Project title
抗甲狀腺藥物引起白血球過低的基因研究
Internal ID
NSC101-2314-B002-130
Principal Investigator
Start Date
August 1, 2012
End Date
July 12, 2013
Investigators
Organizations
Partner Organizations
Project Web Site
Genetic Study of Antithyroid Drugs Associated Agranulocytosis = 抗甲狀腺藥物引起白血球過低的基因研究
Keywords
葛瑞夫茲氏症
硫代酰胺
顆粒性白血球缺乏症
人類白血球表面抗原
次世代定序
藥物基因醫學
藥物基因體學
Graves disease
thionamide
agranulocytosis
human leukocyte antigen (HLA)
next-generation sequencing (NGS)
pharmacogenetics
pharmacogenomics
Description
Graves’ disease [GD (MIM 27500)] is the leading cause of hyperthyroidism worldwide. According to the epidemiologic survey, the prevalence of Graves’ disease is about 2.7% in women, which is only next to diabetes mellitus in endocrine diseases. Thionamides, including methimazole, carbimazole, propylthiouracil, are the major anti-thyroid drugs, and are the treatment of choice for GD. The most serious side effect of thionamides is agranulocytosis (severe drop of neutrophil count to < 500/mm3), which occurs in 0.1% - 0.4 % of the patients. Agranulocytosis inevitably compromises the immune system of the patients, making them at high risk of severe infection. Patients with the complication of agranulocytosis need to be hospitalized for expensive medications and close monitoring. In addition to the medical cost, the fatal rate can be as high as 18.2%. The underlying mechanism is unclear, and to date it has been impossible to predict who will develop agranulocytosis. An immune phenomenon may be involved because the anti-granulocyte antibodies or lymphocyte sensitized to anti-thyroid drugs can be found in these patients. The ultimate goal of this project is to identify the possible genetic variants causing agranulocytosis induced by anti-thyroid drugs. We consider the human leukocyte antigen (HLA) genes to be very good candidates for the idiosyncratic adverse effect; however, we also plan to investigate the possible role of other genes beyond the HLA loci. We will include 30 GD agranulocytosis “cases” and 499 GD non-agranulocytosis “controls” for comprehensive 6-locus HLA genotype analyses. According to the power calculation, this study design has very high statistic power (mostly greater than 99%) to detect the association signal if any of the HLA genes is the causative gene. At the same time, we will perform whole exome sequencing using the next-generation sequencing (NGS) approach on 6 cases to identify any possible risk gene outside the HLA loci. Our team has strong foundation to perform such a complicated pharmacogenomics study because of our long-term devotion in GD patient enrollment and phenotype characterization, our well-established GD genetic study basis, and our expertise in HLA genotyping and NGS experiments. Identification of genetic determinant(s) for anti-thyroid drugs-related agranulocytosis will have paramount clinical and academic importance. It may lead to an efficient genetic test, which can be used before the launch of thionamides to prevent expensive medical cost related to agranulocytosis and to save valuable lives. Furthermore, such breakthrough can also shed light on the pathogenesis, and might facilitate the search of genes responsible for drug-related agranulocytosis by other medications.