HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
102
Journal Issue
11
Pages
4134-4139
Date Issued
2005
Author(s)
Hung S.-L.
Chung W.-H.
Liou L.-B.
Chu C.-C.
Lin M.
Huang H.-P.
Lin Y.-L.
Lan J.-L.
Yang L.-C.
Hong H.-S.
Chen M.-J.
Lai P.-C.
Wu M.-S.
Wang K.-H.
Chen C.-H.
Fann C.S.J.
Wu J.-Y.
Chen Y.-T.
Abstract
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 × 10-24] and in 19 (20%) of 93 of healthy subjects [393.51 (23.23-6665.26); corrected P value = 8.1 × 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. ? 2005 by The National Academy of Sciences of the USA.
SDGs
Other Subjects
allopurinol; HLA B antigen; major histocompatibility antigen class 1; protein MSH5; protein MutS; unclassified drug; allopurinol; antigout agent; HLA B antigen; HLA B*5801 antigen, human; HLA-B*5801 antigen, human; adult; aged; allele; article; controlled study; drug metabolism; female; gene linkage disequilibrium; genetic marker; genetic risk; genetic screening; haplotype; HLA B 5801 allele; human; immune response; major histocompatibility complex; male; priority journal; skin disease; gene frequency; genetic predisposition; genetics; hypersensitivity; immunology; metabolism; middle aged; single nucleotide polymorphism; skin disease; Aged; Aged, 80 and over; Allopurinol; Female; Gene Frequency; Genetic Predisposition to Disease; Gout Suppressants; Haplotypes; HLA-B Antigens; Humans; Hypersensitivity; Male; Middle Aged; Polymorphism, Single Nucleotide; Skin Diseases
Type
journal article