title: Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies.
abstract: 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.
authors.affiliation: Department of Biostatistics, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Maziarz
authors.affiliation: Pacific Northwest Diabetes Research Institute, Seattle, WA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Hagopian
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Palmer
authors.affiliation: Department of Medicine, Karolinska Institute, Solna, Sweden.
authors.forename: C B
authors.initials: CB
authors.lastname: Sanjeevi
authors.affiliation: Department of Clinical Neurosciences, Karolinska Institute, Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Kockum
authors.affiliation: Department of Biostatistics, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Breslow
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Å
authors.initials: Å
authors.lastname: Lernmark
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007223:Infant; D007515:Islets of Langerhans / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D020893:Receptor, ErbB-3 / Q000235:genetics; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D006683:HLA-DQ Antigens; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22