ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 65 OP2.2 | DOI: 10.1530/endoabs.65.OP2.2

The SH2B3 tryptophan 262 variant is associated with Graves' disease and Addison's disease

Georgina Sneddon, Kathleen Allinson, Laura Lane, Anna Mitchell & Simon Pearce

Institute of Genetic Medicine, Newcastle, UK

Objective: The SH2B3 gene encodes the src homology-2B adaptor protein 3, also known as lymphocyte adaptor protein (LNK), and is a negative regulator of T lymphocyte activation and the cytokine signalling pathways involved in inflammation and haematopoiesis. rs3184504, a non-synonymous SNP (R262W) in exon 3 of the SH2B3 gene, has been associated with numerous autoimmune conditions including type 1 diabetes, rheumatoid arthritis and coeliac disease. The overlap of risk alleles across multiple autoimmune diseases is a well-recognised phenomenon. This study aims to investigate the role of the rs3184504 SH2B3 variant in susceptibility to Graves’ disease (GD) and autoimmune Addison’s disease (AAD).

Design and methods: A case-control association analysis was performed in 687 GD and 420 AAD patients. Samples were genotyped by allele discrimination TaqMan PCR and genotype frequencies compared to 5154 healthy controls from the Wellcome Trust case-control consortium (WTCCC2).

Results: The TT genotype was present in 1210 of the 5154 (23.5%) controls, compared to 196 of 687 (28.5%) GD patients (P=0.0036) and 119 of 420 (28.3%) in the AAD cohort (P=0.026), using a recessive model. There was no significant difference in the T allele frequency between the GD patients and controls (47.1% in Graves’ vs. 48.9% in controls; P=0.123), however the T allele was over-represented in AAD patients compared to controls (53.0% vs. 48.9%; P=0.025).

Conclusion: Our study shows for the first time that homozygous carriage of the SH2B3 codon 262 tryptophan allele has a role in the genetic susceptibility to both GD and AAD. Although the function of this SNP has yet to be elucidated in detail, the dysregulation in signalling pathways involving lymphocyte homeostasis may broadly predispose to disease development. Further work is necessary to define the exact mechanism by which this allele contributes to autoimmune disease susceptibility.

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