Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study

Pei-Lung Chen; Shyang-Rong Shih; Pei-Wen Wang; Ying-Chao Lin; Chen-Chung Chu; Jung-Hsin Lin; Szu-Chi Chen; Ching-Chung Chang; Tien-Shang Huang; Keh Sung Tsai; Fen-Yu Tseng; Chih-Yuan Wang; Jin-Ying Lu; Wei-Yih Chiu; Chien-Ching Chang; Yu-Hsuan Chen; Yuan-Tsong Chen; Cathy Shen-Jang Fann; Wei-Shiung Yang; Tien-Chun Chang

doi:10.1038/ncomms8633

Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study

Nat Commun. 2015 Jul 7:6:7633. doi: 10.1038/ncomms8633.

Authors

Pei-Lung Chen¹, Shyang-Rong Shih², Pei-Wen Wang³, Ying-Chao Lin⁴, Chen-Chung Chu⁵, Jung-Hsin Lin⁶, Szu-Chi Chen⁷, Ching-Chung Chang⁸, Tien-Shang Huang⁹, Keh Sung Tsai¹⁰, Fen-Yu Tseng¹¹, Chih-Yuan Wang¹¹, Jin-Ying Lu¹¹, Wei-Yih Chiu¹¹, Chien-Ching Chang⁴, Yu-Hsuan Chen¹², Yuan-Tsong Chen¹³, Cathy Shen-Jang Fann⁴, Wei-Shiung Yang¹⁴, Tien-Chun Chang²

Affiliations

¹ 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.
² 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 Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
⁴ Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
⁵ Immunogenetics Laboratory, Department of Medical Research, Mackay Memorial Hospital, Taipei 251, Taiwan.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
¹² School of Pharmacy, National Taiwan University, Taipei 100, Taiwan.
¹³ 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. [2] Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27708, USA.
¹⁴ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Agranulocytosis / chemically induced*
Agranulocytosis / genetics
Antithyroid Agents / adverse effects*
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Genotype*
HLA Antigens*
HLA-B Antigens
HLA-DRB1 Chains
Humans
Odds Ratio

Substances

Antithyroid Agents
HLA Antigens
HLA-B Antigens
HLA-DRB1 Chains