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Genes Immun. 2015 Dec;16(8):541-51. doi: 10.1038/gene.2015.43. Epub 2015 Oct 29.

Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies.

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Department of Biostatistics, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Pacific Northwest Diabetes Research Institute, Seattle, WA, USA.
Department of Medicine, University of Washington, Seattle, WA, USA.
Department of Medicine, Karolinska Institute, Solna, Sweden.
Department of Clinical Neurosciences, Karolinska Institute, Stockholm, Sweden.
Department of Clinical Sciences, Lund University, Malmö, Sweden.


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.

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