Carbamazepine&HLA-B*1502



Scientific Studies & Publication
Carbamazepine & HLA-B*1502
2011 \| 2010 \| 2009 \| 2008 \| 2007 \| 2006 \| 2005 \| 2004

2011
*Title 1: Association of HLA-B1502 allele with carbamazepine induced toxic epidermal necrolysis and Stevens–Johnson syndrome in the multi-ethnic Malaysian population International Journal of Dermatology 2011, 50, 221–224 Choong-Chor Chang, MRCP, Chun-Lai Too, BSc, Shahnaz Murad, MSc, and Suraiya Hani Hussein, MRCP Background:** Carbamazepine (CBZ), a frequently used anticonvulsant drug, is one of the most common causes of life-threatening cutaneous adverse drug reactions such as toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS). Recent studies have revealed a strong association between HLA-B*1502 and CBZ-induced TEN/SJS in the Taiwan Han Chinese population.
Objectives: This study is aimed to investigate the association between human leucocyte antigens (HLA) and CBZ-induced TEN/SJS in the multi-ethnic Malaysian population.
Methods: A sample of 21 unrelated patients with CBZ-induced TEN/SJS and 300 racematched, healthy controls were genotyped for HLA-A, -B and -DR using polymerase chain reaction (PCR). Allele frequencies were compared.
Results: HLA-B1502 was present in 75.0% (12/16) of Malay patients with CBZ-induced TEN/SJS but in only 15.7% (47/300) of normal controls (odds ratio 16.15, 95% confidence interval 4.57–62.4; corrected P-value = 7.87 • 10)6), which suggests a strong association between HLA and CBZ-induced TEN/SJS. Additionally, HLA-B1502 was found in all three Chinese and two Indian patients. Existing data show that frequencies of the HLA-B*1502 allele are generally much higher in Asian populations than in White European populations, which explains the higher incidences of SJS and TEN in Asian countries.
Conclusions: HLA-B1502 is strongly associated with CBZ-induced TEN/SJS in the Malay population in Malaysia, as has been seen in Han Chinese in Taiwan. This indicates that the genetic association apparent in the incidence of CBZ-induced TEN/SJS is linked with the presence of HLA-B1502, irrespective of racial origin. Screening of patients for this genetic marker can help to prevent the occurrence of TEN/SJS.


Title 2: HLA-B Alleles and Lamotrigine-Induced Cutaneous Adverse Drug Reactions in the Han Chinese Population Basic & Clinical Pharmacology & Toxicology, 109, 42–46 Yi-Wu Shi, Fu-Li Min, Xiao-Rong Liu, Li-Xuan Zan, Mei-Mei Gao, Mei-Juan Yu and Wei-Ping Liao Lamotrigine (LTG) is a commonly used antiepileptic drug. However, the use of LTG is limited because of its cutaneous adverse drug reactions (cADRs) ranging from mild maculopapular eruption (MPE) to severe Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between HLA-B1502 and carbamazepine-induced SJS ⁄TEN has been identified in Chinese and Thai. Although three of seven cases with HLA-B1502 have been reported in LTG-induced SJS ⁄TEN so far, the relationship between HLA-B1502 and LTG-induced SJS ⁄ TEN needs further investigation. It is also unclear whether there is a specific genetic marker associated with LTG-induced MPE in Chinese. In this study, we genotyped 43 Han Chinese patients treated with LTG (14 cases with LTG-induced cADRs and 29 LTG-tolerant controls), using PCR-SSP for HLA-B1502 testing and low-resolution genotyping, as well as sequencing for four-digit genotyping. The two cases with SJS were negative for HLA-B1502, with B1301 ⁄ 1301 and 4601 ⁄ 5610, respectively. Combining the data with previous studies, there was no significant difference in the frequency of subjects with HLA-B1502 between the LTG-induced SJS ⁄TEN group and the LTG-tolerant group (p = 0.08, OR 4.23, 95% CI 0.94–18.97). In the MPE group, only one was positive for HLA-B1502. There was no significant difference in the frequency of a specific HLA-B allele between the MPE group and the LTG-tolerant group either. In this study, no significant association between HLA-B1502 and LTG-induced SJS or MPE was found. Given the small sample size and only HLA-B locus genotyping, further large-scale studies are required to explore genetic associations with LTG-induced cADRs.


