Allopurinol&HLA-B*5801



Scientific Studies & Publication
Allopurinol & HLA-B*5801
2011 \| 2009 \| 2008 \| 2007 \| 2005

2011
*Title 1 : Association of HLA-B5801 Allele and Allopurinol-Induced Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: A Systematic Review and Meta-analysis BMC Medical Genetics 2011, 12:118 Ratchadaporn Somkrua, Elizabeth E. Eickman, Surasak Saokaew, Manupat Lohitnavy, Nathorn Chaiyakunapruk Background:*Despite some studies suggesting a possible association between human leukocyte antigen,HLA-B5801 and allopurinol induced Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), the evidence of association and its magnitude remain inconclusive. This study aims to systematically review and meta-analyze the association between HLA-B*5801 allele and allopurinol-induced SJS/TEN.
Methods:A comprehensive search was performed in databases including MEDLINE, Pre-MEDLINE, Cochrane Library, EMBASE, International Pharmaceutical Abstracts (IPA), CINAHL, PsychInfo, the WHO International, Clinical Trial Registry, and ClinicalTrial.gov from their inceptions to June 2011. Only studies investigating association between HLA-B5801 with allopurinol-induced SJS/TEN were included. All studies were extracted by two independent authors. The primary analysis was the carrier frequency of HLA-B5801 comparison between allopurinol-induced SJS/TEN cases and each comparative group. The pooled odds ratios were calculated using a random effect model.
Results:A total of 4 studies with 55 SJS/TEN cases and 678 matched-controls (allopurinol-tolerant control) was identified, while 5 studies with 69 SJS/TEN cases and 3378 population-controls (general population) were found. SJS/TEN cases were found to be significantly associated with HLA-B*5801 allele in both groups of studies with matched-control (OR 96.60, 95%CI 24.49-381.00, p<0.001) and population-control (OR 79.28, 95%CI 41.51-151.35, p< 0.001). Subgroup analysis for Asian and Non-Asian population yielded similar findings.
Conclusions: We found a strong and significant association between HLA-B5801 and allopurinol-induced SJS/TEN. Therefore, HLA-B5801 allele screening may be considered in patients who will be treated with allopurinol.


Title 2 : HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency Nephrol Dial Transplant (2011) 0: 1–6 Jae-Woo Jung, Woo-Jung Song, Yon-Su Kim, Kwon Wook Joo, Kyung Wha Lee, Sae-Hoon Kim, Heung-Woo Park, Yoon-Seok Chang, Sang-Heon Cho, Kyung-Up Min and Hye-Ryun Kang Background:Although allopurinol is a very effective urate-lowering drug for complicated hyperuricemia, in some patients, it can induce severe cutaneous adverse reactions (SCARs). Recent investigations suggest that HLA-B5801 is a very strong marker for allopurinol-induced SCARs, especially in the population with a high frequency of HLA-B5801. Korea is one of the countries with a high frequency of HLA-B*5801 which is the only subtype of HLA-B58 in the Korean population.
Objective:This study was conducted to find out the incidence of allopurinol-induced hypersensitivity on patients with chronic renal insufficiency (CRI) according to HLA-B58 and the clinical implications of HLA-B58 as a risk marker for the development of allopurinol-induced hypersensitivity.
Methods:We retrospectively reviewed the medical records of patients with CRI who took allopurinol and carried out serologic human leukocyte antigen (HLA) typing for kidney transplantation between January 2003 and May 2010.
Results:Among a total of 448 patients with CRI, 16 (3.6%) patients experienced allopurinol hypersensitivity. Nine of these patients (2.0%) were diagnosed with SCARs (two Stevens–Johnson syndrome and seven allopurinol hypersensitivity syndrome) and seven patients (1.6%) had simple maculopapular rashes. The HLA-B58 allele was present in all patients with allopurinol-induced SCARs, while the frequency of HLA-B58 was only 9.5% in allopurinol-tolerant patients (P < 0.05). The incidence of allopurinol-induced SCARs in CRI shows a wide disparity according to HLA-B58 [18% in HLA-B58 (+) versus 0% in HLA-B58 (－)]. Among patients without HLA-B*58, most (98.2%) of the CRI patients were tolerant to allopurinol and only 1.8% experienced simple rashes after taking allopurinol.
Conclusions:In this study, the incidence of allopurinol induced SCARs was considerably high in CRI patients with HLA-B*58. This finding indicates that the presence of HLA-B58 may increase the risk of allopurinol-induced SCARs. Screening tests for HLA-B58 in CRI patients will be clinically helpful in preventing severe allopurinol hypersensitivity reactions.


