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The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease

BACKGROUND: Autoimmune Addison's disease (AAD) is a rare condition with a complex genetic basis. A panel of rare and functionally defective genetic variants in the sialic acid acetylesterase (SIAE) gene has recently been implicated in several common autoimmune conditions. We performed a case–co...

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Autores principales: Gan, Earn H, MacArthur, Katie, Mitchell, Anna L, Pearce, Simon H S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioScientifica 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494867/
https://www.ncbi.nlm.nih.gov/pubmed/23011869
http://dx.doi.org/10.1530/EJE-12-0579
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author Gan, Earn H
MacArthur, Katie
Mitchell, Anna L
Pearce, Simon H S
author_facet Gan, Earn H
MacArthur, Katie
Mitchell, Anna L
Pearce, Simon H S
author_sort Gan, Earn H
collection PubMed
description BACKGROUND: Autoimmune Addison's disease (AAD) is a rare condition with a complex genetic basis. A panel of rare and functionally defective genetic variants in the sialic acid acetylesterase (SIAE) gene has recently been implicated in several common autoimmune conditions. We performed a case–control study to determine whether these rare variants are associated with a rarer condition, AAD. METHOD: We analysed nine SIAE gene variants (W48X, M89V, C196F, C226G, R230W, T312M, Y349C, F404S and R479C) in a United Kingdom cohort of 378 AAD subjects and 387 healthy controls. All samples were genotyped using Sequenom iPlex chemistry to characterise primer extension products. RESULTS: A heterozygous rare allele at codon 312 (312*M) was found in one AAD patient (0.13%) but was not detected in the healthy controls. The commoner, functionally recessive variant at codon 89 (89*V) was found to be homozygous in two AAD patients but was only found in the heterozygous state in controls. Taking into account all nine alleles examined, 4/378 (1.06%) AAD patients and 1/387 (0.25%) healthy controls carried the defective SIAE alleles, with a calculated odds ratio of 4.13 (95% CI 0.44–97.45, two-tailed P value 0.212, NS). CONCLUSION: We demonstrated the presence of 89*V homozygotes and the 312*M rare allele in the AAD cohort, but overall, our analysis does not support a role for rare variants in SIAE in the pathogenesis of AAD. However, the relatively small collection of AAD patients limits the power to exclude a small effect.
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spelling pubmed-34948672012-12-01 The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease Gan, Earn H MacArthur, Katie Mitchell, Anna L Pearce, Simon H S Eur J Endocrinol Clinical Study BACKGROUND: Autoimmune Addison's disease (AAD) is a rare condition with a complex genetic basis. A panel of rare and functionally defective genetic variants in the sialic acid acetylesterase (SIAE) gene has recently been implicated in several common autoimmune conditions. We performed a case–control study to determine whether these rare variants are associated with a rarer condition, AAD. METHOD: We analysed nine SIAE gene variants (W48X, M89V, C196F, C226G, R230W, T312M, Y349C, F404S and R479C) in a United Kingdom cohort of 378 AAD subjects and 387 healthy controls. All samples were genotyped using Sequenom iPlex chemistry to characterise primer extension products. RESULTS: A heterozygous rare allele at codon 312 (312*M) was found in one AAD patient (0.13%) but was not detected in the healthy controls. The commoner, functionally recessive variant at codon 89 (89*V) was found to be homozygous in two AAD patients but was only found in the heterozygous state in controls. Taking into account all nine alleles examined, 4/378 (1.06%) AAD patients and 1/387 (0.25%) healthy controls carried the defective SIAE alleles, with a calculated odds ratio of 4.13 (95% CI 0.44–97.45, two-tailed P value 0.212, NS). CONCLUSION: We demonstrated the presence of 89*V homozygotes and the 312*M rare allele in the AAD cohort, but overall, our analysis does not support a role for rare variants in SIAE in the pathogenesis of AAD. However, the relatively small collection of AAD patients limits the power to exclude a small effect. BioScientifica 2012-12 /pmc/articles/PMC3494867/ /pubmed/23011869 http://dx.doi.org/10.1530/EJE-12-0579 Text en © 2012 European Society of Endocrinology http://www.bioscientifica.com/journals/reuselicenceeje/ This is an Open Access article distributed under the terms of the European Journal of Endocrinology's Re-use Licence (http://www.bioscientifica.com/journals/reuselicenceeje/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Study
Gan, Earn H
MacArthur, Katie
Mitchell, Anna L
Pearce, Simon H S
The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease
title The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease
title_full The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease
title_fullStr The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease
title_full_unstemmed The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease
title_short The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease
title_sort role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune addison's disease
topic Clinical Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494867/
https://www.ncbi.nlm.nih.gov/pubmed/23011869
http://dx.doi.org/10.1530/EJE-12-0579
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