Cheung C-L, Sing C-W, Tang C S M, Cheng V K F, Pirmohamed M, Choi C-H, Hung C-S, Lau E Y-F, Lee K F, Mak M W-H, Leung J Y Y, Wong T-W, Ho A Y Y, Chan K-W, Hung Vhf, Tam V, Siu S-C, Pang H-K, Wat W Z-M, Lee H H-Y, Chung C-T, Hue R S-M, Sham P-C, Cheung B M Y, Wong I C K, Tan K C B, Kung A W C
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.
Clin Pharmacol Ther. 2016 May;99(5):555-61. doi: 10.1002/cpt.309. Epub 2016 Jan 12.
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-B38:02:01 was in complete linkage disequilibrium with rs185386680. High-resolution HLA typing confirmed that HLA-B38:02:01 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.
硫代酰胺类抗甲状腺药物（ATD）在甲状腺功能亢进症的治疗中具有重要作用。确定ATD诱导的粒细胞缺乏症的易感基因座对临床管理至关重要。我们进行了一项全基因组关联研究（GWAS），纳入了20例ATD诱导的粒细胞缺乏症患者和775名健康对照。对首要发现进行了进一步验证。单核苷酸多态性（SNP）rs185386680在GWAS中显示与ATD诱导的粒细胞缺乏症关联最强（优势比（OR）= 36.4；95%置信区间（CI）= 12.8 - 103.7；P = 1.3×10⁻²⁴），在验证研究中也得到类似结果（OR = 37；95% CI = 3.7 - 367.4；P = 9.6×10⁻⁷）。HLA - B38:02:01与rs185386680完全连锁不平衡。高分辨率HLA分型证实HLA - B38:02:01与卡比马唑（CMZ）/甲巯咪唑（MMI）诱导的粒细胞缺乏症相关（OR = 265.5；95% CI = 27.9 - 2528.0；P = 2.5×10⁻¹⁴），但与丙硫氧嘧啶（PTU）无关。HLA - B*38:02:01预测CMZ/MMI诱导的粒细胞缺乏症的阳性和阴性预测值分别为0.07和0.999。大约需要筛查211例才能预防1例。对风险等位基因进行筛查将有助于在风险等位基因频率较高的人群中预防粒细胞缺乏症。
