PMID- 35170024
OWN - NLM
STAT- MEDLINE
DCOM- 20220413
LR  - 20221015
IS  - 1528-1167 (Electronic)
IS  - 0013-9580 (Print)
IS  - 0013-9580 (Linking)
VI  - 63
IP  - 4
DP  - 2022 Apr
TI  - Potential role of regulatory DNA variants in modifying the risk of severe 
      cutaneous reactions induced by aromatic anti-seizure medications.
PG  - 936-949
LID - 10.1111/epi.17182 [doi]
AB  - OBJECTIVE: Stevens-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. METHODS: We 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. RESULTS: In 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.
CI  - (c) 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of 
      International League Against Epilepsy.
FAU - Mullan, Kerry A
AU  - Mullan KA
AUID- ORCID: 0000-0003-4400-1198
AD  - Infection and Immunity Program, Monash Biomedicine Discovery Institute and 
      Department of Biochemistry and Molecular Biology, Monash University, Clayton, 
      Victoria, Australia.
FAU - Anderson, Alison
AU  - Anderson A
AUID- ORCID: 0000-0002-1490-2262
AD  - Department of Neuroscience, Central Clinical School, Alfred Hospital, Monash 
      University, Melbourne, Victoria, Australia.
FAU - Shi, Yi-Wu
AU  - Shi YW
AD  - 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, China.
FAU - Ding, Jia-Hong
AU  - Ding JH
AD  - Department of Psychiatry, Li Ka Shing Faculty of Medicine, University of Hong 
      Kong, Hong Kong SAR, China.
FAU - Ng, Ching-Ching
AU  - Ng CC
AD  - Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of 
      Science, University of Malaya, Kuala Lumpur, Malaysia.
FAU - Chen, Zhibin
AU  - Chen Z
AD  - Department of Neuroscience, Central Clinical School, Alfred Hospital, Monash 
      University, Melbourne, Victoria, Australia.
AD  - Departments of Medicine and Neurology, Royal Melbourne Hospital, University of 
      Melbourne, Parkville, Victoria, Australia.
FAU - Baum, Larry
AU  - Baum L
AD  - Department of Psychiatry, Li Ka Shing Faculty of Medicine, University of Hong 
      Kong, Hong Kong SAR, China.
FAU - Cherny, Stacey
AU  - Cherny S
AD  - Department of Psychiatry, Li Ka Shing Faculty of Medicine, University of Hong 
      Kong, Hong Kong SAR, China.
AD  - Department of Epidemiology and Preventive Medicine, Tel Aviv University, Tel 
      Aviv, Israel.
FAU - Petrovski, Slave
AU  - Petrovski S
AD  - Epilepsy Research Centre, Department of Medicine, Austin Health, University of 
      Melbourne, Heidelberg, Victoria, Australia.
FAU - Sham, Pak C
AU  - Sham PC
AD  - Department of Psychiatry, Li Ka Shing Faculty of Medicine, University of Hong 
      Kong, Hong Kong SAR, China.
FAU - Lim, Kheng-Seang
AU  - Lim KS
AD  - Division of Neurology, Department of Medicine, Faculty of Medicine, University of 
      Malaya, Kuala Lumpur, Malaysia.
FAU - Liao, Wei-Ping
AU  - Liao WP
AUID- ORCID: 0000-0001-9929-9185
AD  - 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, China.
FAU - Kwan, Patrick
AU  - Kwan P
AUID- ORCID: 0000-0001-7310-276X
AD  - Department of Neuroscience, Central Clinical School, Alfred Hospital, Monash 
      University, Melbourne, Victoria, Australia.
AD  - 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, China.
AD  - Departments of Medicine and Neurology, Royal Melbourne Hospital, University of 
      Melbourne, Parkville, Victoria, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220216
PL  - United States
TA  - Epilepsia
JT  - Epilepsia
JID - 2983306R
RN  - 0 (Anticonvulsants)
RN  - 0 (HLA-B Antigens)
RN  - 0 (HLA-B15 Antigen)
RN  - 33CM23913M (Carbamazepine)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - *Anticonvulsants/adverse effects
MH  - Carbamazepine/adverse effects
MH  - DNA
MH  - Genetic Predisposition to Disease/genetics
MH  - HLA-B Antigens/genetics
MH  - HLA-B15 Antigen/genetics
MH  - Humans
MH  - Risk Factors
MH  - *Stevens-Johnson Syndrome/genetics
PMC - PMC9541367
OTO - NOTNLM
OT  - Han Chinese
OT  - Stevens-Johnson syndrome
OT  - antiseizure medications
OT  - cutaneous adverse drug reactions
OT  - genomics
COIS- Z.C. is supported by an Early Career Fellowship from the National Health and 
      Medical Research Council of Australia (GNT1156444), and he/his institution has 
      received consultancy fees and/or research grants from Arvelle Therapeutics and 
      UCB Pharma. None of the other authors has any conflict of interest to disclose.
EDAT- 2022/02/17 06:00
MHDA- 2022/04/14 06:00
PMCR- 2022/10/07
CRDT- 2022/02/16 05:52
PHST- 2022/01/22 00:00 [revised]
PHST- 2021/06/29 00:00 [received]
PHST- 2022/01/24 00:00 [accepted]
PHST- 2022/02/17 06:00 [pubmed]
PHST- 2022/04/14 06:00 [medline]
PHST- 2022/02/16 05:52 [entrez]
PHST- 2022/10/07 00:00 [pmc-release]
AID - EPI17182 [pii]
AID - 10.1111/epi.17182 [doi]
PST - ppublish
SO  - Epilepsia. 2022 Apr;63(4):936-949. doi: 10.1111/epi.17182. Epub 2022 Feb 16.