MHC class II association study in eight breeds of dog with hypoadrenocorticism
Canine hypoadrenocorticism is an endocrine disorder characterised by inadequate secretion of steroid hormones from the adrenal glands. Pathology results from immune-mediated destruction of the adrenal cortex, which is similar to that seen in the human Addison’s disease. Both the canine and human diseases have similar clinical presentation, with the diagnosis based on performing a dynamic adrenocorticotropic hormone stimulation test. MHC class II has previously been associated with the human and canine diseases. In the current study, we conducted an MHC class II association study in eight breeds of dog with diagnoses of hypoadrenocorticism. We demonstrated significant differences in dog leukocyte antigen (DLA) haplotype frequencies in six of these breeds: Cocker spaniel, Springer spaniel, Labrador, West Highland white terrier (WHWT), Bearded collie, and Standard poodle. In the Springer spaniel, the DLA-DRB1*015:01--DQA1*006:01--DQB1*023:01 haplotype was significantly associated with disease risk (p = 0.014, odds ratio (OR) = 5.14) and showed a similar trend in the Cocker spaniel. This haplotype is related to one associated with hypoadrenocorticism in the Nova Scotia duck tolling retriever. Similar haplotypes shared between breeds were demonstrated, with DLA-DRB1*001:01--DQA1*001:01--DQB1*002:01 more prevalent in both affected Labrador (p = 0.0002, OR = 3.06) and WHWT (p = 0.01, OR = 2.11). Other haplotypes that have not previously been associated with the disease were identified. The inter-breed differences in DLA haplotypes associated with susceptibility to canine hypoadrenocorticism could represent divergent aetiologies. This could have implications for clinical diagnosis and future comparative studies. Alternatively, it may suggest that the gene of interest is closely linked to the MHC.
KeywordsAddison’s DLA MHC Hypoadrenocorticism
We would like to thank Jo Tucker (Canine Immune Mediated Disease Awareness, CIMDA) for being instrumental in encouraging sample collection. We would also like to thank IDEXX laboratories (Harrogate, UK), Nationwide Laboratories (Poulton-le-Fylde, UK), Angela Pedder, Colleen Stead, the Bearded Collie Breed Club (UK Northern Branch), Lucy Davison, Betty Aughey, all dog owners, and clinicians for submitting samples for inclusion in the study. Acknowledgments also go to the technical staff supporting the UK DNA Archive for Companion Animals, namely Steven Quarmby, Ezinne Ibe, and Simon Rothwell. This work was supported by the European Commission FP7 project number 201167, Euradrenal.
Conflict of interest
The authors declare that they have no conflict of interest.
- Barcellos LF, Oksenberg JR, Begovich AB, Martin ER, Schmidt S, Vittinghoff E, Goodin DS, Pelletier D, Lincoln RR, Bucher P, Swerdlin A, Pericak-Vance MA, Haines JL, Hauser SL (2003) HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Am J Hum Genet 72(3):710–716PubMedCrossRefGoogle Scholar
- Betterle C, Volpato M, Pedini B, Chen S, Smith BR, Furmaniak J (1999) Adrenal-cortex autoantibodies and steroid-producing cells autoantibodies in patients with Addison's disease: comparison of immunofluorescence and immunoprecipitation assays. J Clin Endocrinol Metab 84(2):618–622PubMedCrossRefGoogle Scholar
- Falorni A, Laureti S, Nikoshkov A, Picchio ML, Hallengren B, Vandewalle CL, Gorus FK, Tortoioli C, Luthman H, Brunetti P, Santeusanio F (1997) 21-hydroxylase autoantibodies in adult patients with endocrine autoimmune diseases are highly specific for Addison's disease. Belgian Diabetes Registry. Clin Exp Immunol 107(2):341–346PubMedCrossRefGoogle Scholar
- Gambelunghe G, Falorni A, Ghaderi M, Laureti S, Tortoioli C, Santeusanio F, Brunetti P, Sanjeevi CB (1999) Microsatellite polymorphism of the MHC class I chain-related (MIC-A and MIC-B) genes marks the risk for autoimmune Addison's disease. J Clin Endocrinol Metab 84(10):3701–3707PubMedCrossRefGoogle Scholar
- Vaidya B, Imrie H, Geatch DR, Perros P, Ball SG, Baylis PH, Carr D, Hurel SJ, James RA, Kelly WF, Kemp EH, Young ET, Weetman AP, Kendall-Taylor P, Pearce SH (2000) Association analysis of the cytotoxic T lymphocyte antigen-4 (CTLA-4) and autoimmune regulator-1 (AIRE-1) genes in sporadic autoimmune Addison's disease. J Clin Endocrinol Metab 85(2):688–691PubMedCrossRefGoogle Scholar
- Wilbe M, Sundberg K, Hansen IR, Strandberg E, Nachreiner RF, Hedhammar A, Kennedy LJ, Andersson G, Bjornerfeldt S (2010) Increased genetic risk or protection for canine autoimmune lymphocytic thyroiditis in Giant Schnauzers depends on DLA class II genotype. Tissue Antigens 75:712–719PubMedCrossRefGoogle Scholar