*Title 3: HLA-B1502 Strongly Predicts Carbamazepine-Induced Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis in Thai Patients with Neuropathic Pain Pain Pract. 2011 Jun 16 Kulkantrakorn K, Tassaneeyakul W, Tiamkao S, Jantararoungtong T, Prabmechai N, Vannaprasaht S, Chumworathayi P, Chen P, Sritipsukho P. Background:*Carbamazepine (CBZ) is one of the standard pharmacological treatments for neuropathic pain. However, its serious adverse drug reactions include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Recently, HLA-B1502 allele was implicated as a genetic marker of CBZ-induced SJS/TEN in some Asian epilepsy populations.
Methods: This is a case control study to describe the clinical characteristics of SJS/TEN in Thai patients with neuropathic pain who were treated with CBZ, and to determine the association of HLA-B*1502 in these patients, comparing with those who exposed to CBZ for at least 6 months without any cutaneous reactions.
Results: Thirty-four SJS/TEN patients and 40 control patients were included in this study. Mean age of SJS/TEN patients was 47 years. SJS/TEN was developed in 10.8 ± 1.4 days after initiation of CBZ. HLA-B1502 allele was found in 32 of 34 SJS/TEN patients (94.1%) but it was found only in 7 of 40 control patients (17.5%). The association was very strong with an odds ratio of 75.4. Sensitivity and specificity of this HLA-B1502 genotype test were 94.1% and 82.5%, respectively, while the positive predictive value and negative predictive value were 1.43% and 99.98%, respectively. Positive and negative likelihood ratios were 5.37 and 0.07, respectively.
Conclusions: HLA-B*1502 is a strong genetic marker for CBZ-induced SJS/TEN in Thai patients with neuropathic pain. The screening for this marker should be performed prior to initiation of CBZ treatment to assess the risk of this serious side effect.


Title 4: Pharmacogenetic screening of carbamazepine-induced severe cutaneous allergic reactions J Clin Neurosci. 2011 Oct;18(10):1289-94 Locharernkul C, Shotelersuk V, Hirankarn N Recent studies associated the HLA-B 1502 allele with carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in patients from China, Thailand and Malaysia. No association has been found in patients from Europe or Japan. Linkage summary reports from East and South-east Asia predict a highly significant odds ratio (OR) of 84.75 (95% confidence interval [CI]=42.53-168.91; p=8.96×10[-15]) with sensitivity and negative predictive values of 92% and 98%, respectively. The higher prevalence of HLA-B 1502 allele among certain Asian populations (10-15%) compared to Caucasians (1-2%) may explain a 10-fold to 25-fold higher incidence of CBZ-SJS/TEN in patients from Asia. Screening for HLA-B 1502 before using CBZ can prevent SJS/TEN in certain populations, but screening may be less beneficial in populations with low HLA-B 1502 allele frequency and in patients exposed to CBZ for more than 2 months. A retrospective study demonstrated that the costs of HLA-B 1502 screening were less than those of SJS treatment. This article reviews possible benefits and concerns of HLA-B 1502 screening in clinical practice.


*Title 5: Strong association between HLA-B1502 and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in mainland Han Chinese patients Eur J Clin Pharmacol (2011) 67:885–887 Yan Zhang, Jin Wang, Li-Mei Zhao, Wei Peng, Guo-Qing Shen, Ling Xue, Xiao-Xian Zheng, Xiao-Jing HE, Chun-Yan Gong and Li-Yan Miao Purpose:** The purpose of this study is to examine the association of HLA-B*1502 allele with CBZ-induced SJS/TEN in the mainland Han Chinese population.
Methods: HLA-B*1502 genotyping with sequence-specific primer polymerase chain reaction (PCR-SSP) and PCRsequencing based typing (PCR-SBT) was performed on 17 CBZ-induced SJS/TEN patients, 21 CBZ-tolerant controls, and 185 healthy controls recruited during 2008–2010.
Results: HLA-B1502 allele was present in 94.1% (16/17) of CBZ-SJS/TEN patients, 9.5% (2/21) of CBZ-tolerant patients, and 9.2% (17/185) of healthy controls. The risk of CBZ-induced SJS/TEN was significantly higher (P<0.01) in the patients with HLA-B1502. One CBZ-induced SJS patient tested negative for HLA-B1502, and the test result showed HLA-B3503/B*4601.
Conclusions: We found a strong association between HLA-B1502 and CBZ-induced SJS/TEN in the Han Chinese population from central and northern China. Combined with previous studies of the southern Han Chinese subpopulation, our results suggest that HLA-B1502 is strongly associated with CBZ-induced SJS/TEN in the whole Han Chinese population.


