Haplotype analysis discriminates genetic risk for DR3-associated endocrine autoimmunity and helps define extreme risk for Addison's disease.

Baker PR, Baschal EE, Fain PR, Triolo TM, Nanduri P, Siebert JC, Armstrong TK, Babu SR, Rewers MJ, Gottlieb PA, Barker JM, Eisenbarth GS
J Clin Endocrinol Metab. 2010 95 (10): E263-70

PMID: 20631027 · PMCID: PMC3050098 · DOI:10.1210/jc.2010-0508

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.

MeSH Terms (18)

Addison Disease Adult Autoimmune Diseases Autoimmunity DNA Mutational Analysis Endocrine Cells Female Gene Frequency Genetic Predisposition to Disease Haplotypes HLA-B8 Antigen HLA-DR3 Antigen Humans Linkage Disequilibrium Male Pedigree Polymorphism, Single Nucleotide Risk

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