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

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

Author information

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.

PMID:
26151496
PMCID:
PMC4506516
DOI:
10.1038/ncomms8633
[Indexed for MEDLINE]
Free PMC Article

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