Endocrine Abstracts (2012) 28 P321

Rare variants of sialic acid acetylesterase in autoimmune Addison's disease

Earn Gan, Anna Mitchell, Katie MacArthur & Simon Pearce


Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.


Sialic acid acetylesterase (SIAE) has been found to be essential for the maintenance of immune tolerance in mice by negatively regulating B lymphocyte antigen receptor signalling. Recently, numerous rare heterozygous loss-of-function germline variants and a homozygous functionally defective variant of the SIAE gene (M89V) have been identified as conferring a strong genetic susceptibility to several autoimmune disorders, including T1DM and rheumatoid arthritis. We performed a case-control study to determine if these rare variants in the SIAE gene are associated with autoimmune Addison’s disease (AAD). We analysed 9 SIAE gene variants that were previously associated with autoimmunity (M89V, C196F, T312M, C226G, F404S, R230W, R479C, W48X, Y349C) in a cohort of 318 UK AAD subjects and 274 healthy controls. All samples were genotyped using Sequenom iPlex chemistry to characterise primer extension products. Eight AAD subjects (2.5%) and 3 controls (1.09%) carried defective SIAE alleles [OR 2.33; 5–95% CI (0.56–11.20), P value: 0.166)]. One AAD subject was homozygous for the 89V/89V SIAE variant, whereas this was not observed in any of the healthy controls. The Y349C polymorphism was found in 2.8% of AAD patients compared to 0.7% of controls; [OR:4.07; 5–95% CI(0.87–18.90), P allele 0.048]. Of two dominant-negative variants, one T312M was found to be heterozygous in only one AAD subject (0.31%), but a C196F allele was found in both one AAD and one control subject. Five of the nine variants (C226G, F404S, R230W, R479C, W48X), were absent in both AAD subjects and healthy controls. These rare SIAE germline variants, in particular the M89V homozygous and the Y349C heterozygous polymorphisms, were found at similar frequencies in AAD subject to those reported in the original study on multiple autoimmune disorders. Importantly, the presence of some of these ‘pathogenic’ variants in our healthy controls limits the conclusions about their aetiological role in autoimmunity.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.

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