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Association between the DRB1*08032 Histocompatibility Antigen and Methimazole-Induced Agranulocytosis in Japanese Patients with Graves Disease
- Hajime Tamai, MD;
- Tohru Sudo, MD;
- Akinori Kimura, MD;
- Toshio Mukuta, MD;
- Sunao Matsubayashi, MD;
- Kanji Kuma, MD;
- Shigenobu Nagataki, MD; and
- Takehiko Sasazuki, MD
- From Kyushu University, Fukuoka, Japan; Tokyo Medical and Dental University, Tokyo, Japan; Kuma Hospital, Kobe, Japan; and Nagasaki University School of Medicine, Nagasaki, Japan. Grant Support: In part by the Ministry of Education, Culture, and Science, Japan; the Ministry of Health and Welfare, Japan; and the Naito Foundation. Requests for Reprints: Hajime Tamai, MD, Department of Psychosomatic Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan. Current Author Addresses: Drs. Tamai, Mukuta, and Matsubayashi: Department of Psychosomatic Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan.
Objective: To determine the association between HLA class II genes and methimazole-induced agranulocytosis in patients with Graves disease.
Design: Case-control study.
Setting: Kuma Hospital, which specializes in thyroid diseases, in Kobe, Japan.
Subjects: 24 patients with Graves disease who had methimazole-induced agranulocytosis diagnosed by peripheral granulocyte counts of less than 0.5 × 109/L, and 68 patients with Graves disease treated with methimazole, who were free from agranulocytosis. Controls were 525 healthy, unrelated Japanese student volunteers at Kyushu University in Japan.
Measurements: All HLA class II genes were analyzed for polymorphisms at the DNA level by using the polymerase chain reaction sequence-specific oligonucleotide probes method. The allele frequencies in the agranulocytotic Graves disease group were compared with those in the nonagranulocytotic Graves disease and control groups.
Results: A strong positive association was seen in DRB1*08032 between the agranulocytotic group and both the control and nonagranulocytotic Graves disease groups.
Conclusion: The HLA DRB1*08032 allele was strongly associated with susceptibility to methimazole-induced agranulocytosis, suggesting that cellular autoimmunity may be involved in its development.
The thioureylene antithyroid drugs methimazole and propylthiouracil have been widely used to treat Graves disease [1], but side effects are found in 1% to 5% of treated patients [2-4]. One important and serious side effect of this treatment is agranulocytosis, which occurs in 0.1% to 0.3% of treated patients [5-10]. Although the mechanisms responsible for the agranulocytosis are unclear, an immune phenomenon may be involved, because antigranulocyte antibodies [11-20] or lymphocyte sensitization to antithyroid drugs [17] are found in agranulocytotic patients. These autoantibodies may induce agranulocytosis by direct cytotoxicity or through blocking of membrane proteins that are important for the maturation of progenitor cells [19].
Antibodies are generally produced by plasma cells, which are maturated from B lymphocytes in the presence of various cytokines …
