Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study.
Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study.
复制标题
DOI：
10.1038/ncomms8633
复制
发表时间：
2015-07-07
影响因子：
16.6
通讯作者：
Chang TC
中科院分区：
文献类型：
--
作者：
Chen PL;Shih SR;Wang PW;Lin YC;Chu CC;Lin JH;Chen SC;Chang CC;Huang TS;Tsai KS;Tseng FY;Wang CY;Lu JY;Chiu WY;Chang CC;Chen YH;Chen YT;Fann CS;Yang WS;Chang TC
Graves病是甲状腺功能亢进症的主要原因，影响1.0-1.6%的人口。抗甲状腺药物是治疗的基石，但可能导致危及生命的粒细胞缺乏症。在这里，我们使用直接人类白细胞抗原基因分型和基于SNP的全基因组关联研究，对两个独立的受试者集（共42例粒细胞缺乏症病例和1，208例Graves病对照）进行了两阶段关联研究。我们证明HLA-B*38：02（Armitage趋势P组合=6.75 × 10−32）和HLA-DRB 1 *08：03（P组合=1.83 × 10−9）是独立的易感基因座。全基因组关联研究识别了相同的信号。这两个基因座比较有效等位基因携带者与非携带者的估计比值比分别为21.48（95%置信区间=11.13-41.48）和6.13（95%置信区间=3.28-11.46）。同时携带HLA-B*38：02和HLA-DRB 1 *08：03使优势比增加到48.41（P合并=3.32 × 10−21，95%置信区间=21.66-108.22）。我们的研究结果可能是有用的抗甲状腺药物引起的粒细胞缺乏症和潜在的粒细胞缺乏症引起的其他化学品。 格雷夫斯病是甲状腺功能亢进症的主要原因，但治疗方案可导致危及生命的并发症。Chen等人进行了两阶段直接HLA基因分型和全基因组关联研究，以确定HLA-B*38：02和HLA-DRB 1 *08：03为主要药物遗传学决定因素。
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. Graves' disease is the leading cause of hyperthyroidism but treatment options can cause life-threatening complications. Chen et al. conduct two-stage direct HLA genotyping and genome-wide association studies to identify HLA-B*38:02 and HLA-DRB1*08:03 as major pharmacogenetic determinants.