Investigation into the multidimensional genetic basis of drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis.
OBJECTIVE
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe blistering skin diseases, which are mainly caused by drugs. The two idiosyncratic conditions are distinguished on the basis of the degree of blistering, possibly representing diseases at different ends of the same spectrum. A genetic predisposition has been postulated.


METHODS
We have retrospectively identified a heterogeneous group of patients with SJS and TEN (n = 73 cases, 141 matched controls) induced by a number of marketed drugs and evaluated effector candidate genetic predisposition. We have used a multivariate genetic analysis method for the first time to handle the heterogeneity of clinical presentation, drug etiology, ethnicity and gender in these adverse events.


RESULTS
Our results show that predisposition varied according to ethnicity. There was a correlation for SJS with HLA-B*44, DRB1*07 and with the MHC ancestral 57.1 haplotype (and its constituents) in subjects who self-reported as Caucasians, which did not differ with gender. The HLA-DRB and -DRQ genetic predisposition to SJS seemed to be distinct from that of TEN, but further work is needed for both conditions to identify the causal variants. No conclusion concerning correlations with different drugs could be made because of small numbers in each drug group.


CONCLUSIONS
This study stresses the importance of accurate clinical phenotyping, exemplifies a novel analysis method to dissect complicated samples and calls for collaborative prospective studies.
Pirmohamed
Munir
M
The University of Liverpool, Department of Pharmacology and Therapeutics, Ashton Street, Liverpool, L69 3GE, UK.
Arbuckle
Julian B
JB
Bowman
Clive E
CE
Brunner
Margaret
M
Burns
Daniel K
DK
Delrieu
Olivier
O
Dix
Lynn P
LP
Twomey
John A
JA
Stern
Robert S
RS
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002220:Carbamazepine / Q000009:adverse effects; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D015235:HLA-B Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013262:Stevens-Johnson Syndrome / Q000139:chemically induced* / Q000209:etiology* / Q000235:genetics; D044465:White People
D015235:HLA-B Antigens; D006684:HLA-DR Antigens; D002220:Carbamazepine