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

Pei‐Lung Chen ,Chien-Ching Chang,Wei-Shiung Yang,Tien-Shang Huang,Yuan-Tsong Chen,Yu-Hsuan Chen,Szu‐Chi Chen ,Keh–Sung Tsai ,Pei‐Wen Wang ,Chia Ju Chang ,Wei‐Yih Chiu ,Cathy S.j Fann ,Jinying Lü ,Yi‐Hao Lin ,Chih‐Yuan Wang ,Fen‐Yu Tseng ,Chen‐Chung Chu ,Shyang–Rong Shih ,Jung‐Hsin Lin ,Tien–Chun Chang

doi:10.1038/ncomms8633

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 (Pcombined=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 (Pcombined=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.

Highlights

Graves’ disease is the leading cause of hyperthyroidism affecting 1.0–1.6% of the population
The allele frequencies of 6 classical Human leukocyte antigen (HLA) genes in 42 TiA cases and in 1,208 GD controls can be found in Supplementary Data 1
Odds ratios of these two HLA alleles for effective allele carriers compared with non-carriers were 21.48 (95% confidence interval, CI 1⁄4 11.13–41.48) and 6.13, respectively

Summary

Introduction

Graves’ disease is the leading cause of hyperthyroidism affecting 1.0–1.6% of the population. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval 1⁄4 11.13–41.48) and 6.13 (95% confidence interval 1⁄4 3.28–11.46), respectively Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined 1⁄4 3.32 Â 10 À 21, 95% confidence interval 1⁄4 21.66–108.22). Drug-induced adverse effects could be broadly categorized into several types[9,10], including type A (dose-related, augmented) and type B (non-dose-related, bizarre), and can have different genetic predisposition[11]. Non-HLA genes cause numerous drug-induced adverse effects through various pharmacokinetic and pharmacodynamic mechanisms[11]. To comprehensively identify HLA and non-HLA genetic susceptibility to TiA, we conducted both direct HLA genotyping and genome-wide association study (GWAS) on GD patients with or without TiA. Three-dimensional (3D) structure modelling of the two HLA proteins and ATDs provides possible binding modes

Methods

Results

Conclusion