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


METHODS
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.


METHODS
AD and genotype were measured.


RESULTS
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.


CONCLUSIONS
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.
Baker
Peter R
PR
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado 80045-6511, USA.
Baschal
Erin E
EE
Fain
Pam R
PR
Triolo
Taylor M
TM
Nanduri
Priyaanka
P
Siebert
Janet C
JC
Armstrong
Taylor K
TK
Babu
Sunanda R
SR
Rewers
Marian J
MJ
Gottlieb
Peter A
PA
Barker
Jennifer M
JM
Eisenbarth
George S
GS
D000224:Addison Disease / Q000235:genetics* / Q000276:immunology; D000328:Adult; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D004252:DNA Mutational Analysis; D055098:Endocrine Cells / Q000276:immunology*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015795:HLA-B8 Antigen / Q000235:genetics; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D012306:Risk
D015795:HLA-B8 Antigen; D015803:HLA-DR3 Antigen