Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study

Abstract

Graves' disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B∗38:02 (Armitage trend Pcombined =6.75 × 10 -32) and HLA-DRB1∗08:03 (P combined =1.83 × 10 -9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13-41.48) and 6.13 (95% confidence interval=3.28-11.46), respectively. Carrying both HLA-B∗38:02 and HLA-DRB1∗08:03 increases odds ratio to 48.41 (P combined =3.32 × 10 -21, 95% confidence interval=21.66-108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.