Title 6: Genome-wide association study of serious blistering skin rash caused by drugs The Pharmacogenomics Journal (2011), 1–9 Shen Y, Nicoletti P, Floratos A, Pirmohamed M, Molokhia M, Geppetti P, Benemei S, Giomi B, Schena D, Vultaggio A, Stern R, Daly MJ, John S, Nelson MR, Pe'er I. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe, potentially life threatening adverse drug reactions characterized by skin blistering. Previous studies have identified drug-specific and population-specific genetic risk factors with large effects. In this study, we report the first genome-wide association study (GWAS) of SJS/TEN induced by a variety of drugs. Our aim was to identify common genetic risk factors with large effects on SJS/TEN risk. We conducted a genome-wide analysis of 96 retrospective cases and 198 controls with a panel of over one million single-nucleotide polymorphisms (SNPs). We further improved power with about 4000 additional controls from publicly available datasets. No genome-wide significant associations with SNPs or copy number variants were observed, although several genomic regions were suggested that may have a role in predisposing to drug-induced SJS/TEN. Our GWAS did not find common, highly penetrant genetic risk factors responsible for SJS/TEN events in the cases selected.


*Title 7: Carbamazepine-Induced Toxic Effects and HLA-B1502 Screening in Taiwan N Engl J Med. 2011 Mar 24;364(12):1126-33 Chen P, Lin JJ, Lu CS, Ong CT, Hsieh PF, Yang CC, Tai CT, Wu SL, Lu CH, Hsu YC, Yu HY, Ro LS, Lu CT, Chu CC, Tsai JJ, Su YH, Lan SH, Sung SF, Lin SY, Chuang HP, Huang LC, Chen YJ, Tsai PJ, Liao HT, Lin YH, Chen CH, Chung WH, Hung SI, Wu JY, Chang CF, Chen L, Chen YT, Shen CY; Taiwan SJS Consortium. Background:** Carbamazepine, an anticonvulsant and a mood-stabilizing drug, is the main cause of the Stevens-Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), in Southeast Asian countries. Carbamazepine-induced SJS-TEN is strongly associated with the HLA-B1502 allele. We sought to prevent carbamazepine-induced SJS-TEN by using HLA-B1502 screening to prospectively identify subjects at genetic risk for the condition.
Methods: From 23 hospitals in Taiwan, we recruited 4877 candidate subjects who had not taken carbamazepine. We genotyped DNA purified from the subjects' peripheral blood to determine whether they carried the HLA-B1502 allele. Those testing positive for HLA-B1502 (7.7% of the total) were advised not to take carbamazepine and were given an alternative medication or advised to continue taking their prestudy medication; those testing negative (92.3%) were advised to take carbamazepine. We interviewed the subjects by telephone once a week for 2 months to monitor them for symptoms. We used the estimated historical incidence of SJS-TEN as a control.
Results: Mild, transient rash developed in 4.3% of subjects; more widespread rash developed in 0.1% of subjects, who were hospitalized. SJS-TEN did not develop in any of the HLA-B*1502-negative subjects receiving carbamazepine. In contrast, the estimated historical incidence of carbamazepine-induced SJS-TEN (0.23%) would translate into approximately 10 cases among study subjects (P<0.001).
Conclusions: The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects was strongly associated with a decrease in the incidence of carbamazepine-induced SJS-TEN. (Funded by the National Science Council of Taiwan and the Taiwan Drug Relief Foundation.).


