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 () and Tien-Chun Chang ()
Additional contact information
Pei-Lung Chen: National Taiwan University Hospital
Shyang-Rong Shih: National Taiwan University Hospital
Pei-Wen Wang: Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine
Ying-Chao Lin: Institute of Biomedical Sciences, Academia Sinica
Chen-Chung Chu: Immunogenetics Laboratory, Mackay Memorial Hospital
Jung-Hsin Lin: Institute of Biomedical Sciences, Academia Sinica
Szu-Chi Chen: National Taiwan University Hospital
Ching-Chung Chang: National Taiwan University Hospital
Tien-Shang Huang: National Taiwan University Hospital
Keh Sung Tsai: National Taiwan University Hospital
Fen-Yu Tseng: National Taiwan University Hospital
Chih-Yuan Wang: National Taiwan University Hospital
Jin-Ying Lu: National Taiwan University Hospital
Wei-Yih Chiu: National Taiwan University Hospital
Chien-Ching Chang: Institute of Biomedical Sciences, Academia Sinica
Yu-Hsuan Chen: School of Pharmacy, National Taiwan University
Yuan-Tsong Chen: Institute of Biomedical Sciences, Academia Sinica
Cathy Shen-Jang Fann: Institute of Biomedical Sciences, Academia Sinica
Wei-Shiung Yang: National Taiwan University Hospital
Tien-Chun Chang: National Taiwan University Hospital

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8633

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