Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese.
OBJECTIVE
Compared with other categories of drugs, such as antibiotics and NSAIDs, antiepileptic therapies are associated with a high incidence of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We previously reported that carbamazepine (CBZ)-SJS/TEN is strongly associated with the HLA-B*1502 in Han Chinese, which has been confirmed in other Southeast Asian countries where the allele is prevalent. Here, we extend the study of HLA susceptibility to three different antiepileptic drugs, phenytoin (PHT), lamotrigine (LTG) and oxcarbazepine (OXC), which have structure similarity to CBZ.


METHODS
We carried out a case-control association study. We enrolled 26 PHT-, six LTG- and three OXC-induced SJS/TEN patients, 113 PHT-tolerant and 67 LTG-tolerant subjects who were on the drug, respectively, for more than 3 months without the adverse reactions, and 93 normal subjects from the general population. The HLA-A, B, C and DRB1 genotypes were determined.


RESULTS
We found that HLA-B*1502 was present in eight out of 26 (30.8%) PHT-SJS/TEN (OR: 5.1; 95% CI: 1.8-15.1; p = 0.0041), two out of six (33%) LTG-SJS (odds ratio [OR]: 5.1; 95% CI: 0.8-33.8; p = 0.1266) and three out of three (100%) OXC-SJS (OR: 80.7; 95% CI: 3.8-1714.4; p = 8.4 x 10(-4)) patients. In addition, HLA-B*1301, Cw*0801 and DRB1*1602 also showed an association with PHT-SJS/TEN (p = 0.0128-0.0281; OR: 3.0-4.3).


CONCLUSIONS
Our results indicate that OXC, PHT and LTG, which possess an aromatic ring just as CBZ does, when causing SJS/TEN, share a common risk allele. Aromatic antiepileptic drugs causing SJS/TEN in HLA-B*1502 carriers may act on a similar pathogenetic mechanism, although other genetic/nongenetic factor(s) may also contribute to the pathomechanism of the disease. We suggest that aromatic antiepileptic drugs, including CBZ, OXC and PHT, should be avoided in the B*1502 carrier and caution should also be exercised for LTG.
Institute of Biomedical Sciences, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 11529, Taiwan.
Shuen-Iu
SI
Hung
Wen-Hung
WH
Chung
Zhi-Sheng
ZS
Liu
Chien-Hsiun
CH
Chen
Mo-Song
MS
Hsih
Rosaline Chung-yee
RC
Hui
Chia-Yu
CY
Chu
Yuan-Tsong
YT
Chen
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000927:Anticonvulsants / Q000009:adverse effects*; D044466:Asian People / Q000235:genetics; D002220:Carbamazepine / Q000009:adverse effects / Q000031:analogs & derivatives; D016022:Case-Control Studies; D002648:Child; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics* / Q000276:immunology; D005260:Female; D056726:Genetic Association Studies; D006680:HLA Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics*; D059910:HLA-B15 Antigen; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D000078330:Oxcarbazepine; D010597:Pharmacogenetics; D010672:Phenytoin / Q000009:adverse effects; D012307:Risk Factors; D013262:Stevens-Johnson Syndrome / Q000139:chemically induced* / Q000209:etiology* / Q000235:genetics* / Q000276:immunology; D013624:Taiwan; D014227:Triazines / Q000009:adverse effects; D055815:Young Adult
D000927:Anticonvulsants; D006680:HLA Antigens; D015235:HLA-B Antigens; C483536:HLA-B*15:02 antigen; D059910:HLA-B15 Antigen; D014227:Triazines; D002220:Carbamazepine; D010672:Phenytoin; D000077213:Lamotrigine; D000078330:Oxcarbazepine