Title 8: Pharmacogenetic screening of carbamazepine-induced severe cutaneous allergic reactions J Clin Neurosci. 2011 Oct;18(10):1289-94 Locharernkul C, Shotelersuk V, Hirankarn N. Recent studies associated the HLA-B 1502 allele with carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in patients from China, Thailand and Malaysia. No association has been found in patients from Europe or Japan. Linkage summary reports from East and South-east Asia predict a highly significant odds ratio (OR) of 84.75 (95% confidence interval [CI]=42.53-168.91; p=8.96×10[-15]) with sensitivity and negative predictive values of 92% and 98%, respectively. The higher prevalence of HLA-B 1502 allele among certain Asian populations (10-15%) compared to Caucasians (1-2%) may explain a 10-fold to 25-fold higher incidence of CBZ-SJS/TEN in patients from Asia. Screening for HLA-B 1502 before using CBZ can prevent SJS/TEN in certain populations, but screening may be less beneficial in populations with low HLA-B 1502 allele frequency and in patients exposed to CBZ for more than 2 months. A retrospective study demonstrated that the costs of HLA-B 1502 screening were less than those of SJS treatment. This article reviews possible benefits and concerns of HLA-B 1502 screening in clinical practice.


Title 9: Phenotype Standardization for Immune-Mediated Drug-Induced Skin Injury Clin Pharmacol Ther. 2011 Jun;89(6):896-901 Pirmohamed M, Friedmann PS, Molokhia M, Loke YK, Smith C, Phillips E, La Grenade L, Carleton B, Papaluca-Amati M, Demoly P, Shear NH. Advances in genetic research and molecular biology techniques have made it possible to begin to characterize the underlying genetic factors that predispose patients to serious forms of drug-induced skin injury (DISI). To facilitate research in this area, we have set out standardized phenotypic definitions for (i) Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), (ii) acute generalized exanthematous pustulosis (AGEP), and (iii) hypersensitivity syndrome (HSS; also known as drug reaction with eosinophilia and systemic symptoms (DRESS) and drug-induced hypersensitivity syndrome (DIHS)). A DISI Expert Working Group comprising participants with varied expertise reviewed and debated current terminology and diagnostic criteria for DISI and agreed on the minimum phenotypic criteria for selected forms of DISI (SJS/TEN, AGEP, and HSS). In addition, an algorithm has been developed to aid appropriate clinical categorization of patients with DISI. These standardized criteria will be important in facilitating adequate and accurate patient recruitment in order to advance research in pharmacogenomic, immunological, mechanistic, and epidemiological studies.


2010
*Title 1 : Association between carbamazepine-induced cutaneous adverse drug reactions and the HLA-B1502 allele among patients in central China** Epilepsy Behav. 2010 Nov;19(3):405-8 X.T. Wu , F.Y. Hu, D.M. An, B. Yan, X. Jiang, P. Kwan, H. Stefan, D. Zhou The aim of this study was to investigate the association between carbamazepine (CBZ)-induced cutaneous adverse drug reactions (cADRs) and the HLA-B1502 alleleamong patients fromcentral China. Eight patients with Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), 28 with mild maculopapular eruptions (MPEs), 50 CBZ-tolerant controls, and 71 healthy volunteers were recruited. HLA genotyping was performed using the polymerase chain reaction sequence-based typing (SBT)method. As a result, the HLA-B1502 allele was observed at the following rates: (1) 100% (8/8) among thosewith CBZ-induced SJS/TEN, (2) 10.7% (3/28) among those with CBZ-induced MPEs; (3) 8.0% (4/50) among CBZ-tolerant controls; (4) 8.5% (6/71) among healthy volunteers. The eight patients with SJS/TEN positive for the HLA-B1502 allele had an odds ratio (OR) of 184 compared with CBZ-tolerant controls. There was no significant difference in frequency between patients with MPEs and CBZ-tolerant controls (PN0.05). Thus, CBZ-induced SJS/TEN, but not MPEs, is strongly associated with HLA-B1502. Testing for HLA-B*1502 should be recommended for patients fromcentral China prior to initial CBZ treatment.


