Novel Association between &lt;b&gt;&lt;i&gt;Flavin-Containing Monooxygenase 3&lt;/i&gt;&lt;/b&gt; Gene Polymorphism and Antithyroid Drug-Induced Agranulocytosis in the Han Population

He, Yayi; Hasan, Abdulbaqi M.E.; Zhang, Qian; Li, Shaoqing; Yang, Jiangcun; Yan, Cheng; Chen, Pu; Liu, Yan; Nadeem, Asif; Zhang, Bao

doi:10.1159/000497314

Cited by 4 publications

(7 citation statements)

References 19 publications

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“…Although c.769G>A [p.(Val257Met)] has little effect on FMO3-catalyzed S-oxygenation of methimazole in vitro (Dolphin et al, 2000), the variant is associated with antithyroid (methimazole) drug-induced agranulocytosis in Han Chinese being treated for Graves' disease (He et al, 2019). The results suggest that the variant, which is common in this population, would be a useful predictor of antithyroid drug-induced agranulocytosis in Chinese patients undergoing methimazole treatment of hyperthyroidism.…”

Section: Effects On Drug Metabolismmentioning

confidence: 90%

Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease

Phillips

Shephard

2019

Xenobiotica

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1. The review focuses on genetic variants of human flavin-containing monooxygenase 3 (FMO3) and their impact on enzyme activity, drug metabolism and disease. 2. The majority of FMO-mediated metabolism in adult human liver is catalyzed by FMO3. Some drugs are metabolized in human liver predominantly by FMO3, but most drug substrates of FMO3 are metabolized also by other enzymes, particularly cytochromes P-450, and the FMO3-catalyzed reaction is not the major route of metabolism. 3. Rare variants that severely affect production or activity of FMO3 cause the disorder trimethylaminuria and impair metabolism of drug substrates of FMO3. More common variants, particularly p.[(Glu158Lys);(Glu308Gly)], can moderately affect activity of FMO3 in vitro and reduce metabolism of drug substrates in vivo, in some cases increasing drug efficacy or toxicity. 4. Common variants of FMO3 have been associated with a number of disorders, but additional studies are needed to confirm or refute such associations. 5. Elevated plasma concentrations of trimethylamine N-oxide, a product of an FMO3catalyzed reaction, have been implicated in certain diseases, particularly cardiovascular disease. However, the evidence is often contradictory and additional work is required to establish whether trimethylamine N-oxide is a cause, effect or biomarker of the disease. 6. Genetic variants of other FMOs are also briefly discussed.

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Section: Effects On Drug Metabolismmentioning

confidence: 90%

Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease

Phillips

Shephard

2019

Xenobiotica

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“…Peripheral blood samples were collected, and DNA was extracted using a genomic DNA Kit (Tiangen Biotech Co., Ltd.). MICA‐129 genotyping was performed using the iPLEX MassARRAY system as previously reported 35 . Then, genotyping for the MICA‐STR variant was performed according to a fluorescent‐based method in which primers were labelled at the 5′ end with the fluorescent reagent 6‐HEX.…”

Section: Methodsmentioning

confidence: 99%

“…MICA-129 genotyping was performed using the iPLEX MassARRAY system as previously reported. 35 Then, genotyping for the MICA-STR variant was performed according to a fluorescent-based method in which primers were labelled at the 5′ end with the fluorescent reagent 6-HEX. Polymerase chain reaction (PCR) fragments were generated using primers (MICA5 F, 5′-CTTTTTTTCAGGGAAAGTG-3′; MICA5 R, 5′-CCTTACCATCTCCAGAAACTGC-3′) that flank the STR polymorphism in the TM region of the MICA gene.…”

Section: Genotyping Of Mica-str and Mica-129 Genetic Variantsmentioning

confidence: 99%

MICA polymorphisms associated with antithyroid drug‐induced agranulocytosis in the Chinese Han population

