ArticleEpilepsia2022
Potential role of regulatory DNA variants in modifying the risk of severe cutaneous reactions induced by aromatic anti-seizure medications.
Article in Epilepsia, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed, 6 citations in OpenAlex.
- Holistic management of epilepsy in adults with intellectual development disorders.Epileptic disorders : international epilepsy journal with videotape · 2026Article
- Immunological and molecular signatures of carbamazepine-induced maculopapular exanthema.Frontiers in immunology · 2026Article
- Assessment of clinically actionable pharmacogenetic markers to stratify anti-seizure medications.The pharmacogenomics journal · 2023Article
- Potential role of regulatory DNA variants in modifying the risk of severe cutaneous reactions induced by aromatic anti-seizure medications.Epilepsia · 2022Article
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Authors and funding
13 authors at 8 institutions in 6 countries.
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No grant is acknowledged in the PubMed record.
Abstract
objectiveStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Antiseizure medications (ASMs) with aromatic ring structure, including carbamazepine, are among the most common culprits. Screening for human leukocyte antigen (HLA) allele HLA-B*15:02 is recommended prior to initiating treatment with carbamazepine in Asians, but this allele has low positive predictive value.
methodsWe performed whole genome sequencing and analyzed 6 199 696 common variants among 113 aromatic ASM-induced SJS/TEN cases and 84 tolerant controls of Han Chinese ethnicity.
resultsIn the primary analysis, nine variants reached genome-wide significance (p < 5e-08), one in the carbamazepine subanalysis (85 cases vs. 77 controls) and a further eight identified in HLA-B*15:02-negative subanalysis (35 cases and 53 controls). Interaction analysis between each novel variant from the primary analysis found that five increased risk irrespective of HLA-B*15:02 status or zygosity. HLA-B*15:02-positive individuals were found to have reduced risk if they also carried a chromosome 12 variant, chr12.9426934 (heterozygotes: relative risk = .71, p = .001; homozygotes: relative risk = .23, p < .001). All significant variants lie within intronic or intergenic regions with poorly understood functional consequence. In silico functional analysis of suggestive variants (p < 5e-6) identified through the primary and subanalyses (stratified by HLA-B*15:02 status and drug exposure) suggests that genetic variation within regulatory DNA may contribute to risk indirectly by disrupting the regulation of pathology-related genes. The genes implicated were specific either to the primary analysis (CD9), HLA-B*15:02 carriers (DOCK10), noncarriers (ABCA1), carbamazepine exposure (HLA-E), or phenytoin exposure (CD24). SIGNIFICANCE: We identified variants that could explain why some carriers of HLA-B*15:02 tolerate treatment, and why some noncarriers develop ASM-induced SJS/TEN. Additionally, this analysis suggests that the mixing of HLA-B*15:02 carrier status in previous studies might have masked variants contributing to susceptibility, and that inheritance of risk for ASM-induced SJS/TEN is complex, likely involving multiple risk variants.
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