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Screening for human leukocyte antigen (<jats:italic>HLA<\/jats:italic>) allele <jats:italic>HLA<\/jats:italic>\u2010<jats:italic>B*15<\/jats:italic>:<jats:italic>02<\/jats:italic> is recommended prior to initiating treatment with carbamazepine in Asians, but this allele has low positive predictive value.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed whole genome sequencing and analyzed 6\u00a0199\u00a0696 common variants among 113 aromatic ASM\u2010induced SJS\/TEN cases and 84 tolerant controls of Han Chinese ethnicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the primary analysis, nine variants reached genome\u2010wide significance (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a05e\u201008), one in the carbamazepine subanalysis (85 cases vs. 77 controls) and a further eight identified in <jats:italic>HLA<\/jats:italic>\u2010<jats:italic>B*15<\/jats:italic>:<jats:italic>02<\/jats:italic>\u2010negative subanalysis (35 cases and 53 controls). Interaction analysis between each novel variant from the primary analysis found that five increased risk irrespective of <jats:italic>HLA<\/jats:italic>\u2010<jats:italic>B*15<\/jats:italic>:<jats:italic>02<\/jats:italic>\u00a0status or zygosity. <jats:italic>HLA<\/jats:italic>\u2010<jats:italic>B*15<\/jats:italic>:<jats:italic>02<\/jats:italic>\u2010positive individuals were found to have reduced risk if they also carried a chromosome 12 variant, chr12.9426934 (heterozygotes: relative risk = .71, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.001; homozygotes: relative risk = .23, <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.001). All significant variants lie within intronic or intergenic regions with poorly understood functional consequence. In silico functional analysis of suggestive variants (<jats:italic>p<\/jats:italic> &lt; 5e\u20106) identified through the primary and subanalyses (stratified by <jats:italic>HLA<\/jats:italic>\u2010<jats:italic>B*15<\/jats:italic>:<jats:italic>02<\/jats:italic>\u00a0status and drug exposure) suggests that genetic variation within regulatory DNA may contribute to risk indirectly by disrupting the regulation of pathology\u2010related genes. The genes implicated were specific either to the primary analysis (<jats:italic>CD9<\/jats:italic>), <jats:italic>HLA<\/jats:italic>\u2010<jats:italic>B*15<\/jats:italic>:<jats:italic>02<\/jats:italic> carriers (<jats:italic>DOCK10<\/jats:italic>), noncarriers (<jats:italic>ABCA1<\/jats:italic>), carbamazepine exposure (<jats:italic>HLA<\/jats:italic>\u2010<jats:italic>E<\/jats:italic>), or phenytoin exposure (<jats:italic>CD24<\/jats:italic>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>We identified variants that could explain why some carriers of <jats:italic>HLA<\/jats:italic>\u2010<jats:italic>B*15<\/jats:italic>:<jats:italic>02<\/jats:italic> tolerate treatment, and why some noncarriers develop ASM\u2010induced SJS\/TEN. Additionally, this analysis suggests that the mixing of <jats:italic>HLA<\/jats:italic>\u2010<jats:italic>B*15<\/jats:italic>:<jats:italic>02<\/jats:italic> carrier status in previous studies might have masked variants contributing to susceptibility, and that inheritance of risk for ASM\u2010induced SJS\/TEN is complex, likely involving multiple risk variants.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17182","type":"journal-article","created":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T09:48:35Z","timestamp":1645004915000},"page":"936-949","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Potential role of regulatory DNA variants in modifying the risk of severe cutaneous reactions induced by aromatic anti\u2010seizure medications"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4400-1198","authenticated-orcid":false,"given":"Kerry A.","family":"Mullan","sequence":"first","affiliation":[{"name":"Infection and Immunity Program Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology Monash University  Clayton Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1490-2262","authenticated-orcid":false,"given":"Alison","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Central Clinical School Alfred Hospital Monash University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Wu","family":"Shi","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China  Guangzhou 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