Allopurinol, a commonly prescribed medication for
gout and
hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (
SCAR), which include the
drug hypersensitivity syndrome,
Stevens-Johnson syndrome, and
toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify
genetic markers for
allopurinol-
SCAR, we carried out a case-control association study. We enrolled 51 patients with
allopurinol-
SCAR and 228 control individuals (135
allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to
drug metabolism and immune response. The initial screen revealed strong association between
allopurinol-
SCAR and SNPs in the MHC region, including BAT3 (encoding
HLA-B associated transcript 3), MSH5 (
mutS homolog 5), and MICB (MHC class I
polypeptide-related sequence B) (P < 10(-7)). We then determined the alleles of HLA loci A, B, C, and DRB1. The
HLA-B*5801 allele was present in all (100%) 51 patients with
allopurinol-
SCAR, but only in 20 (15%) of 135 tolerant patients [odds ratio 580.3 (95% confidence interval, 34.4-9780.9); corrected P value = 4.7 x 10(-24)] and in 19 (20%) of 93 of healthy subjects [393.51 (23.23-6665.26); corrected P value = 8.1 x 10(-18)]. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with
HLA-B*5801. Our results indicated that
allopurinol-
SCAR is strongly associated with a
genetic predisposition in Han Chinese. In particular,
HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.