2009
Title 1 : Polymorphisms of HLA genes in Western Javaness (Indonesia): close affinities to Southeast Asian populations Tissue Antigens. 2009 Jan;73(1):46-53. Yuliwulandari R, Kashiwase K, Nakajima H, Uddin J, Susmiarsih TP, Sofro AS, Tokunaga K. Identification of human leukocyte antigen (HLA) antigens that are known as the highest polymorphic genes has become a valuable tool for tissue transplantation, platelet transfusion, disease susceptibility or resistance, and forensic and anthropological studies. In the present study, the allele and haplotype frequencies of HLA-A, HLA-B, and HLA-DRB1 were studied in 237 unrelated healthy Western Javanese (Indonesia) by the high-resolution polymerase chain reaction-Luminex method. A total of 18 A, 40 B, and 20 DRB1 alleles were identified. The most frequent HLA-A, -B, and -DRB1 alleles were HLA-A2407 (21.6%), HLA-B1502 (11.6%) and HLA-B1513 (11.2%), and DRB11202 (37.8%), respectively. The most frequent two-locus haplotypes were HLA-A2407-B3505 (7%) and HLA-B1513-DRB11202 (9.2%), and three-locus haplotypes were HLA-A3401-B1521-DRB1150201 (4.6%), HLA-A2407-B3505-DRB11202 (4.3%), and HLA-A330301-B440302-DRB1*070101 (4.2%). HLA allele and haplotype frequencies in addition to phylogenetic tree and principal component analyses based on the four-digit sequence-level allele frequencies for HLA-A, HLA-B, and HLA-DRB1 showed that Western Javanese (Indonesia) was closest to Southeast Asian populations.


*Title 2 : Strong association between HLA-B5801 and allopurinol induced Stevens–Johnson syndrome and toxic epidermal necrolysis in a Thai population Pharmacogenet Genomics. 2009 Sep;19(9):704-9. Tassaneeyakul W, Jantararoungtong T, Chen P, Lin PY, Tiamkao S, Khunarkornsiri U, Chucherd P, Konyoung P, Vannaprasaht S, Choonhakarn C, Pisuttimarn P, Sangviroon A, Tassaneeyakul W. Objective:*Allopurinol, a uric acid lowering drug commonly used for hyperuricemia and gouty arthritis, has been reported as a common cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between allopurinol-induced SCAR and HLA-B5801 was observed in a Han Chinese population with high frequency of this allele, whereas only a moderate association was observed in populations with low frequency (i.e. European and Japanese). This study investigated the relationship between SJS/TEN and HLA-B*5801 in a Thai population that has a high allelic frequency of this allele.
Methods: Twenty-seven allopurinol-induced SJS/TEN and 54 allopurinol-tolerant patients were enrolled in the study. The presence of HLA-B*5801 and HLA-B genotypes in these patients were analyzed using a PG5801 DNA detection kit and sequence-based typing, respectively.
Results:All of the 27 (100%) allopurinol-induced SJS/TEN patients who were examined carried HLA-B5801 whereas only seven (12.96%) of the control patients had this allele. The risk of allopurinol-induced SJS/TEN was significantly greater in patients with HLA-B5801 when compared with those who did not carry this allele, with an odds ratio of 348.3 (95% confidence interval=19.2-6336.9, P = 1.6 x10). The sensitivity and specificity of the HLA-B5801 allele for prediction of allopurinol-induced SJS/TEN were 100 and 87%, respectively. By assuming a 0.2% prevalence rate, the positive predictive value and the negative predictive value of the HLA-B5801 allele was 1.52 and 100%, respectively.
Conclusions:A strong association of allopurinol-induced SJS/TEN with the HLA-B5801 allele was observed in a Thai population. The results suggest that HLA-B5801 is a valid genetic marker for screening Thai individuals who may be at risk for allopurinol-induced life-threatening SJS and TEN.


*Title 3 : Strong association between HLA-B5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population Pharmacogenet Genomics. 2009 Sep;19(9):704-9. Tassaneeyakul W, Jantararoungtong T, Chen P, Lin PY, Tiamkao S, Khunarkornsiri U, Chucherd P, Konyoung P, Vannaprasaht S, Choonhakarn C, Pisuttimarn P, Sangviroon A, Tassaneeyakul W. Objective:** Allopurinol, a uric acid lowering drug commonly used for hyperuricemia and gouty arthritis, has been reported as a common cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between allopurinol-induced SCAR and HLA-B5801 was observed in a Han Chinese population with high frequency of this allele, whereas only a moderate association was observed in populations with low frequency (i.e. European and Japanese). This study investigated the relationship between SJS/TEN and HLA-B5801 in a Thai population that has a high allelic frequency of this allele.
Methods: Twenty-seven allopurinol-induced SJS/TEN and 54 allopurinol-tolerant patients were enrolled in the study. The presence of HLA-B*5801 and HLA-B genotypes in these patients were analyzed using a PG5801 DNA detection kit and sequence-based typing, respectively.
Results:All of the 27 (100%) allopurinol-induced SJS/TEN patients who were examined carried HLA-B5801 whereas only seven (12.96%) of the control patients had this allele. The risk of allopurinol-induced SJS/TEN was significantly greater in patients with HLA-B5801 when compared with those who did not carry this allele, with an odds ratio of 348.3 (95% confidence interval=19.2-6336.9, P = 1.6 x10). The sensitivity and specificity of the HLA-B5801 allele for prediction of allopurinol-induced SJS/TEN were 100 and 87%, respectively. By assuming a 0.2% prevalence rate, the positive predictive value and the negative predictive value of the HLA-B5801 allele was 1.52 and 100%, respectively.
Conclusions: A strong association of allopurinol-induced SJS/TEN with the HLA-B5801 allele was observed in a Thai population. The results suggest that HLA-B5801 is a valid genetic marker for screening Thai individuals who may be at risk for allopurinol-induced life-threatening SJS and TEN.


