Association between the DRB1*08032 Histocompatibility Antigen and Methimazole-Induced Agranulocytosis in Japanese Patients with Graves Disease

Tamai, Hiroshi; Sudo, Tomoko; Kimura, Akinori; Mukuta, Toshio; Matsubayashi, Sunao; Kuma, Kanji; Nagataki, Shigenobu; Sasazuki, Takehiko

doi:10.7326/0003-4819-124-5-199603010-00005

Cited by 69 publications

(48 citation statements)

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“…Despite appropriate management, the mortality rate of agranulocytosis induced by nonchemotherapy drugs is 4-5% [15]. Recently, an association between ATD-induced agranulocytosis and HLAs has been reported in various ethnic groups [1,6,16]. Previously, we also reported that susceptibility to ATD-induced agranulocytosis in Chinese persons is strongly associated with HLA-B*27: 05, HLA-B*38: 02, and HLA-DRB1*08: 03 genetic variation [14].…”

Section: Discussionmentioning

confidence: 89%

Novel Association between Flavin-Containing Monooxygenase 3 Gene Polymorphism and Antithyroid Drug-Induced Agranulocytosis in the Han Population

Hasan

Zhang

et al. 2019

Ann Nutr Metab

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Some effective antithyroid drugs (ATDs) have been widely used for patients with Graves’ disease (GD) but are associated with ATD-induced agranulocytosis. We selected 29 ATD-induced agranulocytosis patients, 44 ATD-induced neutropenia patients, and 140 GD controls among the Chinese Han population who were recruited at the First Affiliated Hospital of Xi’an Jiao Tong University. We assessed their response to ATDs treatment by performing genotyping for a candidate gene association study of samples from patients receiving treatment. Human flavin-containing monooxygenase 3 (FMO3), which is the major hepatic enzyme involved in the production of N-oxide of trimethylamine, catalyzes the oxygenation of a variety of drug compounds. Six single SNP, genotype, haplotype (HAP), and association analyses of the FMO3 gene with ATD-induced agranulocytosis/neutropenia under different models (i.e., additive, dominant, and recessive models) were performed. Rs1736557, which caused an amino acid variation V257M, showed a strong association between ATD-induced agranulocytosis and GD controls after Bonferroni correction (p = 0.011, OR 2.301, 95% CI 1.201–4.409). The presence of HAP 3 (HAP3) in the FMO3 gene HAP was statistically associated with ATD-induced agranulocytosis (p = 0.038, permutation p value). Our findings indicate that genetic variations in the FMO3 gene are associated with the response to ATDs maintenance treatment in ATD-induced agranulocytosis patients of Chinese Han population.

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Section: Discussionmentioning

confidence: 89%

Novel Association between Flavin-Containing Monooxygenase 3 Gene Polymorphism and Antithyroid Drug-Induced Agranulocytosis in the Han Population

Hasan

Zhang

et al. 2019

Ann Nutr Metab

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“…Positive associations between HLA class II allele and agranulocytosis were observed [8], many antibodies such as anti-leukocyte antibodies and anti-granulocyte antibodies have been proposed. PTU-induced autoimmune disease was known as PTU-induced lupus-like syndrome, PTU is also known as a trigger for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis.…”

Section: Discussionmentioning

confidence: 99%

The Relation of Initial Methimazole Dose to the Incidence of Methimazole-induced Agranulocytosis in Patients with Graves' Disease

et al. 2007

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Abstract. The relation between the incidence of methimazole (methylmercaptoimidazole; MMI)-induced agranulocytosis and initial MMI dose was evaluated in a group of 514 patients with Graves' disease who were treated between 1995 and 2005. One hundred and forty-six (28.40%) patients had received an initial dose of 30 mg MMI and 277 (53.89%) patients had been treated with 15 mg MMI. Nine patients (1.75%) developed agranulocytosis due to MMI treatment. Six (4.11%) of 146 patients who received an initial dose of 30 mg MMI, two (4.54%) of 44 patients given an initial dose of 20 mg MMI, and one (0.36%) of 277 patients given an initial dose of 15 mg MMI developed agranulocytosis. There was a statistically significant difference in agranulocytosis incidence between patients receiving an initial dose of 30 mg MMI and those who received an initial dose of 15 mg. Although 8 (4.10%) of 195 patients in the high-dose group (20 mg or higher) developed agranulocytosis, only 1 (0.31%) of 319 patients in the low-dose group (15 mg or lower) did. In conclusion, the incidence of agranulocytosis with low-dose MMI therapy was ten times lower than that of the high-dose regimen.

