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. 2022 Feb;88(2):773-786.
doi: 10.1111/bcp.15022. Epub 2021 Aug 28.

Genetic variants associated with severe cutaneous adverse drug reactions induced by carbamazepine

Nontaya Nakkam  1 , Parinya Konyoung  2 , Warayuwadee Amornpinyo  3 , Niwat Saksit  4 , Somsak Tiamkao  5 , Usanee Khunarkornsiri  2 , Kanyarat Khaeso  1 , Oranuch Pattanacheewapull  6 , Teekayu Plangkoon Jorns  7 , Pansu Chumworathayi  8 , Wichittra Tassaneeyakul  1
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Free article

Genetic variants associated with severe cutaneous adverse drug reactions induced by carbamazepine

Nontaya Nakkam et al. Br J Clin Pharmacol. 2022 Feb.
Free article

Abstract

Aims: Carbamazepine (CBZ) is one of the most common causative drugs of severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reactions with eosinophilia and systemic symptoms. Although genetic polymorphisms of the human leucocyte antigens (HLA) are well recognized key elements for the susceptibility to CBZ-induced SCARs, some evidence suggest that polymorphisms of microsomal epoxide hydrolase 1 (EPHX1) may also contribute to the risk of these SCARs. This study investigated the association between the HLA and EPHX1 polymorphisms on CBZ-induced SCARs in large sample sizes and well-defined SCARs patients.

Methods: Ninety-one CBZ-induced SCARs Thai patients and 144 CBZ-tolerant patients were enrolled in the study. The genotypes of HLA-A, HLA-B and EPHX1 were determined.

Results: Only 2 HLA alleles including HLA-B*15:02 and HLA-A*24:07 were statistically significant association with CBZ-induced SJS/TEN. The highest risk was observed in patients with HLA-B*15:02 allele (OR = 44.33, 95% confidence interval = 20.24-97.09, corrected P-value = 6.80 × 10-29 ). Moreover, HLA-B75 serotypes were significantly associated with CBZ-induced SJS/TEN groups with an odds ratio of 81.00 (95% confidence interval = 32.39-202.56, corrected P-value = 3.84 × 10-34 ). There is no association between EPHX1 c.337 T > C polymorphism and all phenotypes of CBZ-induced SCARs.

Conclusion: The HLA-B*15:02 allele is the strongest genetic marker for the prediction of SJS/TEN induced by CBZ in Thai population. Screening for other alleles in the HLA-B75 serotype increases sensitivity for prediction of a life-threatening SCARs caused by CBZ.

Keywords: EPHX1; HLA-A*24:07; HLA-B*15:02; Stevens-Johnson syndrome; carbamazepine; drug reactions with eosinophilia and systemic symptoms; epoxide hydrolase; severe cutaneous adverse drug reactions; toxic epidermal necrolysis.

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References

REFERENCES

    1. McLean MJ, Macdonald RL. Carbamazepine and 10,11-epoxycarbamazepine produce use- and voltage-dependent limitation of rapidly firing action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther. 1986;238(2):727-738.
    1. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. 1994;331(19):1272-1285.
    1. Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology. 2005;64(7):1134-1138.
    1. Wang YH, Chen CB, Tassaneeyakul W, et al. The Medication Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Asians: The Major Drug Causality and Comparison With the US FDA Label. Clin Pharmacol Ther. 2019;105(1):112-120.
    1. Roujeau JC. Clinical heterogeneity of drug hypersensitivity. Toxicology. 2005;209(2):123-129.

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