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Role of the X-Linked Gene GPR174 in Autoimmune Addison's Disease

Lookup NU author(s): Dr Catherine Napier, Dr Anna MitchellORCiD, Dr Earn Gan, Dr Ian Wilson, Professor Simon PearceORCiD


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Context: Autoimmune endocrinopathies demonstrate a profound gender bias, but the reasons for this remain obscure. The 1000 genes on the X chromosome are likely to be implicated in this inherent susceptibility; various theories, including skewed X chromosome inactivation and fetal microchimerism, have been proposed. GPR174 is an Xq21 putative purinergic receptor that is widely expressed in lymphoid tissues. A single-nucleotide polymorphism, rs3827440, encoding Ser162Pro, has recently been associated with Graves' disease in Chinese and Polish populations, suggesting a role of this X chromosome gene in autoimmune disease.Objective: We investigated the role of rs3827440 in a UK cohort of patients with autoimmune Addison's disease (AAD). Samples from 286 AAD cases and 288 healthy controls were genotyped using TaqMan single-nucleotide polymorphism genotyping assays (C_25954273_10) on the Applied Biosystems 7900HT Fast real-time PCR system.Design: Using a dominant (present/absent) model, the serine-encoding T allele of rs3827440 was present in 189 of 286 AAD patients (66%) compared with 132 of 288 unaffected controls (46%) [P = .010, odds ratio 1.80 (5%-95% confidence interval 1.22-2.67)]. An allele dosage model found a significant excess of the T allele in AAD patients compared with controls [P = .03, odds ratio 1.34 (5%-95% confidence interval 1.07-1.67)].Conclusion: We have demonstrated a significant association of this X chromosome-encoded immunoreceptor with AAD for the first time. This X-linked gene could have a more generalized role in autoimmunity pathogenesis: G protein-coupled receptors are promising drugable targets, and further work to elucidate the functional role of GPR174 is now warranted.

Publication metadata

Author(s): Napier C, Mitchell AL, Gan E, Wilson I, Pearce SHS

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Endocrinology and Metabolism

Year: 2015

Volume: 100

Issue: 1

Pages: E187-E190

Print publication date: 01/01/2015

Online publication date: 08/10/2014

Acceptance date: 01/10/2014

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: Endocrine Society


DOI: 10.1210/jc.2014-2694


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