title: HLA similarities indicate shared genetic risk in 21-hydroxylase autoantibody positive South African and United States Addison's disease.
abstract: Genetic similarities between patients from the United States and South African (SA) Addison's Disease (AD) strengthen evidence for genetic association. SA-AD (n = 73), SA healthy controls (N = 78), and US-AD patients (N = 83) were genotyped for DQA1, DQB1, DRB1, and HLA-B alleles. Serum was tested for the quantity of 21OH-AA and IFNα-AA at the Barbara Davis Center. Although not as profound as in US-AD, in SA-AD 21OH-AA + subjects the predominantly associated risk haplotypes were DRB1*0301-DQB1*0201 (DR3), DRB1*04xx-DQB1*0302 (DR4), and the combined DR3/4 genotype. DQB1*0302 associated DRB1*04xx haplotypes conferred higher risk than those DRB1*04xx haplotypes associated with other DQB1 alleles. We found negative association in 21OH-AA + SA-AD for DQA1*0201-DQB1*0202 and DQA1*0101-DQB1*0501 vs SA controls, and positive association for DQA1*0401-DQB1*0402 vs US-AD. Apart from the class II DR3 haplotype, HLA-B8 did not have an independent effect; however together DR3 and HLA-B8 conferred the highest risk vs 21OH-AA negative SA-AD and SA-controls. HLA-B7 (often with DR4) conferred novel risk in 21OH-AA + SA-AD vs controls. This study represents the first comparison between South African and United States AD populations utilizing genotyping and serology performed at the same center. SA-AD and US-AD 21OH-AA + patients share common HLA risk haplotypes including DR4 (with HLA-B7) and DR3 (with HLA-B8), strengthening previously described HLA associations and implicating similar genetic etiology.
authors.affiliation: University of Cape Town, Cape Town, South Africa.
authors.forename: I L
authors.initials: IL
authors.lastname: Ross
authors.forename: S
authors.initials: S
authors.lastname: Babu
authors.forename: T
authors.initials: T
authors.lastname: Armstrong
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Schatz
authors.forename: A
authors.initials: A
authors.lastname: Pugliese
authors.forename: G
authors.initials: G
authors.lastname: Eisenbarth
authors.forename: P
authors.initials: P
authors.lastname: Baker Ii
mesh_terms: D000224:Addison Disease / Q000235:genetics* / Q000276:immunology; D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013019:South Africa; D013255:Steroid 21-Hydroxylase / Q000276:immunology*; D014481:United States
chemical_list: D001323:Autoantibodies; C477221:HLA-A*02:49 antigen; D015789:HLA-A2 Antigen; D013255:Steroid 21-Hydroxylase
keywords: Addison's disease; autoantibody serology; autoimmune polyendocrine syndrome type 2; human leukocyte antigen genetics