Gong

Chen

et al. 2020

Immunity Inflam & Disease

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Background Graves' disease (GD) is a clinical autoimmune thyroid disease. During the treatment of GD, antithyroid drug‐induced agranulocytosis (TIA) is a common and even life‐threatening adverse drug reaction. Previous studies suggested that susceptibility to TIA is strongly associated with HLA‐B*27:05, HLA‐B*38:02, and HLA‐DRB1*08:03 genetic variation and six single nucleotide polymorphisms (SNPs) in MICA genes. Aims The purpose of this study is to further study the associations between TIA, HLA‐B and MICA. Materials & Methods We genotyped MICA‐STR and MICA‐129 variants in 41 TIA and 308 control patients with GD and investigated the linkage effect among SNPs and short tandem repeat (STR) of MICA and HLA‐B alleles. Results The results showed that MICA*A5.1 was significantly associated with TIA (p = .007, odd ratio = 1.958, 95% confidence interval, 1.192–3.214). In addition, high linkage among MICA‐129 and six SNPs MICA and HLA‐B was detected, and two haplotypes (AAAACAAAAACGGCCTA and AACAAAAAAAACATTAA (p = 5.14E−07 and p = 3.42E−08, respectively)) were significantly associated with TIA. Furthermore, when we analyzed only MICA‐129 and HLA‐B separately, the haplotypes (AAAACAAAAAA with p = 2.49E−07 and AACAAAAAAAA with p = 2.14E−09) were identified with more significant effects. MICA‐129 was completely linked to six SNPs with haplotypes ACATTACA (p = 2.05E−05) significantly associated with TIA. Conclusion These data indicated that there was a significant linkage effect between MICA‐129 and other alleles, suggesting that they exert interactive effects as risk factors for the development of TIA.

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“…Studies by Park et al (13) and Sung et al (14) demonstrated that the SnPs c.855c>T and c.472G>a affected the pharmacokinetics of sulindac in women who underwent preterm labor. Febrile neutropenia, myelosuppression and agranulocytosis related to these SnPs have also been reported previously (25,29,30). considering the relatively high frequency of FMO3 genetic polymorphisms in the population, the functional defects in FMo3 enzymes associated with these SnPs may have notable clinical implications, such as the variations in drug exposure followed by toxicity or delayed elimination of toxic substances.…”

Section: Discussionmentioning

confidence: 54%

“…FMO3 also affects the levels of several clinically important medications, and its polymorphisms are associated with drug toxicity ( 25 , 29 , 30 ). The c.923A>G SNP has been shown to increase voriconazole concentrations by reducing FMO3 enzyme activity ( 25 ), while c.855C>T SNP can increase the concentration of teneligliptin ( 6 ).…”

Section: Discussionmentioning

confidence: 99%

Rapid detection ofFMO3single nucleotide polymorphisms using a pyrosequencing method

Park

Kim

et al. 2021

Mol Med Rep

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The present study aimed to develop a reliable pyrosequencing method to detect four single nucleotide polymorphisms (SnPs) of the flavin-containing monooxygenase 3 (FMO3) gene and to compare the ethnic differences in their allelic frequencies. The pyrosequencing method was used to detect four FMO3 SnPs, namely, c.855c>T (n285n, rs909530), c.441c>T (S147S, rs1800822), c.923a>G (e308G, rs2266780) and c.472G>a (e158K, rs2266782). The allelic frequencies of these SnPs in 122 unrelated Korean subjects were as follows: i) 44.7% for c.855c>T; ii) 23.4% for c.441c>T; iii) 23.0% for c.923a>G; and iv) 27.1% for c.472G>a. linkage disequilibrium (ld) analysis revealed that the SnPs c.923a>G and c.472G>a exhibited a strong ld (d'=0.8289, r 2 =0.5332). in conclusion, the pyrosequencing method developed in this study was successfully applied to detect the c.855c>T, c.441c>T, c.923a>G and c.472G>a SnPs of FMO3.

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

Cited by 4 publications

References 19 publications

Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease

Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease

MICA polymorphisms associated with antithyroid drug‐induced agranulocytosis in the Chinese Han population

Rapid detection ofFMO3single nucleotide polymorphisms using a pyrosequencing method

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