2008
Title 1 : Pharmacogenetic information derived from analysis of HLA alleles Pharmacogenomics. 2008 Feb;9(2):207-14. Gatanaga H, Honda H, Oka S. A large amount of pharmacogenetic information has, in particular, accumulated on the association between human leukocyte antigen (HLA) alleles and hypersensitivity to certain drugs. Prospective HLA typing has dramatically reduced the risk of abacavir hypersensitivity because of its strong association with HLA-B5701. Significant predisposition to nevirapine hypersensitivity has been reported in Caucasian Australians harboring HLA-DRB10101 with high CD4+ T-cell counts, and Sardinians and Japanese harboring HLA-Cw8. A strong association between carbamazepine hypersensitivity and HLA-B1502 has been reported in Han Chinese. Most Han Chinese individuals with allopurinol-induced severe cutaneous adverse reactions are positive for HLA-B5801. HLA typing can stratify risk of hypersensitivity to certain drugs and allow personalized treatment, although the patients should be monitored closely even if they are negative for HLA alleles associated with hypersensitivity.


Title 2 : HLA-B locus in in Japanese patients with anti-epileptics and allopurinol related Stevens-Johnson syndrome and toxic epidermal necrolysis Pharmacogenomics. 2008 Nov;9(11):1617-22. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, Sawada J, Furuya H, Takahashi Y, Muramatsu M, Kinoshita S, Abe M, Ikeda H, Kashiwagi M, Song Y, Ueta M, Sotozono C, Ikezawa Z, Hasegawa R; JSAR research group. Introduction : Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B1502 and HLA-B5801 with carbamazepine- and allopurinol-induced severe cutaneous adverse reactions were found in Han Chinese patients, respectively, but ethnic differences in the associations have been reported. The objective of this study is to clarify the involvement of HLA-B1502 and HLA-B5801 in Japanese SJS/TEN patients..
Methods: HLA-B genotyping was performed on 58 Japanese SJS/TEN patients between July 2006 and April 2008 from multicenters in Japan.
Results: There were no HLA-B1502 carriers among 58 SJS/TEN patients. This patient group included seven carbamazepine-related and 11 aromatic anti-epileptic agent-related SJS/TEN patients. In addition, there were five HLA-B5801 carriers, which included four allopurinol-related SJS/TEN patients.
Conclusion: While HLA-B1502 is unlikely to be associated with carbamazepine-related or aromatic anti-epileptic agent-related SJS/TEN, HLA-B5801 was significantly associated with allopurinol-related SJS/TEN in Japanese.


Title 3 : A European study of HLA-B in Stevens–Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs Pharmacogenet Genomics. 2008 Feb;18(2):99-107. Lonjou C, Borot N, Sekula P, Ledger N, Thomas L, Halevy S, Naldi L, Bouwes-Bavinck JN, Sidoroff A, de Toma C, Schumacher M, Roujeau JC, Hovnanian A, Mockenhaupt M; RegiSCAR study group. Background:Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are rare but life-threatening cutaneous adverse reactions to drugs, especially to allopurinol, carbamazepine, lamotrigine, phenobarbital, phenytoine, sulfamethoxazole, oxicam and nevirapine. Recently, a strong association between carbamazepine and allopurinol induced SJS or TEN has been described with respectively, HLA-B1502 and HLA-B5801 in a Han Chinese population from Taiwan and other Asian countries.
Objective:The objective is to further investigate the relationship between SJS/TEN and HLA-B in a large number of patients in a European population.
Methods:HLA-B genotyping was performed on 150 patients included in a European study (RegiSCAR) of SJS and TEN. We focused on patients related to 'high-risk' drugs including: 31 cases related to allopurinol, 28 to sulfamethoxazole, 19 to lamotrigine and 14 to oxicam.
Results:Sixty-one percent of 31 allopurinol-induced SJS/TEN patients carried the HLA-B5801 allele and the figure was 55% for 27 patients of European ancestry [odds ratio=80 (34-187)], (P<10(-6)) as previously observed in Han Chinese. For other drugs, two rare alleles showed a weaker association with SJS/TEN in a limited number of patients: B38 for sulfamethoxazole or lamotrigine-related patients, and B*73 for oxicam.
Conclusions:At variance with prior results in Asia, this study shows that even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease. Further investigations are necessary to delineate the exact role of the HLA region in SJS/TEN, and to look for other associations in other regions of the genome.


Title 4 : Pharmacogenetics determinants of immediate and delayed reactions of drug hypersensitivitys Curr Pharm Des. 2008;14(27):2770-7. Guéant JL, Guéant-Rodriguez RM, Gastin IA, Cornejo-García JA, Viola M, Barbaud A, Mertes PM, Blanca M, Romano A. Drug allergy refers to a hypersensitivity reaction for which either an IgE or T-cell-mediated mechanism is demonstrated. The recognition of the drug by B and T cells is influenced by variants of HLA genes. The genetic factors involved in IgE-mediated mechanisms have been studied mainly in beta-lactam reactions, and they appear to be related to human leukocyte antigen presentation (HLA A2 and DRw52), TNFA -308G>A, class switching to IgE by B cells (variants of IL-13 and of IL-4RA), and expression of IgE receptors on target cells (variant of the FcepsilonRIbeta gene). Delayed T-cell-mediated reactions are also associated with HLA alleles. Studies have reported an association of HLA-B1502 and HLA-B5801 in patients with the Stevens-Johnson syndrome or toxic epidermal necrolysis provoked by carbamazepine, as well as of HLA-B5701 with abacavir hypersensitivity. HLA-B5701 seems to be a strong predictor in whites, but not in Hispanics or Africans. Carbamazepine hypersensitivity is also influenced by gene variants of cytochrome P450 enzymes on the generation of reactive metabolites, while CYP2C92 and CYP2C93 polymorphisms influence the bioactivation of sulfamethoxazole in prohapten. Pharmacogenetic studies on aspirin hypersensitivity have identified distinct types of predictors, such as HLA genotypes, a polymorphism in the promoter of the FcepsilonRIalpha gene, and variants in genes of enzymes from the arachidonic acid pathway. In the future, identification of genetic predictors will benefit from genomewide association studies that also take ethnic differences into account. Ideally, predictors will help to prevent adverse reactions, as suggested by a recent study on the effectiveness of prospective HLA-B*5701 screening to prevent hypersensitivity reactions to abacavir in HIV patients.


