Haplotype analysis discriminates genetic risk for DR3-associated endocrine autoimmunity and helps define extreme risk for Addison's disease
| Autor: | Marian Rewers, George S. Eisenbarth, Janet C. Siebert, Taylor M. Triolo, Sunanda R. Babu, Taylor K. Armstrong, Peter R. Baker, Pam R. Fain, Jennifer M. Barker, Priyaanka Nanduri, Peter A. Gottlieb, Erin E. Baschal |
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| Rok vydání: | 2010 |
| Předmět: |
musculoskeletal diseases
Adult Male Risk Linkage disequilibrium endocrine system diseases Endocrinology Diabetes and Metabolism Clinical Biochemistry Population DNA Mutational Analysis Single-nucleotide polymorphism Autoimmunity Biology Biochemistry Polymorphism Single Nucleotide Linkage Disequilibrium Autoimmune Diseases HLA-B8 Antigen Endocrinology HLA-DR3 Antigen Addison Disease Gene Frequency immune system diseases Genotype medicine Humans Genetic Predisposition to Disease education skin and connective tissue diseases Allele frequency Genetics education.field_of_study HLA-DQB1 Biochemistry (medical) Haplotype medicine.disease Pedigree Haplotypes Addison's disease Immunology Female Original Article Endocrine Cells |
| Zdroj: | The Journal of clinical endocrinology and metabolism. 95(10) |
| ISSN: | 1945-7197 |
| Popis: | Context: Multiple autoimmune disorders (e.g. Addison’s disease, type 1 diabetes, celiac disease) are associated with HLA-DR3, but it is likely that alleles of additional genes in linkage disequilibrium with HLA-DRB1 contribute to disease. Objective: The objective of the study was to characterize major histocompatability complex (MHC) haplotypes conferring extreme risk for autoimmune Addison’s disease (AD). Design, Setting, and Participants: Eighty-six 21-hydroxylase autoantibody-positive, nonautoimmune polyendocrine syndrome type 1, Caucasian individuals collected from 1992 to 2009 with clinical AD from 68 families (12 multiplex and 56 simplex) were genotyped for HLA-DRB1, HLA-DQB1, MICA, HLA-B, and HLA-A as well as high density MHC single-nucleotide polymorphism (SNP) analysis for 34. Main Outcome Measures: AD and genotype were measured. Result: Ninety-seven percent of the multiplex individuals had both HLA-DR3 and HLA-B8 vs. 60% of simplex AD patients (P = 9.72 × 10−4) and 13% of general population controls (P = 3.00 × 10−19). The genotype DR3/DR4 with B8 was present in 85% of AD multiplex patients, 24% of simplex patients, and 1.5% of control individuals (P = 4.92 × 10−191). The DR3-B8 haplotype of AD patients had HLA-A1 less often (47%) than controls (81%, P = 7.00 × 10−5) and type 1 diabetes patients (73%, P = 1.93 × 10−3). Analysis of 1228 SNPs across the MHC for individuals with AD revealed a shorter conserved haplotype (3.8) with the loss of the extended conserved 3.8.1 haplotype approximately halfway between HLA-B and HLA-A. Conclusion: Extreme risk for AD, especially in multiplex families, is associated with haplotypic DR3 variants, in particular a portion (3.8) but not all of the conserved 3.8.1 haplotype. |
| Databáze: | OpenAIRE |
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