title: Comprehensive genotyping in two homogeneous Graves' disease samples reveals major and novel HLA association alleles.
abstract: BACKGROUND
  Graves' disease (GD) is the leading cause of hyperthyroidism and thyroid eye disease inherited as a complex trait. Although geoepidemiology studies showed relatively higher prevalence of GD in Asians than in Caucasians, previous genetic studies were contradictory concerning whether and/or which human leukocyte antigen (HLA) alleles are associated with GD in Asians.
  
  
  RESULTS
  We conducted a case-control association study (499 unrelated GD cases and 504 controls) and a replication in an independent family sample (419 GD individuals and their 282 relatives in 165 families). To minimize genetic and phenotypic heterogeneity, we included only ethnic Chinese Han population in Taiwan and excluded subjects with hypothyroidism. We performed direct and comprehensive genotyping of six classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1) to 4-digit resolution. Combining the data of two sample populations, we found that B*46:01 (odds ratio under dominant model [OR]  = 1.33, Bonferroni corrected combined P [P(Bc)]  = 1.17 x 10⁻²), DPB1*05:01 (OR  = 2.34, P(Bc) = 2.58 x 10⁻¹⁰), DQB1*03:02 (OR  = 0.62, P(Bc)  = 1.97 x 10⁻²), DRB1*15:01 (OR  = 1.68, P(Bc) = 1.22 x 10⁻²) and DRB1*16:02 (OR  = 2.63, P(Bc)  = 1.46 x 10⁻⁵) were associated with GD. HLA-DPB1*05:01 is the major gene of GD in our population and singly accounts for 48.4% of population-attributable risk.
  
  
  CONCLUSIONS
  These GD-associated alleles we identified in ethnic Chinese Hans, and those identified in other Asian studies, are totally distinct from the known associated alleles in Caucasians. Identification of population-specific association alleles is the critical first step for individualized medicine. Furthermore, comparison between different susceptibility/protective alleles across populations could facilitate generation of novel hypothesis about GD pathophysiology and indicate a new direction for future investigation.
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Pei-Lung
authors.initials: PL
authors.lastname: Chen
authors.forename: Cathy Shen-Jang
authors.initials: CS
authors.lastname: Fann
authors.forename: Chen-Chung
authors.initials: CC
authors.lastname: Chu
authors.forename: Chien-Ching
authors.initials: CC
authors.lastname: Chang
authors.forename: Su-Wei
authors.initials: SW
authors.lastname: Chang
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Hsieh
authors.forename: Marie
authors.initials: M
authors.lastname: Lin
authors.forename: Wei-Shiung
authors.initials: WS
authors.lastname: Yang
authors.forename: Tien-Chun
authors.initials: TC
authors.lastname: Chang
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D005190:Family; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006111:Graves Disease / Q000208:ethnology* / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics*; D006682:HLA-DP Antigens; D006684:HLA-DR Antigens; D006801:Humans; D013624:Taiwan
chemical_list: D006680:HLA Antigens; D006682:HLA-DP Antigens; D006684:HLA-DR Antigens