Title 5 : HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis Pharmacogenomics. 2008 Nov;9(11):1617-22. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, Sawada J, Furuya H, Takahashi Y, Muramatsu M, Kinoshita S, Abe M, Ikeda H, Kashiwagi M, Song Y, Ueta M, Sotozono C, Ikezawa Z, Hasegawa R; JSAR research group. Introduction : Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B1502 and HLA-B5801 with carbamazepine- and allopurinol-induced severe cutaneous adverse reactions were found in Han Chinese patients, respectively, but ethnic differences in the associations have been reported. The objective of this study is to clarify the involvement of HLA-B1502 and HLA-B5801 in Japanese SJS/TEN patients.
Methods : HLA-B genotyping was performed on 58 Japanese SJS/TEN patients between July 2006 and April 2008 from multicenters in Japan.
Results : There were no HLA-B1502 carriers among 58 SJS/TEN patients. This patient group included seven carbamazepine-related and 11 aromatic anti-epileptic agent-related SJS/TEN patients. In addition, there were five HLA-B5801 carriers, which included four allopurinol-related SJS/TEN patients.
Conclusion: While HLA-B1502 is unlikely to be associated with carbamazepine-related or aromatic anti-epileptic agent-related SJS/TEN, HLA-B5801 was significantly associated with allopurinol-related SJS/TEN in Japanese.


2007
Title 1 : Human leukocyte antigens and drug hypersensitivity Allergy and clinical immunology Current Opinion in Allergy & Clinical Immunology: August 2007 - Volume 7 - Issue 4 - p 317-323 Chung, Wen-Hung; Hung, Shuen-Iu; Chen, Yuan-Tsong Purpose of review:The present article reviews the recent literature on the identification of human leukocyte antigen (HLA) alleles as major susceptible genes for drug hypersensitivity and discusses the clinical implications.
Recent findings: Several recent studies have reported strong genetic associations between HLA alleles and susceptibility to drug hypersensitivity. The genetic associations can be drug specific, such as HLA-B1502 being associated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), HLA-B5701 with abacavir hypersensitivity and HLA-B5801 with allopurinol-induced severe cutaneous adverse reactions. A genetic association can also be phenotype-specific, as B1502 is associated solely with carbamazepine-SJS/TEN, and not with either maculopapular eruption or hypersensitivity syndrome. Furthermore, a genetic association can also be ethnicity specific; carbamazepine-SJS/TEN associated with B*1502 is seen in south-east Asians but not in whites, which may be explained by the different allele frequencies.
Summary:The strong genetic association suggests a direct involvement of HLA in the pathogenesis of drug hypersensitivity when the HLA molecule presents an antigenic drug for T cell activation. The high sensitivity/specificity of some markers provides a plausible basis for developing tests to identify individuals at risk for drug hypersensitivity. Application of HLA-B*1502 genotyping as a screening tool before prescribing carbamazepine could be a valuable tool in preventing carbamazepine-induced SJS/TEN in south-east Asian countries.


Title 2 : Stevens-Johnson syndrome, drug-induced hypersensitivity syndrome and toxic epidermal necrolysis caused by allopurinol in patients with a common HLA allele: what causes the diversity? Dermatology. 2007;215(1):86-8. Dainichi T, Uchi H, Moroi Y, Furue M. We have confirmed that SJS, TEN and DIHS/DRESS caused by allopurinol affect patients who have the serological HLA type B58 in common. B58 is exclusively associated with the HLA-B* 5801 allele and is extremely rare in the Japanese population (≦ 0.6%). It has been shown that the HLA-B * 5801 allele was present in all 51 patients with allopurinol-induced severe cutaneous adverse reactions in Taiwan. Another common HLA allele in the present cases, A33 (A * 3303), is in linkage disequilibrium and forms an extended haplotype with B * 5801. The latest report indicates that the HLA-B * 5801 allele is present in 61% of patients who suffer from allopurinol-induced severe adverse drug effects in Europe. Despite regional and ethnic differences, HLA-B * 5801 is undeniably a common key to the pathogenesis of SJS, TEN and DIHS/DRESS induced by allopurinol.


2005
*Title 1 : HLA-B5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol** Proc Natl Acad Sci U S A. 2005 March 15; 102(11): 4134–4139 Hung SI, 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 CS, Wu JY, Chen YT. 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-B5801 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 A3303, Cw0302, and DRB10301 were in linkage disequilibrium and formed an extended haplotype with HLA-B5801. Our results indicated that allopurinol-SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B5801 allele is an important genetic risk factor for this life-threatening condition.



