Genetic and clinical evaluation of hypoadrenocorticism in Nova Scotia duck tolling retrievers.

摘要

Hypoadrenocorticism, also known as Addison's disease, is an endocrine disorder characterized by the lack of glucocorticoid and mineralocorticoid production by the adrenal glands. These hormones affect a large number of organ systems in the body leading to a variety of non-specific clinical signs including lethargy, anorexia, vomiting, diarrhea, weight loss, and weakness. While it occurs at a low frequency in the general dog population, certain breeds appear to be at greater risk of developing hypoadrenocorticism due to a heritable component. Pedigree analysis of 25 Nova Scotia Duck Tolling Retrievers (NSDTRs) with hypoadrenocorticism demonstrated that this disorder is inherited within the breed and the analysis supported a major locus with an autosomal recessive mode of inheritance. Clinical evaluation of these affected NSDTRs demonstrated that they were diagnosed at an earlier age compared to previous reports in the general dog population (3.0 years old versus 4.0 years old) and nearly half the dogs were under 2 years of age at the time of diagnosis. Additionally, one third of the affected dogs had no serum electrolyte abnormalities at the time of diagnosis indicating that they may not have been mineralocorticoid deficient initially, however half of these dogs developed mineralocorticoid deficiency at a later time. These clinical differences are important to consider when clinicians are evaluating an ill NSDTR that seems too young for hypoadrenocorticism or has normal serum electrolyte levels.Genetic analyses found that a major histocompatibility complex (MHC) class II haplotype is associated with this disorder in NSDTRs and dogs that are homozygous for their MHC class II haplotype are at significantly higher risk of developing hypoadrenocorticism (OR = 6.7, RR = 1.9). However, a number of candidate genes which have been implicated with inherited forms of human hypoadrenocorticism and other immune-mediated disorders were excluded based on linkage analyses within pedigrees of affected NSDTRs. A whole genome linkage study using 390 microsatellite markers demonstrated large blocks of homozygosity within the breed indicating relatively low levels of diversity in those regions consistent with a limited gene pool. One region on chromosome 15 had four microsatellite markers with LOD scores >2.0, however further analysis of this region failed to identify a common haplotype in affected dogs.This research will continue by utilizing the recently developed SNP array technologies which can evaluate a hundred thousand genetic markers across the NSDTR genome in a case-control association study which should allow identification of the region(s) associated with this disorder. Discovery of the genetic mutation(s) responsible for inherited hypoadrenocorticism in NSDTRs may reveal a novel gene not yet implicated with immune-mediated disease and could shed more light on the genetic and pathological mechanisms of hypoadrenocorticism and immune-mediated diseases in both dogs and humans.