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

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.