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“…In hematology, agranulocytosis secondary to clozapine (HLA-B38, HLA-DR4, and DQw3) or methimazole (HLA-DR8) and mixed cryoglobulinemia in hepatitis C virus-infected patients (HLA-B8 and HLA-DR3) exemplify links between immunogenetics and pathophysiology. [3][4][5][6] Fundamentally, the presence of particular HLA alleles likely allows for preferential presentation of particular peptides, perhaps derived from autoantigens, to specific T cells, driving the autoimmune process.In AA, HLA associations have also been examined. [7][8][9][10][11][12][13][14][15][16][17][18][19] An increased frequency of HLA-DR2 has been reported in some but not all studies.…”

mentioning

confidence: 99%

Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome

Maciejewski

Follmann

Nakamura

et al. 2001

Blood

138

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Many autoimmune diseases are associated with HLA alleles, and such a relationship also has been reported for aplastic anemia (AA). AA and paroxysmal nocturnal hemoglobinuria (PNH) are related clinically, and glycophosphoinositol (GPI)-anchored protein (AP)-deficient cells can be found in many patients with AA. The hypothesis was considered that expansion of a PNH clone may be a marker of immune-mediated disease and its association with HLA alleles was examined. The study involved patients with a primary diagnosis of AA, patients with myelodysplastic syndrome (MDS), and patients with primary PNH. Tests of proportions were used to compare allelic frequencies. For patients with a PNH clone (defined by the presence of GPI-APdeficient granulocytes), regardless of clinical manifestations, there was a higher than normal incidence of HLA-DR2 (58% versus 28%; z ‫؍‬ 4.05). The increased presence of HLA-DR2 was found in all frankly hemolytic PNH and in PNH associated with bone marrow failure (AA/PNH and MDS/PNH). HLA-DR2 was more frequent in AA/PNH (56%) than in AA without a PNH clone (37%; z ‫؍‬ 3.36). Analysis of a second cohort of patients with bone marrow failure treated with immunosuppression showed that HLA-DR2 was associated with a hematologic response (50% of responders versus 34% of nonresponders; z ‫؍‬ 2.69). IntroductionIdiopathic aplastic anemia (AA) shows striking similarities to diseases of other organ systems with classically established autoimmune pathophysiology: AA frequently affects younger individuals, there is laboratory evidence for immune activation and destruction of the target organ by autoreactive T cells, 1 and patients often respond to immunosuppressive therapies. 2 Many autoimmune diseases have clear associations with particular HLA alleles: ankylosing spondylitis with HLA-B27 is the classical example, but similar relationships have been found in psoriasis (HLA-B13, HLA-B17-Cw6), rheumatoid arthritis (HLA-DR1 and HLA-DR4), juvenile diabetes mellitus (HLA-B8, HLA-B15, and HLA-B54), and multiple sclerosis (HLA-B7 and HLA-DR2). In hematology, agranulocytosis secondary to clozapine (HLA-B38, HLA-DR4, and DQw3) or methimazole (HLA-DR8) and mixed cryoglobulinemia in hepatitis C virus-infected patients (HLA-B8 and HLA-DR3) exemplify links between immunogenetics and pathophysiology. [3][4][5][6] Fundamentally, the presence of particular HLA alleles likely allows for preferential presentation of particular peptides, perhaps derived from autoantigens, to specific T cells, driving the autoimmune process.In AA, HLA associations have also been examined. [7][8][9][10][11][12][13][14][15][16][17][18][19] An increased frequency of HLA-DR2 has been reported in some but not all studies. [9][10][11][12][13]16 An association with class I alleles (especially HLA-A2) has been inconsistently identified. 7,10,[13][14][15] The presence of HLA-DR15 (split of DR2) was associated with good response to cyclosporine therapy, suggesting that this allele may be a specific predisposing factor for the development of immune-med...

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Association between the DRB1*08032 Histocompatibility Antigen and Methimazole-Induced Agranulocytosis in Japanese Patients with Graves Disease

Abstract: The HLA DRB1*08032 allele was strongly associated with susceptibility to methimazole-induced agranulocytosis, suggesting that cellular autoimmunity may be involved in its development.

Cited by 69 publications

References 0 publications

Novel Association between <b><i>Flavin-Containing Monooxygenase 3</i></b> Gene Polymorphism and Antithyroid Drug-Induced Agranulocytosis in the Han Population

Novel Association between <b><i>Flavin-Containing Monooxygenase 3</i></b> Gene Polymorphism and Antithyroid Drug-Induced Agranulocytosis in the Han Population

The Relation of Initial Methimazole Dose to the Incidence of Methimazole-induced Agranulocytosis in Patients with Graves' Disease

Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome

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