HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol

Shuen Lu Hung; Wen Hung Chung; Lieh Bang Liou; Chen Chung Chu; Marie Lin; Hsien Ping Huang; Yen Ling Lin; Joung Liang Lan; Li Cheng Yang; Hong Shang Hong; Ming Jing Chen; Ping Chin Lai; Mai Szu Wu; Chia Yu Chu; Kuo Hsien Wang; Chien Hsiun Chen; Cathy S.J. Fann; Jer Yuarn Wu; Yuan Tsong Chen

doi:10.1073/pnas.0409500102

HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol

Shuen Lu Hung, Wen Hung Chung, Lieh Bang Liou, Chen Chung Chu, Marie Lin, Hsien Ping Huang, Yen Ling Lin, Joung Liang Lan, Li Cheng Yang, Hong Shang Hong, Ming Jing Chen, Ping Chin Lai, Mai Szu Wu, Chia Yu Chu, Kuo Hsien Wang, Chien Hsiun Chen, Cathy S.J. Fann, Jer Yuarn Wu, Yuan Tsong Chen

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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.

Original language	English
Pages (from-to)	4134-4139
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	102
Issue number	11
DOIs	https://doi.org/10.1073/pnas.0409500102
Publication status	Published - Mar 15 2005
Externally published	Yes

Keywords

Adverse drug reactions
Genetic polymorphism
Pharmacogenetics
Stevens-Johnson syndrome
Toxic epidermal necrolysis

ASJC Scopus subject areas

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10.1073/pnas.0409500102

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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., Chu, C. Y., Wang, K. H., Chen, C. H., Fann, C. S. J., Wu, J. Y., & Chen, Y. T. (2005). HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proceedings of the National Academy of Sciences of the United States of America, 102(11), 4134-4139. https://doi.org/10.1073/pnas.0409500102

Hung, SL, Chung, WH, Liou, LB, Chu, CC, Lin, M, Huang, HP, Lin, YL, Lan, JL, Yang, LC, Hong, HS, Chen, MJ, Lai, PC, Wu, MS, Chu, CY, Wang, KH, Chen, CH, Fann, CSJ, Wu, JY & Chen, YT 2005, 'HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 11, pp. 4134-4139. https://doi.org/10.1073/pnas.0409500102

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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 × 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.",

keywords = "Adverse drug reactions, Genetic polymorphism, Pharmacogenetics, Stevens-Johnson syndrome, Toxic epidermal necrolysis",

author = "Hung, {Shuen Lu} and Chung, {Wen Hung} and Liou, {Lieh Bang} and Chu, {Chen Chung} and Marie Lin and Huang, {Hsien Ping} and Lin, {Yen Ling} and Lan, {Joung Liang} and Yang, {Li Cheng} and Hong, {Hong Shang} and Chen, {Ming Jing} and Lai, {Ping Chin} and Wu, {Mai Szu} and Chu, {Chia Yu} and Wang, {Kuo Hsien} and Chen, {Chien Hsiun} and Fann, {Cathy S.J.} and Wu, {Jer Yuarn} and Chen, {Yuan Tsong}",

year = "2005",

month = mar,

day = "15",

doi = "10.1073/pnas.0409500102",

language = "English",

volume = "102",

pages = "4134--4139",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

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T1 - HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol

AU - Hung, Shuen Lu

AU - Chung, Wen Hung

AU - Liou, Lieh Bang

AU - Chu, Chen Chung

AU - Lin, Marie

AU - Huang, Hsien Ping

AU - Lin, Yen Ling

AU - Lan, Joung Liang

AU - Yang, Li Cheng

AU - Hong, Hong Shang

AU - Chen, Ming Jing

AU - Lai, Ping Chin

AU - Wu, Mai Szu

AU - Chu, Chia Yu

AU - Wang, Kuo Hsien

AU - Chen, Chien Hsiun

AU - Fann, Cathy S.J.

AU - Wu, Jer Yuarn

AU - Chen, Yuan Tsong

PY - 2005/3/15

Y1 - 2005/3/15

N2 - 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.

AB - 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.

KW - Adverse drug reactions

KW - Genetic polymorphism

KW - Pharmacogenetics

KW - Stevens-Johnson syndrome

KW - Toxic epidermal necrolysis

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HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol

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