*Title 2 : Association between HLA-B1502 and carbamazepine-induced severe cutaneous adverse drug reactions in a Thai population** Epilepsia. 2010 May;51(5):926-30. Epub 2010 Mar 19 Tassaneeyakul W, Tiamkao S, Jantararoungtong T, Chen P, Lin SY, Chen WH, Konyoung P, Khunarkornsiri U, Auvichayapat N, Pavakul K, Kulkantrakorn K, Choonhakarn C, Phonhiamhan S, Piyatrakul N, Aungaree T, Pongpakdee S, Yodnopaglaw P. Carbamazepine (CBZ) has been reported as the most common culprit drug for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in several Asian countries including Thailand. A strong association between HLA-B1502 and CBZ-induced SJS/TEN has been reported in Han Chinese but not in Caucasian and Japanese populations. A case-control study was conducted to determine whether HLA-B1502 is a valid pharmacogenetic test for SJS/TEN caused by CBZ in a Thai population. Among 42 CBZ-induced patients with SJS/TEN, 37 (88.10%) patients carried the HLA-B1502 while only 5 (11.90%) of the CBZ-tolerant controls had this allele. The risk of CBZ-induced SJS/TEN was significantly higher in the patients with HLA-B1502, with an odds ratio (OR) of 54.76 [95% confidence interval (CI) 14.62-205.13, p = 2.89 x 10(-12)]. The sensitivity and specificity of HLA-B1502 for prediction of CBZ-induced SJS/TEN were 88.10%. By assuming a 0.27% as a prevalence rate of CBZ-induced SJS/TEN in a Thai population, the positive predictive value (PPV) and negative predictive value (NPV) of the HLA-B1502 were 1.92% and 99.96%. Results from this study suggest that HLA-B*1502 may be a useful pharmacogenetic test for screening Thai individuals who may be at risk for CBZ-induced SJS and TEN.


*Title 3 : Association study of lamotrigine-induced cutaneous adverse reactions and HLA-B1502 in a Han Chinese population** Epilepsy Res. 2010 Dec;92(2-3):226-30. Epub 2010 Nov 10 An DM, Wu XT, Hu FY, Yan B, Stefan H, Zhou D. Antiepileptic drugs including lamotrigine (LTG) and carbamazepine (CBZ) are among the most common causes of cutaneous adverse reactions (cADRs). Human leukocyte antigen (HLA)-B1502 has been strongly associated with CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). To investigate this relationship, we performed high-resolution HLA genotyping on LTG-tolerant controls, healthy volunteers, and patients affected by LTG-induced cADRs, ranging from maculopapular exanthema (MPE) to SJS/TEN. Patients with LTG-induced cADRs (n=25, including three with SJS/TEN and 22 with MPE), 21 LTG-tolerant controls, and 71 healthy volunteers were enrolled. The differences in the starting dosage of LTG among the SJS/TEN, MPE, and LTG-tolerant control groups were not statistically significant. HLA-B1502 frequency was 33.3% (1/3; LTG-induced SJS/TEN group), 9.1% (2/22; LTG-induced MPE group), 4.8% (1/21; LTG-tolerant group), and 8.5% (6/71; healthy volunteers). There was no significant difference in the frequency of subjects with the HLA-B1502 allele between the SJS/TEN group and LTG-tolerant group (p=0.239, OR=10.0, 95% CI 0.44-228.7), and healthy volunteers (p=0.26, OR=5.42, 95% CI 0.43-68.8), MPE and LTG-tolerant groups (p=1.0, OR=1.08, 95% CI 0.20-5.8), and healthy volunteers (p=1.0, OR=2.0, 95% CI 0.17-23.9). None of the HLA alleles detected were associated with LTG-induced cADRs. In conclusion, HLA-B1502 and other HLA alleles are not directly associated with LTG-induced MPE. The possibility that HLA-B*1502 is associated with an increased risk of LTG-induced SJS/TEN could not be excluded.


*Title 4 : HLA-B 1502 screening: Time to clinical practice** Epilepsia, 51(5):931–939, 2010 Chaichon Locharernkul Abacavir has been at the center of research and clinical interest in the last two years. The frequency of the associated abacavir hypersensitivity syndrome has decreased substantially since the introduction of routine testing for the HLA-B*5701 allele; the activity of the drug in HIV-infected persons with HIV RNA values more than 100,000 copies/mL has been questioned; the possible increased risk of myocardial infarction after recent exposure to abacavir has been debated; and the drug has been moved from the “recommended” category to the “alternative” category in several guidelines. Still, the drug remains a useful agent in combination with other drugs, including lamivudine, for the treatment of HIV infection. This review will focus on the pharmacokinetics, activity, side effects, and resistance profile of both abacavir and lamivudine, including a thorough review of all of the recent studies relevant to both drugs.


