title: Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study.
abstract: Graves' disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined=6.75 × 10(-32)) and HLA-DRB1*08:03 (Pcombined=1.83 × 10(-9)) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13-41.48) and 6.13 (95% confidence interval=3.28-11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined=3.32 × 10(-21), 95% confidence interval=21.66-108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. [2] Department of Medical Genetics, National Taiwan University Hospital, Taipei 100, Taiwan. [3] Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei 100, Taiwan. [4] Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan. [5] Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Pei-Lung
authors.initials: PL
authors.lastname: Chen
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. [2] Department of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Shyang-Rong
authors.initials: SR
authors.lastname: Shih
authors.affiliation: Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Ying-Chao
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Immunogenetics Laboratory, Department of Medical Research, Mackay Memorial Hospital, Taipei 251, Taiwan.
authors.forename: Chen-Chung
authors.initials: CC
authors.lastname: Chu
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. [2] School of Pharmacy, National Taiwan University, Taipei 100, Taiwan. [3] Research Center for Applied Sciences, Academia Sinica, Taipei 833, Taiwan.
authors.forename: Jung-Hsin
authors.initials: JH
authors.lastname: Lin
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. [2] Department of Internal Medicine, New Taipei City Hospital, New Taipei 220, Taiwan.
authors.forename: Szu-Chi
authors.initials: SC
authors.lastname: Chen
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. [2] Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan. [3] Department of Internal Medicine, China Medical University, Taichung 404, Taiwan.
authors.forename: Ching-Chung
authors.initials: CC
authors.lastname: Chang
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. [2] Department of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan. [3] Department of Social Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan. [4] Department of Internal Medicine, Cathay General Hospital, Taipei 106, Taiwan.
authors.forename: Tien-Shang
authors.initials: TS
authors.lastname: Huang
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. [2] Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. [3] Department of Laboratory Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Keh Sung
authors.initials: KS
authors.lastname: Tsai
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Fen-Yu
authors.initials: FY
authors.lastname: Tseng
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Chih-Yuan
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Jin-Ying
authors.initials: JY
authors.lastname: Lu
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Wei-Yih
authors.initials: WY
authors.lastname: Chiu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Chien-Ching
authors.initials: CC
authors.lastname: Chang
authors.affiliation: School of Pharmacy, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Chen
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. [2] Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27708, USA.
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Cathy Shen-Jang
authors.initials: CS
authors.lastname: Fann
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. [2] Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei 100, Taiwan. [3] Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan. [4] Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei 106, Taiwan. [5] Department of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Wei-Shiung
authors.initials: WS
authors.lastname: Yang
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. [2] Department of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Tien-Chun
authors.initials: TC
authors.lastname: Chang
mesh_terms: D000380:Agranulocytosis / Q000139:chemically induced* / Q000235:genetics; D013956:Antithyroid Agents / Q000009:adverse effects*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006680:HLA Antigens; D015235:HLA-B Antigens; D059811:HLA-DRB1 Chains; D006801:Humans; D016017:Odds Ratio
chemical_list: D013956:Antithyroid Agents; D006680:HLA Antigens; D015235:HLA-B Antigens; D059811:HLA-DRB1 Chains