Scientific Studies & Publication
Allopurinol & HLA-B*5801
2011 \| 2009 \| 2008 \| 2007 \| 2005

2011
*Title 1 : Association of HLA-B5801 Allele and Allopurinol-Induced Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: A Systematic Review and Meta-analysis BMC Medical Genetics 2011, 12:118 Ratchadaporn Somkrua, Elizabeth E. Eickman, Surasak Saokaew, Manupat Lohitnavy, Nathorn Chaiyakunapruk Background:*Despite some studies suggesting a possible association between human leukocyte antigen,HLA-B5801 and allopurinol induced Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), the evidence of association and its magnitude remain inconclusive. This study aims to systematically review and meta-analyze the association between HLA-B*5801 allele and allopurinol-induced SJS/TEN.
Methods:A comprehensive search was performed in databases including MEDLINE, Pre-MEDLINE, Cochrane Library, EMBASE, International Pharmaceutical Abstracts (IPA), CINAHL, PsychInfo, the WHO International, Clinical Trial Registry, and ClinicalTrial.gov from their inceptions to June 2011. Only studies investigating association between HLA-B5801 with allopurinol-induced SJS/TEN were included. All studies were extracted by two independent authors. The primary analysis was the carrier frequency of HLA-B5801 comparison between allopurinol-induced SJS/TEN cases and each comparative group. The pooled odds ratios were calculated using a random effect model.
Results:A total of 4 studies with 55 SJS/TEN cases and 678 matched-controls (allopurinol-tolerant control) was identified, while 5 studies with 69 SJS/TEN cases and 3378 population-controls (general population) were found. SJS/TEN cases were found to be significantly associated with HLA-B*5801 allele in both groups of studies with matched-control (OR 96.60, 95%CI 24.49-381.00, p<0.001) and population-control (OR 79.28, 95%CI 41.51-151.35, p< 0.001). Subgroup analysis for Asian and Non-Asian population yielded similar findings.
Conclusions: We found a strong and significant association between HLA-B5801 and allopurinol-induced SJS/TEN. Therefore, HLA-B5801 allele screening may be considered in patients who will be treated with allopurinol.


Title 2 : HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency Nephrol Dial Transplant (2011) 0: 1–6 Jae-Woo Jung, Woo-Jung Song, Yon-Su Kim, Kwon Wook Joo, Kyung Wha Lee, Sae-Hoon Kim, Heung-Woo Park, Yoon-Seok Chang, Sang-Heon Cho, Kyung-Up Min and Hye-Ryun Kang Background:Although allopurinol is a very effective urate-lowering drug for complicated hyperuricemia, in some patients, it can induce severe cutaneous adverse reactions (SCARs). Recent investigations suggest that HLA-B5801 is a very strong marker for allopurinol-induced SCARs, especially in the population with a high frequency of HLA-B5801. Korea is one of the countries with a high frequency of HLA-B*5801 which is the only subtype of HLA-B58 in the Korean population.
Objective:This study was conducted to find out the incidence of allopurinol-induced hypersensitivity on patients with chronic renal insufficiency (CRI) according to HLA-B58 and the clinical implications of HLA-B58 as a risk marker for the development of allopurinol-induced hypersensitivity.
Methods:We retrospectively reviewed the medical records of patients with CRI who took allopurinol and carried out serologic human leukocyte antigen (HLA) typing for kidney transplantation between January 2003 and May 2010.
Results:Among a total of 448 patients with CRI, 16 (3.6%) patients experienced allopurinol hypersensitivity. Nine of these patients (2.0%) were diagnosed with SCARs (two Stevens–Johnson syndrome and seven allopurinol hypersensitivity syndrome) and seven patients (1.6%) had simple maculopapular rashes. The HLA-B58 allele was present in all patients with allopurinol-induced SCARs, while the frequency of HLA-B58 was only 9.5% in allopurinol-tolerant patients (P < 0.05). The incidence of allopurinol-induced SCARs in CRI shows a wide disparity according to HLA-B58 [18% in HLA-B58 (+) versus 0% in HLA-B58 (－)]. Among patients without HLA-B*58, most (98.2%) of the CRI patients were tolerant to allopurinol and only 1.8% experienced simple rashes after taking allopurinol.
Conclusions:In this study, the incidence of allopurinol induced SCARs was considerably high in CRI patients with HLA-B*58. This finding indicates that the presence of HLA-B58 may increase the risk of allopurinol-induced SCARs. Screening tests for HLA-B58 in CRI patients will be clinically helpful in preventing severe allopurinol hypersensitivity reactions.


