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HLA-B*39:01:01 is a novel risk factor for antithyroid drug-induced agranulocytosis in Japanese population

The Pharmacogenomics Journal volume 21, pages 94–101 (2021)Cite this article

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Abstract

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-DRB1*08:03) 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-DRB1*08:03:02 and ATD-induced agranulocytosis (P = 5.2 × 10−7, odds ratio = 2.80), and identified HLA-B*39:01:01 as an independent risk factor (P = 1.4 × 10−3, odds ratio = 3.35). To verify reproducibility of the novel association of HLA-B*39:01:01, we reanalyzed allele frequency data for HLA-B*39:01:01 from previous case-control association studies. The association of HLA-B*39:01:01 was significantly replicated in Chinese (P = 9.0 × 10−3), Taiwanese (P = 1.1 × 10−3), and European populations (P = 5.2 × 10−4). 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 (Pmeta = 1.2 × 10−9, 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.

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Fig. 1: Linkage disequilibrium coefficients among four HLA alleles.
Fig. 2: Meta-analysis for association between ATD-induced agranulocytosis and HLA-B*39:01:01 by combining previous three studies and current study.

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Acknowledgements

We are grateful to Shigeru Shuto, Yoko Watanabe, and Shigeko Wakiya for their contributions to sample collection. We thank Junko Kajiwara, Junko Kitayama, and Yumiko Sato for their technical assistance.

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Authors and Affiliations

  1. Human Genetics Laboratory, National Institute of Genetics, Mishima, Japan

    Saya Nakakura, Ituro Inoue & Hirofumi Nakaoka

  2. Department of Genetics, School of Life Science, The Graduate University for Advanced Studies, SOKENDAI, Mishima, Japan

    Saya Nakakura, Ituro Inoue & Hirofumi Nakaoka

  3. Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan

    Kazuyoshi Hosomichi

  4. Department of Surgery, Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Japan

    Shinya Uchino

  5. Department of Research and Clinical Laboratory, Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Japan

    Akiko Murakami

  6. The Institute of Medical Sciences, Tokai University, Isehara, Japan

    Akira Oka

  7. Department of Cancer Genome Research, Sasaki Institute, Sasaki Foundation, Chiyoda-ku, Japan

    Hirofumi Nakaoka

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  1. Saya Nakakura
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Correspondence to Hirofumi Nakaoka.

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Nakakura, S., Hosomichi, K., Uchino, S. et al. HLA-B*39:01:01 is a novel risk factor for antithyroid drug-induced agranulocytosis in Japanese population. Pharmacogenomics J 21, 94–101 (2021). https://doi.org/10.1038/s41397-020-00187-4

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