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