HLA‐B*38:02:01 predicts carbimazole/methimazole‐induced agranulocytosis

Abstract

Thioamides antithyroid-drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD-induced agranulocytosis is important for clinical management. We performed a genome-wide association study (GWAS) involving 20 patients with ATD-induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single-nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD-induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8-103.7; P = 1.3 × 10(-24)) and replication (OR = 37; 95% CI = 3.7-367.4; P = 9.6 × 10(-7)). HLA-B*38:02:01 was in complete linkage disequilibrium with rs185386680. High-resolution HLA typing confirmed that HLA-B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)-induced agranulocytosis (OR = 265.5; 95% CI = 27.9-2528.0; P = 2.5 × 10(-14)), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA-B*38:02:01 in predicting CMZ/MMI-induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.

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

“…A similar observation was found in a Taiwanese study, which showed that HLA-B*38: 02 was less associated with PTU-induced agranulocytosis than with MMI-induced agranulocytosis. We did not find any association between the FMO3 gene and ATD-induced neutropenia, suggesting that the mechanism of ATD-induced agranulocytosis could be different from that of ATD-induced neutropenia, which is similar to a previous study of the Hong Kong population [8]. Sample sizes of PTU/MMI-induced agranulocytosis and neutropenia are rare, and future collaborative efforts are required to elucidate the role of genetic variants in these adverse drug reactions.…”

“…Another postulated mechanism is that neutrophils are against by the T cell-mediated reaction, and ATD can also have a direct toxic effect on the bone marrow [5][6][7]. To date, 3 genome-wide association studies of ATD-associated agranulocytosis have been performed in Taiwan (42 agranulocytosis cases [1,8,9]. Non-HLA genes also cause numerous drug-induced adverse effects through various pharmacokinetic and pharmacodynamic mechanisms [1].…”

Periodic Granulocyte Count Measuring Is Useful for Detecting Asymptomatic Agranulocytosis in Antithyroid Drug-Treated Patients with Graves' Disease

“…A similar study has been just reported from Hong Kong, China. Cheung et al [20] identified HLA-B*38:02:01 as the susceptibility locus of carbimazole-/MMI-induced AG, whereas the association with HLA-DRB1*08:03 did not reach significance. On the other hand, Hallberg et al [21] performed a GWAS in 234 European patients with nonchemotherapeutic-induced AG, including 39 ATD-induced AG, and found an association with HLA-B*27:05 and other single nucleotide polymorphisms on chromosome 6.…”

Associations of HLA genotypes with antithyroid drug‐induced agranulocytosis: A systematic review and meta‐analysis of pharmacogenomics studies

“…Since PTU‐induced agranulocytosis has been suggested to possess different genetic susceptibility from CMZ/MMI‐induced agranulocytosis by some researchers, we conducted a sensitivity analysis by excluding PTU‐induced agranulocytosis. Also, we conducted an additional sensitivity analysis by including studies that had used population controls …”