Novel Association between Flavin-Containing Monooxygenase 3 Gene Polymorphism and Antithyroid Drug-Induced Agranulocytosis in the Han Population

• Published in: Annals of nutrition and metabolism 2019-01, Vol.74 (3), p.200-206
• Main Authors: He, Ya-Yi, Hasan, Abdulbaqi Mohamed Esmail, Zhang, Qian, Li, Shao-Qing, Yang, Jing-Si, Yan, Chun-Xia, Chen, Pu, Liu, Yan, Nadeem, Asif, Zhang, Bao
• Format: Article
• Language: English
• Subjects: Agranulocytosis - chemically induced; Agranulocytosis - genetics; Alleles; Amino acids; Analysis; Antithyroid Agents - adverse effects; Asian Continental Ancestry Group; Care and treatment; China; Dimethylaniline monooxygenase (N-oxide-forming); Drugs; Enzymes; Female; Flavin; Gene expression; Gene Frequency; Gene polymorphism; Genes; Genetic diversity; Genetic polymorphisms; Genotype; Genotype & phenotype; Genotyping; Granulocytes; Granulocytopenia; Graves disease; Graves Disease - drug therapy; Haplotypes; Humans; Male; Medical research; Methimazole; Neutropenia; Neutropenia - chemically induced; Original Paper; Oxygen; Oxygenases - genetics; Oxygenation; Patients; Permutations; Polymorphism; Single-nucleotide polymorphism; Statistical methods; Trimethylamine
• ISSN: 0250-6807; 1421-9697
• DOI: 10.1159/000497314

Some effective antithyroid drugs (ATDs) have been widely used for patients with Graves’ disease (GD) but are associated with ATD-induced agranulocytosis. We selected 29 ATD-induced agranulocytosis patients, 44 ATD-induced neutropenia patients, and 140 GD controls among the Chinese Han population who were recruited at the First Affiliated Hospital of Xi’an Jiao Tong University. We assessed their response to ATDs treatment by performing genotyping for a candidate gene association study of samples from patients receiving treatment. Human flavin-containing monooxygenase 3 (FMO3), which is the major hepatic enzyme involved in the production of N-oxide of trimethylamine, catalyzes the oxygenation of a variety of drug compounds. Six single SNP, genotype, haplotype (HAP), and association analyses of the FMO3 gene with ATD-induced agranulocytosis/neutropenia under different models (i.e., additive, dominant, and recessive models) were performed. Rs1736557, which caused an amino acid variation V257M, showed a strong association between ATD-induced agranulocytosis and GD controls after Bonferroni correction (p = 0.011, OR 2.301, 95% CI 1.201–4.409). The presence of HAP 3 (HAP3) in the FMO3 gene HAP was statistically associated with ATD-induced agranulocytosis (p = 0.038, permutation p value). Our findings indicate that genetic variations in the FMO3 gene are associated with the response to ATDs maintenance treatment in ATD-induced agranulocytosis patients of Chinese Han population.