Genetic determinants of 21-hydroxylase autoantibodies amongst patients of the Type 1 Diabetes Genetics Consortium.
BACKGROUND
Autoantibodies to 21-hydroxylase (21OH-AA) precede the onset of autoimmune Addison's disease (AD) and are found in 1.5% of individuals with type 1 diabetes mellitus (T1DM). The greatest genetic risk for both disorders is found in the major histocompatibility complex (MHC), suggesting a common pathophysiology between AD and T1DM. Screening for 21OH-AA in newly diagnosed T1DM patients is a valuable prognostic tool, made stronger when MHC genotype is considered.


METHODS
The Type 1 Diabetes Genetics Consortium has collected genotype data in T1DM subjects with tissue-specific autoantibody typing. Genotype and phenotype data in individuals positive and negative for 21OH-AA are compared.


RESULTS
Major genetic risk for 21OH-AA is in the MHC haplotypes DRB1*04-DQB1*0302 (primarily DRB1*0404) and DRB1*0301-DQB1*0201. Protective effects in class II MHC haplotypes DRB1*0101-DQB1*0501 and DRB1*0701-DQB1*0202 also were detected. There is no difference in the presence of HLA-B15 and little difference in the presence of HLA-B8 (after class II effects are accounted for) in T1DM patients with 21OH-AA compared with known associations (HLA-B8 positive and HLA-B15 negative) in AD.


CONCLUSIONS
In 21OH-AA(+) subjects, genetic risk is found mainly in MHC class II haplotypes DR3 and DR4 but not class I alleles (HLA-B8 or HLA-B15). This suggests a difference between autoantibody formation (class II dependent) and progression to overt disease (class I dependent) in AD.
Barbara Davis Center for Childhood Diabetes, Aurora, Colorado 80045, USA.
Peter
P
Baker
Pam
P
Fain
Heinrich
H
Kahles
Liping
L
Yu
John
J
Hutton
Janet
J
Wenzlau
Marian
M
Rewers
Klaus
K
Badenhoop
George
G
Eisenbarth
D000224:Addison Disease / Q000209:etiology / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D059910:HLA-B15 Antigen / Q000032:analysis; D015795:HLA-B8 Antigen / Q000032:analysis; D015803:HLA-DR3 Antigen / Q000032:analysis; D015804:HLA-DR4 Antigen / Q000032:analysis; D059811:HLA-DRB1 Chains / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D013255:Steroid 21-Hydroxylase / Q000032:analysis / Q000276:immunology*
D001323:Autoantibodies; D059910:HLA-B15 Antigen; D015795:HLA-B8 Antigen; D015803:HLA-DR3 Antigen; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; D013255:Steroid 21-Hydroxylase