2009
Title 1 : Polymorphisms of HLA genes in Western Javaness (Indonesia): close affinities to Southeast Asian populations Tissue Antigens. 2009 Jan;73(1):46-53. Yuliwulandari R, Kashiwase K, Nakajima H, Uddin J, Susmiarsih TP, Sofro AS, Tokunaga K. Identification of human leukocyte antigen (HLA) antigens that are known as the highest polymorphic genes has become a valuable tool for tissue transplantation, platelet transfusion, disease susceptibility or resistance, and forensic and anthropological studies. In the present study, the allele and haplotype frequencies of HLA-A, HLA-B, and HLA-DRB1 were studied in 237 unrelated healthy Western Javanese (Indonesia) by the high-resolution polymerase chain reaction-Luminex method. A total of 18 A, 40 B, and 20 DRB1 alleles were identified. The most frequent HLA-A, -B, and -DRB1 alleles were HLA-A2407 (21.6%), HLA-B1502 (11.6%) and HLA-B1513 (11.2%), and DRB11202 (37.8%), respectively. The most frequent two-locus haplotypes were HLA-A2407-B3505 (7%) and HLA-B1513-DRB11202 (9.2%), and three-locus haplotypes were HLA-A3401-B1521-DRB1150201 (4.6%), HLA-A2407-B3505-DRB11202 (4.3%), and HLA-A330301-B440302-DRB1*070101 (4.2%). HLA allele and haplotype frequencies in addition to phylogenetic tree and principal component analyses based on the four-digit sequence-level allele frequencies for HLA-A, HLA-B, and HLA-DRB1 showed that Western Javanese (Indonesia) was closest to Southeast Asian populations.


*Title 2 : Strong association between HLA-B5801 and allopurinol induced Stevens–Johnson syndrome and toxic epidermal necrolysis in a Thai population Pharmacogenet Genomics. 2009 Sep;19(9):704-9. Tassaneeyakul W, Jantararoungtong T, Chen P, Lin PY, Tiamkao S, Khunarkornsiri U, Chucherd P, Konyoung P, Vannaprasaht S, Choonhakarn C, Pisuttimarn P, Sangviroon A, Tassaneeyakul W. Objective:*Allopurinol, a uric acid lowering drug commonly used for hyperuricemia and gouty arthritis, has been reported as a common cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between allopurinol-induced SCAR and HLA-B5801 was observed in a Han Chinese population with high frequency of this allele, whereas only a moderate association was observed in populations with low frequency (i.e. European and Japanese). This study investigated the relationship between SJS/TEN and HLA-B*5801 in a Thai population that has a high allelic frequency of this allele.
Methods: Twenty-seven allopurinol-induced SJS/TEN and 54 allopurinol-tolerant patients were enrolled in the study. The presence of HLA-B*5801 and HLA-B genotypes in these patients were analyzed using a PG5801 DNA detection kit and sequence-based typing, respectively.
Results:All of the 27 (100%) allopurinol-induced SJS/TEN patients who were examined carried HLA-B5801 whereas only seven (12.96%) of the control patients had this allele. The risk of allopurinol-induced SJS/TEN was significantly greater in patients with HLA-B5801 when compared with those who did not carry this allele, with an odds ratio of 348.3 (95% confidence interval=19.2-6336.9, P = 1.6 x10). The sensitivity and specificity of the HLA-B5801 allele for prediction of allopurinol-induced SJS/TEN were 100 and 87%, respectively. By assuming a 0.2% prevalence rate, the positive predictive value and the negative predictive value of the HLA-B5801 allele was 1.52 and 100%, respectively.
Conclusions:A strong association of allopurinol-induced SJS/TEN with the HLA-B5801 allele was observed in a Thai population. The results suggest that HLA-B5801 is a valid genetic marker for screening Thai individuals who may be at risk for allopurinol-induced life-threatening SJS and TEN.


*Title 3 : Strong association between HLA-B5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population Pharmacogenet Genomics. 2009 Sep;19(9):704-9. Tassaneeyakul W, Jantararoungtong T, Chen P, Lin PY, Tiamkao S, Khunarkornsiri U, Chucherd P, Konyoung P, Vannaprasaht S, Choonhakarn C, Pisuttimarn P, Sangviroon A, Tassaneeyakul W. Objective:** Allopurinol, a uric acid lowering drug commonly used for hyperuricemia and gouty arthritis, has been reported as a common cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between allopurinol-induced SCAR and HLA-B5801 was observed in a Han Chinese population with high frequency of this allele, whereas only a moderate association was observed in populations with low frequency (i.e. European and Japanese). This study investigated the relationship between SJS/TEN and HLA-B5801 in a Thai population that has a high allelic frequency of this allele.
Methods: Twenty-seven allopurinol-induced SJS/TEN and 54 allopurinol-tolerant patients were enrolled in the study. The presence of HLA-B*5801 and HLA-B genotypes in these patients were analyzed using a PG5801 DNA detection kit and sequence-based typing, respectively.
Results:All of the 27 (100%) allopurinol-induced SJS/TEN patients who were examined carried HLA-B5801 whereas only seven (12.96%) of the control patients had this allele. The risk of allopurinol-induced SJS/TEN was significantly greater in patients with HLA-B5801 when compared with those who did not carry this allele, with an odds ratio of 348.3 (95% confidence interval=19.2-6336.9, P = 1.6 x10). The sensitivity and specificity of the HLA-B5801 allele for prediction of allopurinol-induced SJS/TEN were 100 and 87%, respectively. By assuming a 0.2% prevalence rate, the positive predictive value and the negative predictive value of the HLA-B5801 allele was 1.52 and 100%, respectively.
Conclusions: A strong association of allopurinol-induced SJS/TEN with the HLA-B5801 allele was observed in a Thai population. The results suggest that HLA-B5801 is a valid genetic marker for screening Thai individuals who may be at risk for allopurinol-induced life-threatening SJS and TEN.


