Spectrum of cutaneous adverse reactions to aromatic antiepileptic drugs and human leukocyte antigen genotypes in Thai patients and meta-analysis

• Published in: The pharmacogenomics journal Vol. 21; no. 6; pp. 682 - 690
• Main Authors: Sukasem, Chonlaphat, Sririttha, Suthida, Chaichan, Chonlawat, Nakkrut, Thapanat, Satapornpong, Patompong, Jaruthamsophon, Kanoot, Jantararoungtong, Thawinee, Koomdee, Napatrupron, Medhasi, Sadeep, Oo-Puthinan, Sarawut, Rerkpattanapipat, Ticha, Klaewsongkram, Jettanong, Rerknimitr, Pawinee, Tuchinda, Papapit, Chularojanamontri, Leena, Tovanabutra, Napatra, Suvannang, Naravut, Rungrotmongkol, Thanyada, Saokaew, Surasak, Aekplakorn, Wichai, Puangpetch, Apichaya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2021; Nature Publishing Group
• Subjects: 38/47; 38/77; 631/154/53/2422; 692/53/2422; 692/700/1750; Adverse and side effects; Alleles; Allelomorphism; Anticonvulsants; Anticonvulsants - adverse effects; Antiepileptic agents; Antigens; Biomedical and Life Sciences; Biomedicine; Carbamazepine; Case-Control Studies; Complications and side effects; Cutaneous manifestations of general diseases; Drug Eruptions - diagnosis; Drug Eruptions - genetics; Drug Eruptions - immunology; Drugs; Eosinophilia; Gene Expression; Gene Frequency; Genetic aspects; Genotype; Genotypes; Health aspects; Heterocyclic Compounds - adverse effects; Histocompatibility antigen HLA; Histocompatibility antigens; HLA histocompatibility antigens; HLA-B Antigens - genetics; Human Genetics; Humans; Lamotrigine; Meta-analysis; Oligonucleotides; Oncology; Oxcarbazepine; Patients; Pharmacology, Experimental; Pharmacotherapy; Phenobarbital; Phenotypes; Phenytoin; Polymerase chain reaction; Population genetics; Population studies; Psychopharmacology; Risk Assessment; Risk Factors; Seizures; Thailand; Toxic epidermal necrolysis; Thailand
• ISSN: 1470-269X; 1473-1150; 1473-1150
• DOI: 10.1038/s41397-021-00247-3

Aromatic antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs) add up to the limited use of the AEDs in the treatment and prevention of seizures. Human leukocyte antigen-B ( HLA-B ) alleles have been linked to AEDs-induced cADRs. We investigated the association between cADRs (including Stevens–Johnson syndrome; SJS/toxic epidermal necrolysis; TEN, drug reaction with eosinophilia and systemic symptoms; DRESS, and Maculopapular eruption; MPE) caused by AEDs (phenytoin, carbamazepine, lamotrigine, phenobarbital and oxcarbazepine) and HLA-B alleles in Thai population. Through the case-control study, 166 patients with AEDs-induced cADRs, 426 AEDs-tolerant patients (AEDs-tolerant controls), and 470 healthy subjects (Thai population) were collected. The HLA genotypes were detected using the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. We also performed a meta-analysis with these data and other populations. The carrier rate of HLA-B*15:02 was significantly different between AEDs-induced cADRs group and AEDs-tolerant group (Odds ratio; OR 4.28, 95% Confidence interval; CI 2.64–6.95, p  < 0.001), AEDs-induced cADRs group and Thai population (OR 2.15, 95%CI 1.41–3.29, p  < 0.001). In meta-analysis showed the strong association HLA-B*15:02 with AEDs-induced cADRs (OR 4.77, 95%CI 1.79–12.73, p  < 0.001). Furthermore, HLA-B*15:02 was associated with SJS/TEN induced by AEDs (OR 10.28, 95%CI 6.50–16.28, p  < 0.001) Phenytoin (OR 4.12, 95%CI 1.77–9.59, p  = 0.001) and carbamazepine (OR 137.69, 95%CI 50.97–371.98, p  < 0.001). This study demonstrated that genetic association for AEDs-induced cADRs was phenotype-specific. A strong association between HLA-B*15:02 and AEDs-induced SJS/TEN was demonstrated with an OR of 10.79 (95%CI 5.50–21.16, p  < 0.001) when compared with AEDs-tolerant group. On the other hand, the carrier rates of HLA-B*08:01 , HLA-B*13:01 , and HLA-B*56:02 were significantly higher in the DRESS group compared with the AEDs-tolerant group ( p  = 0.029, 0.007, and 0.017, respectively). The HLA-B*15:02 allele may represent a risk factor for AEDs-induced cADRs.