this Swedish replication set including that the increased risk of minor PTPN22 allele and high-risk HLA was modified by GAD65 autoantibodies. The association between T1D and the minor AA+AC genotype in ERBB3 gene was stronger among IA-2 autoantibody-positive patients (comparison P=0.047). The association between T1D and the common insulin (AA) genotype was stronger among insulin autoantibody (IAA)-positive patients (comparison P=0.008). In contrast, the association between T1D and unidentified 26471 gene was stronger among IAA-negative (comparison P=0.049) and IA-2 autoantibody-negative (comparison P=0.052) patients. Finally, the association between IL2RA and T1D was stronger among IAA-positive than among IAA-negative patients (comparison P=0.028). These results suggest that the increased risk of T1D by non-HLA genes is often modified by both islet autoantibodies and HLA-DQ. The interactions between non-HLA genes, islet autoantibodies and HLA-DQ should be taken into account in T1D prediction studies as well as in prevention trials aimed at inducing immunological tolerance to islet autoantigens. FAU - Maziarz, M AU - Maziarz M AD - Department of Biostatistics, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. FAU - Hagopian, W AU - Hagopian W AD - Pacific Northwest Diabetes Research Institute, Seattle, WA, USA. FAU - Palmer, J P AU - Palmer JP AD - Department of Medicine, University of Washington, Seattle, WA, USA. FAU - Sanjeevi, C B AU - Sanjeevi CB AD - Department of Medicine, Karolinska Institute, Solna, Sweden. FAU - Kockum, I AU - Kockum I AD - Department of Clinical Neurosciences, Karolinska Institute, Stockholm, Sweden. FAU - Breslow, N AU - Breslow N AD - Department of Biostatistics, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. FAU - Lernmark, A AU - Lernmark A AD - Department of Clinical Sciences, Lund University, Malmo, Sweden. CN - Swedish Childhood Diabetes Register CN - Diabetes Incidence in Sweden Study Group CN - Type 1 Diabetes Genetics Consortium LA - eng GR - R01 DK026190/DK/NIDDK NIH HHS/United States GR - DK26190/DK/NIDDK NIH HHS/United States GR - UC4 DK063861/DK/NIDDK NIH HHS/United States GR - U01 DK062418/DK/NIDDK NIH HHS/United States GR - U01 DK063861/DK/NIDDK NIH HHS/United States GR - DK63861/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151029 PL - England TA - Genes Immun JT - Genes and immunity JID - 100953417 RN - 0 (Autoantibodies) RN - 0 (HLA-DQ Antigens) RN - EC 2.7.10.1 (ERBB3 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-3) RN - EC 3.1.3.48 (PTPN22 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 22) SB - IM MH - Adolescent MH - Adult MH - Autoantibodies/genetics/*immunology MH - Child MH - Child, Preschool MH - Diabetes Mellitus, Type 1/*genetics/*immunology MH - HLA-DQ Antigens/*genetics/immunology MH - Humans MH - Infant MH - Islets of Langerhans/*immunology MH - Polymorphism, Single Nucleotide MH - Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics MH - Receptor, ErbB-3/genetics MH - Young Adult PMC - PMC4670274 MID - NIHMS719384 FIR - Graham, Jinko IR - Graham J FIR - MacNeney, Brad IR - MacNeney B FIR - Arnqvist, Hans IR - Arnqvist H FIR - Landin-Olsson, Mona IR - Landin-Olsson M FIR - Nystrom, Lennarth IR - Nystrom L FIR - Ohlson, Lars Olof IR - Ohlson LO FIR - Ostman, Jan IR - Ostman J FIR - Halmstad, M Aili IR - Halmstad MA FIR - Ostersund, L E Baath IR - Ostersund LE FIR - Kalmar, E Carlsson IR - Kalmar EC FIR - Karlskrona, H Edenwall IR - Karlskrona HE FIR - Falun, G Forsander IR - Falun GF FIR - Gallivare, Bw Granstrom IR - Gallivare BG FIR - Skelleftea, I Gustavsson IR - Skelleftea IG FIR - Uddevalla, R Hanas IR - Uddevalla RH FIR - Nykoping, L Hellenberg IR - Nykoping LH FIR - Lidkoping, H Hellgren IR - Lidkoping HH FIR - Umea, E Holmberg IR - Umea EH FIR - Hudiksvall, H Hornell IR - Hudiksvall HH FIR - Malmo, Sten-A Ivarsson IR - Malmo SA FIR - Jonkoping, C Johansson IR - Jonkoping CJ FIR - Karlstad, G Jonsell IR - Karlstad GJ FIR - Molndal, B Lindblad IR - Molndal BL FIR - Boras, A Lindh IR - Boras AL FIR - Linkoping, J Ludvigsson IR - Linkoping JL FIR - Vasteras, U Myrdal IR - Vasteras UM FIR - Helsingborg, J Neiderud IR - Helsingborg JN FIR - Eskilstuna, K Segnestam IR - Eskilstuna KS FIR - Boden, L Skogsberg IR - Boden LS FIR - Norrkoping, L Stromberg IR - Norrkoping LS FIR - Angelholm, U Stahle IR - Angelholm US FIR - Huddinge, B Thalme IR - Huddinge BT FIR - Danderyd, K Tullus IR - Danderyd KT FIR - Uppsala, T Tuvemo IR - Uppsala TT FIR - Stockholm, M Wallensteen IR - Stockholm MW FIR - Goteborg, O Westphal IR - Goteborg OW FIR - Orebro, J Aman IR - Orebro JA EDAT- 2015/10/30 06:00 MHDA- 2016/08/20 06:00 PMCR- 2016/05/18 CRDT- 2015/10/30 06:00 PHST- 2015/01/10 00:00 [received] PHST- 2015/08/25 00:00 [revised] PHST- 2015/08/27 00:00 [accepted] PHST- 2015/10/30 06:00 [entrez] PHST- 2015/10/30 06:00 [pubmed] PHST- 2016/08/20 06:00 [medline] PHST- 2016/05/18 00:00 [pmc-release] AID - gene201543 [pii] AID - 10.1038/gene.2015.43 [doi] PST - ppublish SO - Genes Immun. 2015 Dec;16(8):541-51. doi: 10.1038/gene.2015.43. Epub 2015 Oct 29.