title: Role of the X-linked gene GPR174 in autoimmune Addison's disease.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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)].
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Genetic Medicine (C.N., A.L.M., E.G., I.W., S.H.S.P.), Newcastle University, Newcastle upon Tyne NE1 4EP, United Kingdom; and Endocrine Department (C.N., A.L.M., S.H.S.P.), Newcastle upon Tyne Hospitals, Newcastle upon Tyne NE1 4LP, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Napier
authors.forename: A L
authors.initials: AL
authors.lastname: Mitchell
authors.forename: E
authors.initials: E
authors.lastname: Gan
authors.forename: I
authors.initials: I
authors.lastname: Wilson
authors.forename: S H S
authors.initials: SH
authors.lastname: Pearce
mesh_terms: D000224:Addison Disease / Q000235:genetics* / Q000276:immunology; D000483:Alleles; D005260:Female; D005787:Gene Frequency; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
chemical_list: C581018:GPR174 protein, human; D043562:Receptors, G-Protein-Coupled