2008
Title 1 : Pharmacogenetic information derived from analysis of HLA alleles Pharmacogenomics. 2008 Feb;9(2):207-14. Gatanaga H, Honda H, Oka S. A large amount of pharmacogenetic information has, in particular, accumulated on the association between human leukocyte antigen (HLA) alleles and hypersensitivity to certain drugs. Prospective HLA typing has dramatically reduced the risk of abacavir hypersensitivity because of its strong association with HLA-B5701. Significant predisposition to nevirapine hypersensitivity has been reported in Caucasian Australians harboring HLA-DRB10101 with high CD4+ T-cell counts, and Sardinians and Japanese harboring HLA-Cw8. A strong association between carbamazepine hypersensitivity and HLA-B1502 has been reported in Han Chinese. Most Han Chinese individuals with allopurinol-induced severe cutaneous adverse reactions are positive for HLA-B5801. HLA typing can stratify risk of hypersensitivity to certain drugs and allow personalized treatment, although the patients should be monitored closely even if they are negative for HLA alleles associated with hypersensitivity.


Title 2 : HLA-B locus in in Japanese patients with anti-epileptics and allopurinol related Stevens-Johnson syndrome and toxic epidermal necrolysis Pharmacogenomics. 2008 Nov;9(11):1617-22. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, Sawada J, Furuya H, Takahashi Y, Muramatsu M, Kinoshita S, Abe M, Ikeda H, Kashiwagi M, Song Y, Ueta M, Sotozono C, Ikezawa Z, Hasegawa R; JSAR research group. Introduction : Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B1502 and HLA-B5801 with carbamazepine- and allopurinol-induced severe cutaneous adverse reactions were found in Han Chinese patients, respectively, but ethnic differences in the associations have been reported. The objective of this study is to clarify the involvement of HLA-B1502 and HLA-B5801 in Japanese SJS/TEN patients..
Methods: HLA-B genotyping was performed on 58 Japanese SJS/TEN patients between July 2006 and April 2008 from multicenters in Japan.
Results: There were no HLA-B1502 carriers among 58 SJS/TEN patients. This patient group included seven carbamazepine-related and 11 aromatic anti-epileptic agent-related SJS/TEN patients. In addition, there were five HLA-B5801 carriers, which included four allopurinol-related SJS/TEN patients.
Conclusion: While HLA-B1502 is unlikely to be associated with carbamazepine-related or aromatic anti-epileptic agent-related SJS/TEN, HLA-B5801 was significantly associated with allopurinol-related SJS/TEN in Japanese.


Title 3 : A European study of HLA-B in Stevens–Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs Pharmacogenet Genomics. 2008 Feb;18(2):99-107. Lonjou C, Borot N, Sekula P, Ledger N, Thomas L, Halevy S, Naldi L, Bouwes-Bavinck JN, Sidoroff A, de Toma C, Schumacher M, Roujeau JC, Hovnanian A, Mockenhaupt M; RegiSCAR study group. Background:Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are rare but life-threatening cutaneous adverse reactions to drugs, especially to allopurinol, carbamazepine, lamotrigine, phenobarbital, phenytoine, sulfamethoxazole, oxicam and nevirapine. Recently, a strong association between carbamazepine and allopurinol induced SJS or TEN has been described with respectively, HLA-B1502 and HLA-B5801 in a Han Chinese population from Taiwan and other Asian countries.
Objective:The objective is to further investigate the relationship between SJS/TEN and HLA-B in a large number of patients in a European population.
Methods:HLA-B genotyping was performed on 150 patients included in a European study (RegiSCAR) of SJS and TEN. We focused on patients related to 'high-risk' drugs including: 31 cases related to allopurinol, 28 to sulfamethoxazole, 19 to lamotrigine and 14 to oxicam.
Results:Sixty-one percent of 31 allopurinol-induced SJS/TEN patients carried the HLA-B5801 allele and the figure was 55% for 27 patients of European ancestry [odds ratio=80 (34-187)], (P<10(-6)) as previously observed in Han Chinese. For other drugs, two rare alleles showed a weaker association with SJS/TEN in a limited number of patients: B38 for sulfamethoxazole or lamotrigine-related patients, and B*73 for oxicam.
Conclusions:At variance with prior results in Asia, this study shows that even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease. Further investigations are necessary to delineate the exact role of the HLA region in SJS/TEN, and to look for other associations in other regions of the genome.


Title 4 : Pharmacogenetics determinants of immediate and delayed reactions of drug hypersensitivitys Curr Pharm Des. 2008;14(27):2770-7. Guéant JL, Guéant-Rodriguez RM, Gastin IA, Cornejo-García JA, Viola M, Barbaud A, Mertes PM, Blanca M, Romano A. Drug allergy refers to a hypersensitivity reaction for which either an IgE or T-cell-mediated mechanism is demonstrated. The recognition of the drug by B and T cells is influenced by variants of HLA genes. The genetic factors involved in IgE-mediated mechanisms have been studied mainly in beta-lactam reactions, and they appear to be related to human leukocyte antigen presentation (HLA A2 and DRw52), TNFA -308G>A, class switching to IgE by B cells (variants of IL-13 and of IL-4RA), and expression of IgE receptors on target cells (variant of the FcepsilonRIbeta gene). Delayed T-cell-mediated reactions are also associated with HLA alleles. Studies have reported an association of HLA-B1502 and HLA-B5801 in patients with the Stevens-Johnson syndrome or toxic epidermal necrolysis provoked by carbamazepine, as well as of HLA-B5701 with abacavir hypersensitivity. HLA-B5701 seems to be a strong predictor in whites, but not in Hispanics or Africans. Carbamazepine hypersensitivity is also influenced by gene variants of cytochrome P450 enzymes on the generation of reactive metabolites, while CYP2C92 and CYP2C93 polymorphisms influence the bioactivation of sulfamethoxazole in prohapten. Pharmacogenetic studies on aspirin hypersensitivity have identified distinct types of predictors, such as HLA genotypes, a polymorphism in the promoter of the FcepsilonRIalpha gene, and variants in genes of enzymes from the arachidonic acid pathway. In the future, identification of genetic predictors will benefit from genomewide association studies that also take ethnic differences into account. Ideally, predictors will help to prevent adverse reactions, as suggested by a recent study on the effectiveness of prospective HLA-B*5701 screening to prevent hypersensitivity reactions to abacavir in HIV patients.


Title 5 : HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis Pharmacogenomics. 2008 Nov;9(11):1617-22. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, Sawada J, Furuya H, Takahashi Y, Muramatsu M, Kinoshita S, Abe M, Ikeda H, Kashiwagi M, Song Y, Ueta M, Sotozono C, Ikezawa Z, Hasegawa R; JSAR research group. Introduction : Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B1502 and HLA-B5801 with carbamazepine- and allopurinol-induced severe cutaneous adverse reactions were found in Han Chinese patients, respectively, but ethnic differences in the associations have been reported. The objective of this study is to clarify the involvement of HLA-B1502 and HLA-B5801 in Japanese SJS/TEN patients.
Methods : HLA-B genotyping was performed on 58 Japanese SJS/TEN patients between July 2006 and April 2008 from multicenters in Japan.
Results : There were no HLA-B1502 carriers among 58 SJS/TEN patients. This patient group included seven carbamazepine-related and 11 aromatic anti-epileptic agent-related SJS/TEN patients. In addition, there were five HLA-B5801 carriers, which included four allopurinol-related SJS/TEN patients.
Conclusion: While HLA-B1502 is unlikely to be associated with carbamazepine-related or aromatic anti-epileptic agent-related SJS/TEN, HLA-B5801 was significantly associated with allopurinol-related SJS/TEN in Japanese.


2007
Title 1 : Human leukocyte antigens and drug hypersensitivity Allergy and clinical immunology Current Opinion in Allergy & Clinical Immunology: August 2007 - Volume 7 - Issue 4 - p 317-323 Chung, Wen-Hung; Hung, Shuen-Iu; Chen, Yuan-Tsong Purpose of review:The present article reviews the recent literature on the identification of human leukocyte antigen (HLA) alleles as major susceptible genes for drug hypersensitivity and discusses the clinical implications.
Recent findings: Several recent studies have reported strong genetic associations between HLA alleles and susceptibility to drug hypersensitivity. The genetic associations can be drug specific, such as HLA-B1502 being associated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), HLA-B5701 with abacavir hypersensitivity and HLA-B5801 with allopurinol-induced severe cutaneous adverse reactions. A genetic association can also be phenotype-specific, as B1502 is associated solely with carbamazepine-SJS/TEN, and not with either maculopapular eruption or hypersensitivity syndrome. Furthermore, a genetic association can also be ethnicity specific; carbamazepine-SJS/TEN associated with B*1502 is seen in south-east Asians but not in whites, which may be explained by the different allele frequencies.
Summary:The strong genetic association suggests a direct involvement of HLA in the pathogenesis of drug hypersensitivity when the HLA molecule presents an antigenic drug for T cell activation. The high sensitivity/specificity of some markers provides a plausible basis for developing tests to identify individuals at risk for drug hypersensitivity. Application of HLA-B*1502 genotyping as a screening tool before prescribing carbamazepine could be a valuable tool in preventing carbamazepine-induced SJS/TEN in south-east Asian countries.


Title 2 : Stevens-Johnson syndrome, drug-induced hypersensitivity syndrome and toxic epidermal necrolysis caused by allopurinol in patients with a common HLA allele: what causes the diversity? Dermatology. 2007;215(1):86-8. Dainichi T, Uchi H, Moroi Y, Furue M. We have confirmed that SJS, TEN and DIHS/DRESS caused by allopurinol affect patients who have the serological HLA type B58 in common. B58 is exclusively associated with the HLA-B* 5801 allele and is extremely rare in the Japanese population (≦ 0.6%). It has been shown that the HLA-B * 5801 allele was present in all 51 patients with allopurinol-induced severe cutaneous adverse reactions in Taiwan. Another common HLA allele in the present cases, A33 (A * 3303), is in linkage disequilibrium and forms an extended haplotype with B * 5801. The latest report indicates that the HLA-B * 5801 allele is present in 61% of patients who suffer from allopurinol-induced severe adverse drug effects in Europe. Despite regional and ethnic differences, HLA-B * 5801 is undeniably a common key to the pathogenesis of SJS, TEN and DIHS/DRESS induced by allopurinol.


2005
*Title 1 : HLA-B5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol** Proc Natl Acad Sci U S A. 2005 March 15; 102(11): 4134–4139 Hung SI, 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 CS, Wu JY, Chen YT. 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-B5801 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 A3303, Cw0302, and DRB10301 were in linkage disequilibrium and formed an extended haplotype with HLA-B5801. Our results indicated that allopurinol-SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B5801 allele is an important genetic risk factor for this life-threatening condition.