HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol.
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.
Hung
Shuen-Iu
SI
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
Chung
Wen-Hung
WH
Liou
Lieh-Bang
LB
Chu
Chen-Chung
CC
Lin
Marie
M
Huang
Hsien-Ping
HP
Lin
Yen-Ling
YL
Lan
Joung-Liang
JL
Yang
Li-Cheng
LC
Hong
Hong-Shang
HS
Chen
Ming-Jing
MJ
Lai
Ping-Chin
PC
Wu
Mai-Szu
MS
Chu
Chia-Yu
CY
Wang
Kuo-Hsien
KH
Chen
Chien-Hsiun
CH
Fann
Cathy S J
CS
Wu
Jer-Yuarn
JY
Chen
Yuan-Tsong
YT
D000368:Aged; D000369:Aged, 80 and over; D000493:Allopurinol / Q000276:immunology*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006074:Gout Suppressants / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012871:Skin Diseases / Q000209:etiology / Q000235:genetics / Q000276:immunology*
D006074:Gout Suppressants; D015235:HLA-B Antigens; C500126:HLA-B*58:01 antigen; D000493:Allopurinol
Rheumatology (Oxford). 1999 Dec;38(12):1301
10587570
Ann Hum Genet. 1956 May;20(4):309-11
13314400
Nucleic Acids Res. 2000 Jan 1;28(1):352-5
10592272
Ann Rheum Dis. 2001 Oct;60(10):981-3
11557658
Tissue Antigens. 2001 Jul;58(1):9-18
11580850
Lancet. 2002 Mar 2;359(9308):727-32
11888582
Curr Opin Rheumatol. 2002 May;14(3):281-6
11981327
Am J Kidney Dis. 2002 Jul;40(1):37-42
12087559
J Natl Cancer Inst. 2002 Dec 4;94(23):1780-9
12464650
Am J Pathol. 2003 May;162(5):1515-20
12707034
Am J Hum Genet. 2003 Sep;73(3):580-90
12920676
N Engl J Med. 2003 Oct 23;349(17):1647-55
14573737
Cancer Res. 2003 Nov 1;63(21):7475-82
14612548
Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4180-5
15024131
Nature. 2004 Apr 1;428(6982):486
15057820
N Engl J Med. 1973 Apr 5;288(14):704-6
4688372
Lancet. 1973 Apr 28;1(7809):904-7
4123836
Arch Intern Med. 1974 Sep;134(3):553-8
4546912
Am J Med. 1984 Jan;76(1):47-56
6691361
Br Med J (Clin Res Ed). 1985 Jun 29;290(6486):1969-70
3924329
Tissue Antigens. 1986 Oct;28(4):251-4
3544335
Arch Dermatol. 1987 Sep;123(9):1171-3
3477129
Dermatologica. 1989;179(1):32-3
2527769
Ann Pharmacother. 1993 Mar;27(3):337-43
8453174
Clin Immunol Immunopathol. 1994 Feb;70(2):145-51
8299230
J Invest Dermatol. 1994 Jun;102(6):28S-30S
8006430
JAMA. 1995 Feb 15;273(7):586-91
7837393
N Engl J Med. 1995 Dec 14;333(24):1600-7
7477195
N Engl J Med. 1996 Feb 15;334(7):445-51
8552148
Arch Ophthalmol. 1997 Apr;115(4):550-3
9109770
J Biol Chem. 1997 Jul 25;272(30):18542-5
9228018
Arch Dermatol. 1998 Sep;134(9):1108-12
9762023
J Clin Invest. 1998 Oct 15;102(8):1591-8
9788973
Am J Epidemiol. 1999 Apr 15;149(8):706-11
10206619