title: Identification of a Hashimoto thyroiditis susceptibility locus via a genome-wide comparison with Graves' disease.
abstract: BACKGROUND
  Hashimoto thyroiditis (HT) and Graves' disease (GD) share some immunological features. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these two related diseases.
  
  
  OBJECTIVE
  The aim of this study was to identify a non-HLA susceptibility locus that is specific to either HT or GD.
  
  
  METHODS
  We performed a two-stage genome-wide comparison between HT and GD in Japan. During the discovery stage, we performed a logistic regression analysis adjusting for sex using 727 413 single nucleotide polymorphisms (SNPs) for 265 HT and 261 GD patients. During the replication stage, 35 SNPs were analyzed for 181 HT and 286 GD cases. A combined meta-analysis was performed using the results from these two stages. An SNP showing a genome-wide significant level was further analyzed using 1363 healthy controls to determine the specificity of susceptibility.
  
  
  RESULTS
  A genome-wide direct comparison between HT and GD revealed an SNP at the VAV3 locus with genome-wide significant association signals (rs7537605: P(combined) = 3.90 × 10(-8); odds ratio(combined) = 1.77; 95% confidence interval = 1.44-2.17). An association analysis using healthy controls showed that rs7537605 is significantly associated with HT (P = 1.24 × 10(-5); odds ratio = 1.60; 95% confidence interval = 1.30-1.97) but not with GD (P = .50), suggesting that the variant specifically affects susceptibility to HT.
  
  
  CONCLUSIONS
  A genome-wide direct comparison between HT and GD revealed an HT-specific variant within VAV3 in the Japanese. Considering physiological roles of VAV3, such as a guanine nucleotide exchange factor, our finding provides new insight into the molecular mechanism of HT.
authors.affiliation: Institute for Advanced Study (D.O., S.U., T.S.), Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan; Department of Medical Chemistry (K.Y.), Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; Ito Hospital (J.Y.N., N.W., A.Y., K.I.), Shibuya-ku, Tokyo 150-8308, Japan; Department of Medicine and Clinical Science (K.O.), Graduate School of Medicine, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan; and Department of Diabetes Research (M.N.), National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 16-8655, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Oryoji
authors.forename: Sho
authors.initials: S
authors.lastname: Ueda
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Jaeduk
authors.initials: J
authors.lastname: Yoshimura Noh
authors.forename: Ken
authors.initials: K
authors.lastname: Okamura
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Noda
authors.forename: Natsuko
authors.initials: N
authors.lastname: Watanabe
authors.forename: Ai
authors.initials: A
authors.lastname: Yoshihara
authors.forename: Koichi
authors.initials: K
authors.lastname: Ito
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006111:Graves Disease / Q000235:genetics*; D006239:Haplotypes; D050031:Hashimoto Disease / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide