Addison's disease (AD) is a rare autoimmune disorder affecting approximately 1/10,000 in the general population. It typically occurs sporadically with a single member of a family affected (simplex families). Rarely, multiple members of a family can be affected with AD (multiplex families). The purpose of this study is to characterize the HLA haplotypes and genotypes of a group of individuals with AD and evaluate the differences between simplex and multiplex cases. Individuals with AD were recruited for participation in this study through the National Adrenal Diseases Foundation and through screening individuals with type 1 diabetes (T1D) for AD. A total of 62 families and 239 individuals with at least one member with AD were identified. They were divided into four groups: multiplex AD (9 families, 82 members), simplex AD (34 families, 91 members), multiplex T1D (5 families, 32 members) and T1D with AD (14 families, 34 members). HLA haplotypes were remarkably restricted in this group of families with AD. Seventy-seven percent of unrelated probands had at least one DR3 and 47% had at least one DR4. Five of the seven unrelated probands who had neither DR3 nor DR4 were either DR2/2, DR2/5 or DR 5/5. The DR2 haplotype was concentrated in the simplex AD probands in which there was a 16% haplotype frequency of DR2 compared with 0% in the other groups (p=0.0015). Unrelated probands from multiplex AD families had an increase of the DRB1*0404, DQ8/ DR3 genotype (56%) compared with 10% of simplex AD probands (p≤0.01). Similarly, unrelated probands of multiplex T1D families had a higher rate of this genotype compared with simplex T1D probands (80% vs. 23%, p=0.047). T1D tended to occur at an increased frequency in the patients of multiplex AD families compared with the patients of the simplex AD families (24% vs. 3%, p=0.07). In conclusion, there is a restricted pattern of HLA haplotypes in these individuals with AD. DRB1*0404,DQ8/DR3 was highly associated with multiplex AD and T1D families. This may suggest that refined HLA analysis can identify groups of people with risk for AD approaching that found in the population with T1D, a group in which some centers are screening for the adrenal autoimmunity associated with AD.
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