Human Genetics Laboratory, National Institute of Genetics, Mishima, Japan.
Department of Genetics, School of Life Science, The Graduate University for Advanced Studies, SOKENDAI, Mishima, Japan.
Pharmacogenomics J. 2021 Feb;21(1):94-101. doi: 10.1038/s41397-020-00187-4. Epub 2020 Sep 22.
Antithyroid drug (ATD) is a mainstay of Graves' disease (GD). About 0.1-0.5% of patients with GD treated with ATD exhibit ATD-induced agranulocytosis, which is characterized by severe reduction of circulating neutrophils. Immune-mediated responses have been proposed as a possible mechanism for the pathogenesis of ATD-induced agranulocytosis. Although it has been reported that the HLA class II allele (HLA-DRB108:03) was associated with ATD-induced agranulocytosis in multiple populations, the entire HLA region have not been explored in Japanese. Therefore, we performed HLA sequencing for 10 class I and 11 class II genes in 87 patients with ATD-induced agranulocytosis and 384 patients with GD who did not show ATD-induced agranulocytosis. By conducting case-control association studies at the HLA allele and haplotype levels, we replicated the association between HLA-DRB108:03:02 and ATD-induced agranulocytosis (P = 5.2 × 10, odds ratio = 2.80), and identified HLA-B39:01:01 as an independent risk factor (P = 1.4 × 10, odds ratio = 3.35). To verify reproducibility of the novel association of HLA-B39:01:01, we reanalyzed allele frequency data for HLA-B39:01:01 from previous case-control association studies. The association of HLA-B39:01:01 was significantly replicated in Chinese (P = 9.0 × 10), Taiwanese (P = 1.1 × 10), and European populations (P = 5.2 × 10). A meta-analysis combining results from the previous and current studies reinforced evidence of the association between HLA-B*39:01:01 and ATD-induced agranulocytosis (P = 1.2 × 10, pooled OR = 3.66, 95% CI; 2.41-5.57). The results of this study will provide a better understanding of the pathogenesis of ATD-induced agranulocytosis in the context of HLA-mediated hypersensitivity reactions.
抗甲状腺药物 (ATD) 是治疗格雷夫斯病 (GD) 的主要方法。大约 0.1-0.5%接受 ATD 治疗的 GD 患者会出现 ATD 诱导的粒细胞缺乏症，其特征是循环中性粒细胞严重减少。免疫介导的反应已被提议作为 ATD 诱导的粒细胞缺乏症发病机制的一种可能机制。尽管已经报道 HLA Ⅱ类等位基因 (HLA-DRB108:03) 与多个群体中的 ATD 诱导的粒细胞缺乏症相关，但日本尚未对整个 HLA 区域进行研究。因此，我们对 87 例 ATD 诱导的粒细胞缺乏症患者和 384 例未出现 ATD 诱导的粒细胞缺乏症的 GD 患者的 10 个 I 类和 11 个 II 类基因进行了 HLA 测序。通过在 HLA 等位基因和单倍型水平上进行病例对照关联研究，我们复制了 HLA-DRB108:03:02 与 ATD 诱导的粒细胞缺乏症之间的关联（P=5.2×10，优势比=2.80），并确定 HLA-B39:01:01 为独立危险因素（P=1.4×10，优势比=3.35）。为了验证 HLA-B39:01:01 新关联的可重复性，我们重新分析了之前病例对照关联研究中 HLA-B39:01:01 的等位基因频率数据。HLA-B39:01:01 在中国（P=9.0×10）、台湾（P=1.1×10）和欧洲人群（P=5.2×10）中显著复制了该关联。将之前和当前研究的结果进行荟萃分析，进一步证实了 HLA-B*39:01:01 与 ATD 诱导的粒细胞缺乏症之间的关联（P=1.2×10，合并优势比=3.66，95%CI：2.41-5.57）。这项研究的结果将为 HLA 介导的超敏反应背景下 ATD 诱导的粒细胞缺乏症的发病机制提供更好的理解。
