Comprehensive genotyping in two homogeneous Graves’ disease samples reveals major and novel HLA association alleles

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. Methodology/Principal Findings: 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 [PBc] = 1.1761