Title 5 : Common risk allele in aromatic antiepileptic-drug induced Stevens–Johnson syndrome and toxic epidermal necrolysis in Han Chinese Pharmacogenomics. 2010 Mar;11(3):349-56 Hung SI, Chung WH, Liu ZS, Chen CH, Hsih MS, Hui RC, Chu CY, Chen YT Aims: Compared with other categories of drugs, such as antibiotics and NSAIDs, antiepileptic therapies are associated with a high incidence of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We previously reported that carbamazepine (CBZ)-SJS/TEN is strongly associated with the HLA-B*1502 in Han Chinese, which has been confirmed in other Southeast Asian countries where the allele is prevalent. Here, we extend the study of HLA susceptibility to three different antiepileptic drugs, phenytoin (PHT), lamotrigine (LTG) and oxcarbazepine (OXC), which have structure similarity to CBZ.
Methods: We carried out a case-control association study. We enrolled 26 PHT-, six LTG- and three OXC-induced SJS/TEN patients, 113 PHT-tolerant and 67 LTG-tolerant subjects who were on the drug, respectively, for more than 3 months without the adverse reactions, and 93 normal subjects from the general population. The HLA-A, B, C and DRB1 genotypes were determined.
Results: We found that HLA-B1502 was present in eight out of 26 (30.8%) PHT-SJS/TEN (OR: 5.1; 95% CI: 1.8-15.1; p = 0.0041), two out of six (33%) LTG-SJS (odds ratio [OR]: 5.1; 95% CI: 0.8-33.8; p = 0.1266) and three out of three (100%) OXC-SJS (OR: 80.7; 95% CI: 3.8-1714.4; p = 8.4 x 10(-4)) patients. In addition, HLA-B1301, Cw0801 and DRB11602 also showed an association with PHT-SJS/TEN (p = 0.0128-0.0281; OR: 3.0-4.3).
Conclusion: Our results indicate that OXC, PHT and LTG, which possess an aromatic ring just as CBZ does, when causing SJS/TEN, share a common risk allele. Aromatic antiepileptic drugs causing SJS/TEN in HLA-B1502 carriers may act on a similar pathogenetic mechanism, although other genetic/nongenetic factor(s) may also contribute to the pathomechanism of the disease. We suggest that aromatic antiepileptic drugs, including CBZ, OXC and PHT, should be avoided in the B1502 carrier and caution should also be exercised for LTG.


Title 6 : Genetic Markers and Danger Signals in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Allergol Int. 2010 Dec;59(4):325-32. Epub 2010 Oct 25 Chung WH, Hung SI Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse reactions, which could be induced by a variety of drugs. It was proposed that human leukocyte antigen (HLA)-restricted presentation of antigens (drugs or their metabolites) to T lymphocytes initiates the immune reactions of SJS/TEN. However, the genetic susceptibility and the exact pathogenesis were not clear until the recent studies. We first identified that HLA-B1502 is strongly associated with carbamazepine (CBZ)-induced SJS/TEN and HLA-B5801 with allopurinol-SJS/TEN in Han Chinese. The same associations had been validated across different human populations. For the downstream danger signals, Fas-Fas ligand (FasL) and perforin/granzyme B had been advocated as cytotoxic mediators for keratinocyte death in SJS/TEN. However, expression levels of these cytotoxic proteins from the skin lesions were too low to explain the distinct and extensive epidermal necrosis. Our recent study identified that the granulysin, a cytotoxic protein released from cytotoxic T cells or natural killer (NK) cells, is a key mediator for disseminated keratinocyte death in SJS/TEN. This article aims to provide an overview of both of the genomic and immunologic perspectives of SJS/TEN. These studies give us a better understanding of the immune mechanisms, biomarkers for disease prevention and early diagnosis, as well as providing the therapeutic targets for the treatments of SJS/TEN.


