Endocrine Abstracts

Background: Autoimmune Addison’s disease (AAD) is a rare endocrinopathy arising from a complex interplay between multiple genetic susceptibility polymorphisms and environmental factors. Several variants in immune pathways have been identified through hypothesis-driven candidate gene analysis, though these associations can prove difficult to replicate. The first genome wide association study (GWAS) with patients from Scandinavian Addison’s registries identified association signals at four novel loci in the genes LPP, SH2B3, SIGLEC5 and UBASH3A. To verify these novel risk loci, we studied five SNPs for association in our independent cohort of patients with AAD from the UK.

Methods: Genotypes at five SNPs [rs4686484 (LPP), rs12634152 (LPP), rs4801888 (SIGLEC5-SPACA6), rs11203203 (UBASH3A), rs3184504 (SH2B3)] from 420 UK-based AAD patients were compared with either 544 healthy controls, or in the case of rs3184504 (SH2B3) with 5154 healthy controls provided by the Wellcome Trust case-control consortium (WTCCC2). Chi-squared analysis was performed on allele and genotype frequencies and odds ratios were calculated for risk alleles. P-values of <0.012 were considered significant, reflecting Bonferroni correction for tests at four independent loci.

Results: We report significant association of variants in the LPP and UBASH3A genes (odds ratio [95% confidence intervals], 1.46 [1.21-1.75; P=5.4x10^-5] and 1.40 [1.16-1.68; P=3.7x10^-4], respectively) with AAD in the UK cohort. In addition, we report nominal association of AAD with SH2B3 (P=0.02). No significant association was seen with the SIGLEC5/SPACA6 locus.

Conclusion: Our study replicates that variants at the LPP and UBASH3A loci confer susceptibility to AAD for the first time, in an independent patient population. These loci have been implicated in coeliac disease, type 1 diabetes, Graves’ disease and Hashimoto’s thyroiditis, and thus contribute to the autoimmune comorbidity seen in AAD patients. Further studies with larger patient cohorts are required to robustly confirm the association of SH2B3 and SIGLEC5/SPACA6 alleles.