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

Abstract

Aims Antithyroid drug (ATD)‐induced agranulocytosis is a life‐threatening adverse drug reaction. Previous studies suggested that HLA genotypes may play an important role in ATD‐induced agranulocytosis. To examine the associations between HLA genotypes and ATD‐induced agranulocytosis, we conducted a systematic review and meta‐analysis of pharmacogenomics studies. Methods We searched the MEDLINE, Embase and CENTRAL databases on 16 June 2018 for case–control studies on the associations between HLA genotypes with ATD‐induced agranulocytosis. The Newcastle–Ottawa scale was used to evaluate the risk of bias of included studies. We conducted random‐effects model meta‐analysis to obtain pooled odds ratios (ORs) with 95% confidence intervals (CIs) to determine the associations between HLA genotypes and ATD‐induced agranulocytosis. Results We included 5 studies with 142 ATD‐induced agranulocytosis cases, 1529 matched ATD‐tolerant controls and 5945 healthy controls. The risk of bias of included studies was generally low. ATD‐induced agranulocytosis was associated with HLA‐B*27:05 (OR 10.97; 95% CI 0.75–159.99), HLA‐B*38:02 (OR 19.85; 95% CI 7.94–49.57) and HLA‐DRB1*08:03 (OR 5.29; 95% CI 3.44–8.14). After excluding propylthiouracil, the associations of ATD‐induced agranulocytosis with HLA‐B*27:05 and HLA‐B*38:02 were strengthened (OR being 20.61 (95% CI 5.21–81.58) and 40.59 (95% CI 13.24–124.47), respectively). The associations of ATD‐induced agranulocytosis with HLA‐B*27:05, HLA‐B*38:02 and HLA‐DRB1*08:03 remained significant when compared to population controls (OR being 7.37 (95% CI 3.86–14.07), 36.43 (95% CI 12.80–103.70) and 5.42 (95% CI 2.36–12.47), respectively). HLA‐B*27:05, HLA‐B*38:02, and HLA‐DRB1*08:03 alleles were associated with ATD‐induced agranulocytosis, especially in carbimazole/methimazole‐induced agranulocytosis. Conclusions HLA‐B*27:05, HLA‐B*38:02 and HLA‐DRB1*08:03 alleles were associated with ATD‐induced agranulocytosis, especially in carbimazole/methimazole‐induced agranulocytosis.

A Review of β-Lactam–Associated Neutropenia and Implications for Cross-reactivity

“…In the case of thionamide antithyroid drugs, antineutrophil cytoplasmic antibodies against antigens on the surface of neutrophils have been found, and T-cell responses to oxidative metabolites may also play a role. 70,71,73 Class I HLA alleles such as HLA-B*27:05 in European populations and HLA-B*38:02 in Asian populations have also been associated with thionamide agranulocytosis. 70,71,73 HLA associations have also been described with agranulocytosis associated with other drugs such as HLA-B*27:05 and levamisole as well as HLA-B38, DR4, and DQw3 with clozapine-induced agranulocytosis in Ashkenazi Jewish populations.…”

“…70,71,73 Class I HLA alleles such as HLA-B*27:05 in European populations and HLA-B*38:02 in Asian populations have also been associated with thionamide agranulocytosis. 70,71,73 HLA associations have also been described with agranulocytosis associated with other drugs such as HLA-B*27:05 and levamisole as well as HLA-B38, DR4, and DQw3 with clozapine-induced agranulocytosis in Ashkenazi Jewish populations. 74,75 At this time, a detailed and thorough understanding of the mechanisms underlying β-lactam-induced neutropenia remains elusive, and no relevant HLA class I or II associations have been defined.…”

Anemia aplásica inducida por metimazol: presentación de caso

“…Los polimorfismos específicos de los genotipos hla desempeñan un papel crucial en diversas reacciones asociadas con medicamentos (ram). Se han asociado alteraciones en los alelos hla-b 27:05 y 38:02 y en hla-drb1 08:03, que podrían favorecer reacciones mediadas por células T contra la proliferación y diferenciación de células madre hematopoyéticas pluripotentes en la médula ósea ante los metabolitos oxidativos de las tionamidas (9). La parte inmunológica toma fuerza actualmente como el mecanismo asociado a aa y tionamidas, dada la frecuente relación con anemia hemolítica y síndromes parecidos al lupus en pacientes manejados con estos medicamentos (10).…”

Drug-induced hypersensitivity syndrome induced by propylthiouracil: case report and literature review

“…We retrospectively summarize recent progresses in identifying pharmacogenetic associations with DIHS in different populations (Table 3 ) [ 19 ]. A systematic meta-analysis of pharmacogenomics studies by Chi et al revealed that HLA-B*27:05, HLA-B*38:02, and HLA-DRB1*08:03 alleles were linked to ATD-induced agranulocytosis, particularly in MMI [ 20 ]. Additionally, our case possessed HLA-DRB1*08:03 allele.…”