Sex-specific DLA Class II haplotypes are associated with primary hypoadrenocorticism in Standard Poodle dogs

Abstract

Abstract Autoimmune Addison’s Disease (AAD) is a life-threatening endocrine disorder that occurs spontaneously in humans and dogs and whose clinical features are highly similar between the species. Associations between MHC class II genes and AAD have been shown in several human studies. Our goal was to identify MHC class II associations with AAD in a large population of Standard Poodles, a breed highly predisposed to AAD. We sequenced exon 2 of the class II genes DRB1, DQA1, and DQB1 in 110 affected and 101 unaffected Standard Poodles and tested for association with AAD. Two haplotypes were found to confer risk of developing AAD in a gender-specific manner: 015:01-006:01-023:01 in males (□2 p = 0.03, OR 2.1) and 009:01-001:01-008:011 in females (□2 p = 0.02, OR 8.43). Sex-specific associations have been previously described in human populations, but this is the first report of this kind in dogs. Consistent with findings in other studies, we also found the DQA1*006:01 allele (□2 p = 0.04) to be associated with AAD in males independent of haplotype. In females, the haplotype 009:01-001:01-008:011 appears to confer a very high risk for developing AAD, though its frequency was rare (9 of 124 females) in our study population. Further studies are warranted to assess the usefulness of this haplotype as a genetic risk marker for AAD in female Standard Poodles. Our findings highlight the importance of evaluating MHC class II-disease associations in large populations, and accounting for both gender and population structure in order to uncover clinically relevant associations.