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Human Leukocyte Antigen and Stevens-Johnson Syndrome
probably because in Caucasians the HLA-B12 Table 1: Carrier Frequency of Stevens-Johnson-
antigen is primarily coded by
syndrome-associated Alleles in Japanese and
HLA-B*4402 whereas in the Japanese
population it is almost exclusively coded by HLA-B*4403.
contrast, HLA-A*0206, strongly associated with SJS/TEN with ocular
complications in Japanese individuals, is absent in Caucasians. We
Allele Japanese Caucasians
detected no significant association between SJS/TEN and
SJS Control SJS Control
A*0206 42.3% 15.0% – (0~1.4%)
although HLA-DQB1*0601 was associated with ocular
B*4402 1.4% 0.0% – (6.7~26.5%)
complications in Caucasian SJS patients.
B*4403 22.5% 20.4% – (6.6~20.0%)
DQB1*0601 35.2% 27.4% 17% 3%
Thus, our findings suggest strong ethnic differences in the
( ): data from www.allelefrequencies.net/test/default1.asp
association of SJS/TEN with HLA (see Table 1). Because SJS/TEN is
SJS = Stevens-Johnson syndrome.
rare and probably has a complex genetic inheritance background,
Table 2: Carrier Frequency of Drug-induced
specific combinations of genes and certain environmental factors
Stevens-Johnson-syndrome-associated Alleles in
may be required for the manifestation of this rare phenotype.
Taiwanese and Caucasian Patients
Drugs and Human Leukocyte Antigen
Allele Taiwanese Caucasian
The association between HLA and drug-induced severe cutaneous
Drug-induced Control Drug-induced Control
adverse reactions including SJS and TEN has been reported. The HLA-
B*1502 allele showed a very strong association with carbamazepine-
Carbamazepine 100% 8.6% 0% (0~0.2%)
induced SJS/TEN in the Han Chinese of Taiwan.
In that study,
dermatologists examined 44 patients with carbamazepine-induced
Allopurinol 100% 20% 55% 1.5%
SJS. They found that the frequency of HLA-B*1502 was significantly B*5801
increased compared with a carbamazepine-tolerant control group of
( ): data from www.allelefrequencies.net/test/default1.asp
101 individuals (100 versus 3%; pc=3.13x10
; OR 2504) and a control
SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis.
population consisting of 93 normal subjects (8.6%; pc=1.38x10
; OR patients. Thus, the strong allopurinol-specific association between
In supplemental data, they showed that 28 of the 44 patients HLA-B*5801 and allopurinol-induced severe cutaneous adverse
(63.6%) manifested ocular surface erosion.
In contrast, no such reactions including SJS, TEN and DIHS may be universal (see Table 2).
strong carbamazepine-specific association between HLA-B*1502 and
carbamazepine-induced SJS/TEN was found in Caucasian patients.
and French dermatologists
In our study of 71 Japanese SJS/TEN patients with ocular complications documented that the HLA-B12 (HLA-Bw44) antigen was significantly
and 113 Japanese controls, we did not detect HLA-B*1502 in either increased in Caucasian SJS patients. However, in our Japanese study
because the allele frequency of HLA-B*1502 is very low in population there was no association with HLA-B12, probably because
Japanese individuals. We suggest that the carbamazepine-specific in Caucasians the HLA-B12 antigen is primarily coded by HLA-
association between HLA and carbamazepine-induced SJS may also B*4402, whereas in the Japanese it is almost exclusively coded by
be specific to certain ethnic groups (see
Table 2). HLA-B*4403. In contrast, while HLA-A*0206 was strongly associated
with SJS/TEN with ocular complications in Japanese patients,
Another Taiwanese study showed that HLA-B*5801 was present in absent in Caucasian populations. Thus, HLA-A*0206 may be related
all Han Chinese with allopurinol-induced SJS/TEN and drug-induced to Japanese ethnicity. These findings suggest strong ethnic
All 51 patients with allopurinol-induced differences in the HLA-SJS/TEN association and point to the need for
severe cutaneous reactions including SJS, TEN and DIHS carried studies in other ethnic populations to obtain a global picture.
HLA-B*5801 compared with 20 of 135 (15%) allopurinol-tolerant
; OR=580) and 19 of 93 (20%) controls drawn With respect to the association between HLA and drug-induced
from the general population (pc=8.1x10
Of the 51 severe cutaneous adverse reactions (SCAR), including SJS and TEN,
patients, 21 (41%) manifested ocular surface erosion.
Lonjou et the association between the HLA-B*1502 allele and carbamazepine-
also reported an association between HLA-B*5801 and induced SJS/TEN
and between the HLA-B*5801 allele and
allopurinol-induced SJS/TEN: 15 of 27 European patients (56%) allopurinol-induced severe cutaneous adverse reactions
with allopurinol-related SJS/TEN had HLA-B*5801 compared with 28 been reported.
of 1,822 individuals (1.5%) from a mixed European population
; OR 80).
In Han Chinese
but not in Caucasian patients,
there was a
strong carbamazepine-specific association between HLA-B*1502
Neither our 71 Japanese SJS/TEN patients with ocular complications and carbamazepine-induced SJS/TEN. We did not identify HLA-
nor our 113 Japanese controls manifested HLA-B*5801,
because B*1502 in either our Japanese SJS/TEN patients or our controls,
the allele frequency of HLA-B*5801 is very low in Japanese because the allele frequency of HLA-B*1502 is very low in the
individuals. None of our 71 patients had allopurinol-related SJS/TEN Japanese. Thus, the carbamazepine-specific association between
(Ueta et al., unpublished data). In contrast, the Japanese HLA and carbamazepine-induced SJS may be specific to certain
dermatologist Dainichi and colleagues
identified three HLA-B*5801 ethnic groups.
carriers among patients with allopurinol-associated SJS, DIHS and
SJS/TEN. These findings suggest that HLA-B*5801 may represent a An allopurinol-specific association between HLA-B*5801 and
genetic biomarker for allopurinol-associated SJS/TEN in Japanese allopurinol-induced SCAR was identified in all Han Chinese,
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