HLA-DQA1*0301-Associated Susceptibility for Autoimmune Polyglandular Syndrome Type II and III

Abstract

No significant differences were reported for the frequency of DR3-DQ2 and DR4-DQ8 haplotypes in a recent study of one of the largest cohorts worldwide of patients with isolated Addison's disease compared to patients with APS II. However, previous studies had suggested that the HLA-DQ genes, especially DQA1*0102, may be a genetic marker for resistance to autoimmune thyroid disease, which is the most frequent disease in APS II or III. Until now, HLA-DQA1 alleles have not been systematically investigated in APS. We determined the HLA-DR and HLA-DQA1 association in 112 unrelated patients with APS II (n = 29), APS III (n = 83) and 184 unrelated patients with single-component diseases without further manifestations of APS: Graves' disease (n = 70), Hashimoto’s thyroiditis (n = 53), autoimmune Addison's disease (n = 15), vitiligo (n = 16) and alopecia (n = 30), and 72 healthy controls - German Caucasians - to identify possible predisposing and protective HLA class II alleles in APS. In agreement with previous studies, we detected a significantly higher frequency of DR 3 and/or DR 4 in patients with APS II and III compared to controls. In patients with APS II, we detected a significantly higher frequency of DQA1*0301 and *0501 compared to controls confirming the increased frequency of an extended HLA DRB1-*04-DQA1-*03-DQB-*03 haplotype as previously described. In contrast, only DQA1*0301 was increased in our patients with APS III compared to controls. Moreover, we detected an increased frequency of DQA1*0301 in patients with APS, whereas DQA1*0301 was only significantly elevated in alopecia in patients with single-component diseases without APS. Therefore, our results indicate an association between DQA1*0301 and APS II or III since this allele was otherwise not significantly associated with any of its component diseases except alopecia. Moreover, our data imply that the allele DQA1*0301 is a marker of increased risk for further APS manifestations in patients who suffer from an organ-specific autoimmune disease.

Key words

Polyglandular autoimmune syndrome - HLA

References

• 1 Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients.  N Engl J Med. 1990;  322 1829-1836
• 2 Betterle C, Greggio N A, Volpato M. Clinical review 93: autoimmune polyglandular syndrome type 1.  J Clin Endocrinol Metab. 1998;  83 1049-1055
• 3 The Finnish-German APECED Consortium L .Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet 1997 17: 399-403
• 4 Nagamine K, Peterson P, Scott H S, Kudoh J, Minoshima S, Heino M, Krohn K J, Lalioti M D, Mullis P E, Antonarakis S E, Kawasaki K, Asakawa S, Ito F, Shimizu N. Positional cloning of the APECED gene.  Nat Genet. 1997;  17 393-398
• 5 Neufeld M, Maclaren N, Blizzard R. Autoimmune polyglandular syndromes.  Pediatr Ann. 1980;  9 154-162
• 6 Malnati M S, Marti M, LaVaute T, Jaraquemada D, Biddison W, DeMars R, Long E O. Processing pathways for presentation of cytosolic antigen to MHC class II-restricted T cells.  Nature 25. 1992;  357(6380) 702-704
• 7 Badenhoop K, Walfish P G, Rau H, Fischer S, Nicolay A, Bogner U, Schleusener H, Usadel K H. Susceptibility and resistance alleles of human leukocyte antigen (HLA) DQA1 and HLA DQB1 are shared in endocrine autoimmune disease.  J Clin Endocrinol Metab. 1995;  80 2112-2117
• 8 Myhre A G, Undlien D E, Lovas K, Uhlving S, Nedrebo B G, Fougner K J, Trovik T, Sorheim J I, Husebye E S. Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II associations related to clinical features.  J Clin Endocrinol Metab. 2002;  87 618-623
• 9 Scott H S, Heino M, Peterson P. et al . Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins.  Mol Endocrinol. 1998;  12 1112-1119
• 10 Wang C Y, Davoodi-Semiromi A, Huang W, Connor E, Shi J D, She J X. Characterization of mutations in patients with autoimmune polyglandular syndrome type 1 (APS1).  Hum Genet. 1998;  103 681-685
• 11 Heino M, Scott H S, Chen Q. et al . Mutation analyses of North American APS-1 patients.  Hum Mutat. 1999;  13 69-74
• 12 Maclaren N K, Riley W J. Inherited susceptibility to autoimmune Addison's disease is linked to human leukocyte antigens-DR3 and/or DR4, except when associated with type I autoimmune polyglandular syndrome.  J Clin Endocrinol Metab. 1986;  62 455-459
• 13 Tamai H, Kimura A, Dong R P, Matsubayashi S, Kuma K, Nagataki S, Sasazuki T. Resistance to autoimmune thyroid disease is associated with HLA-DQ.  J Clin Endocrinol Metab. 1994;  78 94-97
• 14 Maclaren N K, Riley W J. Inherited susceptibility to autoimmune Addison's disease is linked to human leukocyte antigens-DR3 and/or DR4, except when associated with type I autoimmune polyglandular syndrome.  J Clin Endocrinol Metab. 1986;  62 455-459
• 15 Huang W, Connor E, Rosa T D, Schatz D, Silverstein J, Crockett S, She J X, Maclaren N K. Although DR3-DQB1*0201 may be associated with multiple component diseases of the autoimmune polyglandular syndromes, the human leukocyte antigen DR4-DQB1*0302 haplotype is implicated only in beta-cell autoimmunity.  J Clin Endocrinol Metab. 1996;  81 2559-2563
• 16 Weetman A P, Zhang L, Tandon N, Edwards O M. HLA associations with autoimmune Addison's disease.  Tissue Antigens. 1991;  38 31-33