title: Impact of the HLA-B(*)58:01 Allele and Renal Impairment on Allopurinol-Induced Cutaneous Adverse Reactions.
abstract: Allopurinol, a common drug for treating hyperuricemia, is associated with cutaneous adverse drug reactions ranging from mild maculopapular exanthema to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We have previously reported that HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese, but the associations of the HLA-B*58:01 genotype in an allopurinol-induced hypersensitivity phenotype remain unclear. To investigate the comprehensive associations of HLA-B*58:01, we enrolled 146 patients with allopurinol-induced cutaneous adverse drug reactions (severe cutaneous adverse reactions, n = 106; maculopapular exanthema, n = 40) and 285 allopurinol-tolerant control subjects. Among these allopurinol-induced cutaneous adverse drug reactions, HLA-B*58:01 was strongly associated with severe cutaneous adverse reactions (odds ratio [OR] = 44.0; 95% confidence interval = 21.5-90.3; P = 2.6 × 10(-41)), and the association was correlated with disease severity (OR = 44.0 for severe cutaneous adverse reactions, OR = 8.5 for maculopapular exanthema). The gene dosage effect of HLA-B*58:01 also influenced the development of allopurinol-induced cutaneous adverse drug reactions (OR = 15.25 for HLA-B*58:01 heterozygotes and OR = 72.45 for homozygotes). Furthermore, coexistence of HLA-B*58:01 and renal impairment increased the risk and predictive accuracy of allopurinol-induced cutaneous adverse drug reactions (heterozygous HLA-B*58:01 and normal renal function: OR = 15.25, specificity = 82%; homozygous HLA-B*58:01 and severe renal impairment: OR = 1269.45, specificity = 100%). This HLA-B*58:01 correlation study suggests that patients with coexisting HLA-B*58:01 and renal impairment (especially estimated glomerular filtration rate < 30ml/minute/1.73 m(2)) should be cautious and avoid using allopurinol.
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chau Yee
authors.initials: CY
authors.lastname: Ng
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Yeh
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chuang-Wei
authors.initials: CW
authors.lastname: Wang
authors.affiliation: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shuen-Iu
authors.initials: SI
authors.lastname: Hung
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chih-Hsun
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Clinical Medical Science, Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan; Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Yu-Jr
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Graduate Institute of Clinical Medical Science, Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan; Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Chee-Jen
authors.initials: CJ
authors.lastname: Chang
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Shih-Chi
authors.initials: SC
authors.lastname: Su
authors.affiliation: Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Fan
authors.affiliation: Department of Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Der-Yuan
authors.initials: DY
authors.lastname: Chen
authors.affiliation: School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Division of Allergy, Immunology and Rheumatology, Department of Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Yeong-Jian Jan
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: Department of Nephrology, Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ya-Chung
authors.initials: YC
authors.lastname: Tian
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: ba1128@adm.cgmh.org.tw.
authors.forename: Rosaline Chung-Yee
authors.initials: RC
authors.lastname: Hui
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linko and Keelung, Taiwan; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan. Electronic address: wenhungchung@yahoo.com.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Chung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000493:Allopurinol / Q000009:adverse effects*; D002648:Child; D002681:China; D003875:Drug Eruptions / Q000473:pathology; D004802:Eosinophilia; D005076:Exanthema / Q000139:chemically induced / Q000473:pathology; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D015235:HLA-B Antigens / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D033461:Hyperuricemia / Q000209:etiology; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012372:ROC Curve; D012306:Risk; D012680:Sensitivity and Specificity; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D013262:Stevens-Johnson Syndrome / Q000473:pathology; D055815:Young Adult
chemical_list: D015235:HLA-B Antigens; C500126:HLA-B*58:01 antigen; D000493:Allopurinol