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 (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.

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

“…Chen et al [19] demonstrated HLA-B*38:02 and HLA-DRB1*08:03 as independent susceptibility loci in Taiwanese patients. The odds ratio for carriers of both HLA-B*38:02 and HLA-DRB1*08:03 to noncarriers is as high as 48.41.…”

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

“…Graves' disease (GD) is the most important cause of hyperthyroidism, with a prevalence as high as 1.0-1.6% in the general population [1]. Some effective antithyroid drugs (ATDs), such as methimazole (MMI), propylthiouracil (PTU) and carbimazole, have been widely used for patients with GD across the globe.…”

“…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].…”

The Effects of GCSF on the Recovery Time and Duration of Hospitalization in Patients with Anti-thyroid Drug-Induced Agranulocytosis in a Tertiary Hospital

“…Although this is the largest research on the genetics of ATD-induced agranulocytosis with 2-stage study design, the researchers recommended to conduct another study using the same or other populations to support the validity of the result. 9 Several studies have described the clinical characteristics of ATD-induced agranulocytosis. It was found to be more common in elderly patients using MMI in dosages more than 40 mg/day, while the prevalence with PTU was not dose-dependent.…”

“…2 A recent advancement on genetics showed 2 risk genotypes (HLA-B*38:02 and HLA-DRB1*08:03) that have independent association with ATD-induced agranulocytosis by human leukocyte antigen (HLA) genotyping and genome-wide association study (GWAS). 9 A study on GD included 42 patients with ATD-induced agranulocytosis and 927 with normal white blood cell count. HLA-B*38:02 was found in 59.52% of ATD-induced agranulocytosis, but only in 6.41% of those who did not experience agranulocytosis.…”