title: The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease.
abstract: 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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK. earn.gan@ncl.ac.uk
authors.forename: Earn H
authors.initials: EH
authors.lastname: Gan
authors.forename: Katie
authors.initials: K
authors.lastname: MacArthur
authors.forename: Anna L
authors.initials: AL
authors.lastname: Mitchell
authors.forename: Simon H S
authors.initials: SH
authors.lastname: Pearce
mesh_terms: D000115:Acetylesterase / Q000235:genetics*; D000224:Addison Disease / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001327:Autoimmune Diseases / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D000115:Acetylesterase; C046298:sialate O-acetylesterase