Two loci of HLA genes were found linked to anti-thyroid drug induced agranulocytosis Many people may be familiar with Graves’ disease, which is the leading cause of hyperthyroidism. Around 1%-1.6% in the general population may be affected. Graves’ disease is mainly caused by the circulating autoantibody, which targets thyroid stimulating hormone (TSH) receptor on the thyroid gland. After the antibody binds the receptor, the thyroid gland gets out of control, and starts producing and secreting excessive thyroid hormone. Those with Graves’ disease may present with body weight loss, palpitation, hand tremor, enlarged thyroid gland, and even bulging eyes. Medical treatment for Graves’ disease includes anti-thyroid drugs and radioactive iodine. If medical treatment fails, then surgical resection should be considered. Anti-thyroid drugs include methimazole, carbimazole and propylthiouracil (PTU), which can suppress thyroid gland from producing excessive hormone to achieve clinical remission. These anti-thyroid agents are the cornerstone for Graves’ disease treatment. However, some patient developed deadly agranulocytosis after initiation of these agents. The so-called agranulocytosis, defined as an absolute neutrophil count less than 500/mm3, is the breakdown of immune system. Once developed, the risk of severe infection and mortality will highly increase. Is there any method to predict agranulocytosis after taking anti-thyroid drugs? On 2015 July, Professor Chang and his team published their study, mainly about the gene highly associated with anti-thyroid drug induced agranulocytosis, on Nature Communications. However, how do they identify the exact gene they want? When talking about gene associated drug adverse effect, Human Leukocyte Antigen (HLA) should be kept in mind. Located on chromosome 6, HLA has the highest variation and is closely associated with immune function, autoimmune disease and some drug adverse effects. Aside from HLA, non-HLA genes may affect the metabolism of drugs, and are also associated with some side effects. In this study, the research team utilized “Direct HLA loci genotyping” and “Genome-wide association study (GWAS)” to analyze the genetic difference between those who developed agranulocytosis or not. Direct HLA loci genotyping focuses on the difference of HLA alone and GWAS analyzes single nucleotide polymorphism (SNPs) of the whole genome. The research team identified two loci highly associated with anti-thyroid drugs induced agranulocytosis, including HLA-B*38:02 and HLA-DRB1*08:03. Estimated odds ratios for these two loci comparing allele carriers to non-carriers are 21.48 and 6.13. What’s more, if one carries both HLA-B*38:02 and HLA-DRB1*08:03, the risk will increase to 48.41. These results may guide clinicians’ decision-making in Asia. After commercialized, doctors can arrange genetic testing before initiating anti-thyroid drugs. If the above two HLA loci are noted, alternative treatment should be considered to avoid agranulocytosis. Reference Pei-Lung Chen, Shyang-Rong Shih, Pei-Wen Wang, Ying-Chao Lin, Chen-Chung Chu, Jung-Hsin Lin, Szu-Chi Chen, Ching-Chung Chang, Tien-Shang Huang, Keh-Sung Tsai, Fen-Yu Tseng, Chih-Yuan Wang, Jin- Ying Lu, Wei-Yih Chiu, Chien-Ching Chang, Yu-Hsuan Chen, Yuan-Tsong Chen, Cathy Shen-Jang Fann, Wei- Shiung Yang & Tien-Chun Chang. Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study. Nat. Commun. 6:7633 DOI: 10.1038/ ncomms8633 (2015). Professor Tien-Chun Chang Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital tienchunchang@ntu.edu.tw Professor Wei-Shiung Yang Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital wsyang@ntu.edu.tw