title: HLA-B*38:02:01 predicts carbimazole/methimazole-induced agranulocytosis.
abstract: Thioamides antithyroid-drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD-induced agranulocytosis is important for clinical management. We performed a genome-wide association study (GWAS) involving 20 patients with ATD-induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single-nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD-induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8-103.7; P = 1.3 × 10(-24)) and replication (OR = 37; 95% CI = 3.7-367.4; P = 9.6 × 10(-7)). HLA-B*38:02:01 was in complete linkage disequilibrium with rs185386680. High-resolution HLA typing confirmed that HLA-B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)-induced agranulocytosis (OR = 265.5; 95% CI = 27.9-2528.0; P = 2.5 × 10(-14)), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA-B*38:02:01 in predicting CMZ/MMI-induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.
authors.affiliation: Pharmacogenomics and Precision Therapeutics Laboratory, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.|The State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.|Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.|Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: C-L
authors.initials: CL
authors.lastname: Cheung
authors.affiliation: Pharmacogenomics and Precision Therapeutics Laboratory, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: C-W
authors.initials: CW
authors.lastname: Sing
authors.affiliation: Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.|Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: C S M
authors.initials: CS
authors.lastname: Tang
authors.affiliation: Pharmacogenomics and Precision Therapeutics Laboratory, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: V K F
authors.initials: VK
authors.lastname: Cheng
authors.affiliation: Department of Molecular and Clinical Pharmacology, The University of Liverpool, United Kingdom.|Royal Liverpool and Broadgreen University Hospital NHS Trust, Liverpool, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: Department of Medicine, Queen Elizabeth Hospital, Hong Kong, China.
authors.forename: C-H
authors.initials: CH
authors.lastname: Choi
authors.affiliation: Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong, China.
authors.forename: C-S
authors.initials: CS
authors.lastname: Hung
authors.affiliation: Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China.
authors.forename: E Y-F
authors.initials: EY
authors.lastname: Lau
authors.affiliation: Department of Medicine and Geriatrics, Kwong Wah Hospital, Hong Kong, China.
authors.forename: K F
authors.initials: KF
authors.lastname: Lee
authors.affiliation: Department of Medicine and Geriatrics, Kwong Wah Hospital, Hong Kong, China.
authors.forename: M W-H
authors.initials: MW
authors.lastname: Mak
authors.affiliation: Department of Medicine and Geriatrics, Ruttonjee & Tang Shiu Kin Hospitals, Hong Kong, China.
authors.forename: J Y Y
authors.initials: JY
authors.lastname: Leung
authors.affiliation: Department of Medicine and Geriatrics, Ruttonjee & Tang Shiu Kin Hospitals, Hong Kong, China.
authors.forename: T-W
authors.initials: TW
authors.lastname: Wong
authors.affiliation: Department of Medicine and Geriatrics, Tuen Mun Hospital, Hong Kong, China.
authors.forename: A Y Y
authors.initials: AY
authors.lastname: Ho
authors.affiliation: Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong, China.
authors.forename: K-W
authors.initials: KW
authors.lastname: Chan
authors.affiliation: Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong, China.
authors.forename: Vhf
authors.initials: V
authors.lastname: Hung
authors.affiliation: F.H.K.A.M, Department of Medicine, Caritas Medical Centre, Hong Kong, China.
authors.forename: V
authors.initials: V
authors.lastname: Tam
authors.affiliation: Department of Medicine, Tung Wah Eastern Hospital, Hong Kong, China.
authors.forename: S-C
authors.initials: SC
authors.lastname: Siu
authors.affiliation: Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China.
authors.forename: H-K
authors.initials: HK
authors.lastname: Pang
authors.affiliation: Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China.
authors.forename: W Z-M
authors.initials: WZ
authors.lastname: Wat
authors.affiliation: Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China.
authors.forename: H H-Y
authors.initials: HH
authors.lastname: Lee
authors.affiliation: Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China.
authors.forename: C-T
authors.initials: CT
authors.lastname: Chung
authors.affiliation: Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China.
authors.forename: R S-M
authors.initials: RS
authors.lastname: Hue
authors.affiliation: Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.|Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: P-C
authors.initials: PC
authors.lastname: Sham
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.|Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.|Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: B M Y
authors.initials: BM
authors.lastname: Cheung
authors.affiliation: Pharmacogenomics and Precision Therapeutics Laboratory, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.|The State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.|Research Department of Practice and Policy, UCL School of Pharmacy, London, United Kingdom.
authors.forename: I C K
authors.initials: IC
authors.lastname: Wong
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: K C B
authors.initials: KC
authors.lastname: Tan
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: A  W C
authors.initials: A
authors.lastname: Kung
mesh_terms: D000380:Agranulocytosis / Q000139:chemically induced* / Q000235:genetics; D013956:Antithyroid Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002231:Carbimazole / Q000008:administration & dosage / Q000009:adverse effects*; D016022:Case-Control Studies; D005260:Female; D055106:Genome-Wide Association Study; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008713:Methimazole / Q000008:administration & dosage / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011441:Propylthiouracil / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D013956:Antithyroid Agents; D015235:HLA-B Antigens; D008713:Methimazole; D011441:Propylthiouracil; D002231:Carbimazole