Polymorphisms in the CTLA4 promoter sequence are associated with canine hypoadrenocorticism

Abstract

Background: Canine hypoadrenocorticism is an immune-mediated endocrinopathy that shares both clinical and pathophysiological similarities with Addison's disease in humans. Several dog breeds are overrepresented in the disease population, suggesting that a genetic component is involved, although this is likely to be polygenic. Previous research has implicated CTLA4 as a potential susceptibility gene. CTLA4 is an important regulator of T cell function and polymorphisms/mutations in CTLA4 have been associated with a number of autoimmune phenotypes in both humans and rodent models of autoimmunity. The aim of the current study was to undertake a case:control association study of CTLA4 promotor polymorphisms in three dog breeds, cocker spaniels, springer spaniels and West Highland white terriers (WHWT).

Results: Polymorphisms in the CTLA4 promoter were determined by PCR and sequence-based typing. There were significant associations with three promoter haplotypes in cocker spaniels (p = 0.003). A series of SNPs were also associated with hypoadrenocorticism in cocker spaniels and springer spaniels, including polymorphisms in predicted NFAT and SP1 transcription factor binding sites.

Conclusions: This study provides further evidence that CTLA4 promotor polymorphisms are associated with this complex genetic disease and supports an immune mediated aetiopathogenesis of canine hypoadrenocorticism.

Keywords: Addison’s; CTLA-4; Canine; Hypoadrenocorticism; Promoter.

Fig. 1

Canine CTLA4 promoter region variation and selected response elements. Primer binding sites are shown, highlighted yellow with arrow denoting the starting base in a 5′-3′ direction. Variations are as named, indicated byor; SNPs highlighted green, Dog Genome Assembly allele followed by variant shown; INDELs highlighted red, capital letters denote a variant present in, and lowercase letters denote variation not present in, the dog genome assembly sequence. Predicted response elements NFAT TTTCC (a) highlighted pink; partial SP1 site highlighted turquoise; partial GATA1 site highlighted blue; predicted AP-1 site highlighted purple; FoxP3 TTTGTT highlighted grey; TCF site highlighted dark green. SNP codes: M: A/C; R: A/G; S: C/G; Y: C/T; K: G/T. Exon sequence is orange. The ATG start codon isbold double underlined.The TATA box isbold single underlined