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Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes.
Aydemir, Özkan; Noble, Janelle A; Bailey, Jeffrey A; Lernmark, Åke; Marsh, Patrick; Andersson Svärd, Agnes; Bearoff, Frank; Blankenhorn, Elizabeth P; Mordes, John P.
Afiliación
  • Aydemir Ö; Division of Transfusion Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
  • Noble JA; Children's Hospital Oakland Research Institute, Oakland, CA.
  • Bailey JA; Division of Transfusion Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
  • Lernmark Å; Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Malmö, Sweden.
  • Marsh P; Division of Transfusion Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
  • Andersson Svärd A; Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Malmö, Sweden.
  • Bearoff F; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA.
  • Blankenhorn EP; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA.
  • Mordes JP; Division of Endocrinology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA john.mordes@umassmed.edu.
Diabetes ; 68(7): 1523-1527, 2019 07.
Article en En | MEDLINE | ID: mdl-30962219
Type 1 diabetes (T1D) involves the interaction of multiple gene variants, environmental factors, and immunoregulatory dysfunction. Major T1D genetic risk loci encode HLA-DR and -DQ. Genetic heterogeneity and linkage disequilibrium in the highly polymorphic HLA region confound attempts to identify additional T1D susceptibility loci. To minimize HLA heterogeneity, T1D patients (N = 365) and control subjects (N = 668) homozygous for the HLA-DR3 high-risk haplotype were selected from multiple large T1D studies and examined to identify new T1D susceptibility loci using molecular inversion probe sequencing technology. We report that risk for T1D in HLA-DR3 homozygotes is increased significantly by a previously unreported haplotype of three single nucleotide polymorphisms (SNPs) within the first intron of HLA-DRA1. The homozygous risk haplotype has an odds ratio of 4.65 relative to the protective homozygous haplotype in our sample. Individually, these SNPs reportedly function as "expression quantitative trait loci," modulating HLA-DR and -DQ expression. From our analysis of available data, we conclude that the tri-SNP haplotype within HLA-DRA1 may modulate class II expression, suggesting that increased T1D risk could be attributable to regulated expression of class II genes. These findings could help clarify the role of HLA in T1D susceptibility and improve diabetes risk assessment, particularly in high-risk HLA-DR3 homozygous individuals.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Antígeno HLA-DR3 / Predisposición Genética a la Enfermedad / Polimorfismo de Nucleótido Simple / Diabetes Mellitus Tipo 1 / Cadenas alfa de HLA-DR Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Female / Humans / Male Idioma: En Revista: Diabetes Año: 2019 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Antígeno HLA-DR3 / Predisposición Genética a la Enfermedad / Polimorfismo de Nucleótido Simple / Diabetes Mellitus Tipo 1 / Cadenas alfa de HLA-DR Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Female / Humans / Male Idioma: En Revista: Diabetes Año: 2019 Tipo del documento: Article