Title 7 : Genetic predisposition of life threatening antiepileptic-induced skin reactions Expert Opin Drug Saf. 2010 Jan;9(1):15-21 Chung WH, Hung SI, Chen YT Importance of the field: Recent advances in pharmacogenetic studies have uncovered increasingly more genes that predispose individuals to adverse drug reactions. Aromatic antiepileptic drugs (AEDs) are a frequent cause of severe cutaneous adverse reactions (SCAR). A strong genetic association between HLA-B*1502 and carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) has been shown in Han Chinese patients.
Areas covered in this review: This article reviews and updates genetic information associated with CBZ and other AEDs causing SCAR in different ethnic populations.
What the reader will gain: Independent studies from different countries confirmed that patients carrying the HLA-B1502 are at high risk of SJS/TEN when exposed to CBZ. The US FDA and similar regulatory agencies in Canada and Taiwan have updated the CBZ drug label to include the genetic information. Available data also suggest that HLA-B1502 is a risk allele for SJS/TEN caused by other aromatic AEDs with a similar structure to CBZ.
Take home message: Screening for HLA-B1502 allele before starting treatment with CBZ is justified in patients from high-risk populations as recommended by regulatory agencies. Similar chemicals should also be avoided in individuals who test positive for HLA-B1502.


*Title 8 : HLA-B15 subtypes distribution in Han population in Beijing, China, as compared with those of other populations** Int J Immunogenet. 2010 Jun;37(3):205-12. Epub 2010 Mar 14 Yang G, Deng YJ, Qin H, Zhu BF, Chen F, Shen CM, Sun ZM, Chen LP, Wu J, Mu HF, Lucas R. To identify HLA-B15 subtypes distribution in Han population in Beijing, People's Republic of China, 826 unrelated healthy individuals were typed using the polymerase chain reaction-sequence-based typing method. Within the 246 HLA-B15 positive individuals, 29 HLA-B15 alleles were identified, the most predominant of which is B1501 (40.07%), followed by B1502 (12.87%), B1511 (12.87%), B1518 (9.19%) and B1532 (3.31%). The distribution of HLA-B*15 subtype frequencies was compared between the Beijing Han, eight other Chinese ethnic minorities and six Chinese populations covering the mainland of China, Taiwan, Hong Kong and Singapore. A neighbor-joining phylogenetic tree was constructed and revealed that the Beijing Han population clustered into the northern populations group and had a closer relationship with northern Han and Hui than with southern Han or other ethnic minorities. These results thus provide useful information that can be used in anthropology, selection for bone marrow transplantation as well as in disease-association study, such as in carbamazepine (CBZ)-induced Stevens-Johnson syndrome and toxic epidermal necrolysis.


Title 9 : Pharmacogenetics of cutaneous adverse drug reactions J Dermatol. 2011 Mar;38(3):246-54 Aihara M. Drug-induced hypersensitivity reactions are of major medical concern because they are associated with high morbidity and high mortality. In addition, individual patients' reactions are impossible to predict in each patient. In the field of severe cutaneous adverse drug reactions (cutaneous ADR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DHIS) or drug rash with eosinophilia and systemic symptoms (DRESS), major advances have recently been gained through studies of an association between HLA alleles and drug hypersensitivity induced by specific drugs. The results of these pharmacogenomic studies allow prediction of the risk of adverse reactions in patients treated with certain drugs, including carbamazepine and other aromatic antiepileptic drugs, allopurinol and abacavir. However, different ethnic populations show variations in the genetic associations. A strong association between carbamazepine-induced SJS/TEN and HLA-B1502 has been found in Southeast Asian patients but not in Caucasian and Japanese patients. Moderate associations between aromatic amine anticonvulsants and other HLA alleles have been proposed in Japanese patients. In contrast, HLA-B5801 was found to be associated with allopurinol-induced cutaneous ADR, including SJS/TEN and DIHS/DRESS, in Caucasian and Asian patients, including the Japanese. These differences may, at least in part, be due to the differences in allele frequency in different ethnic populations. This article reviews the progress in pharmacogenomics, associated mainly with carbamazepine and allopurinol in different ethnic populations. Pharmacogenetic screening based on associations between adverse reactions and specific HLA alleles helps to avoid serious conditions associated with drug hypersensitivity.


Title 10 : Pharmacogenetics of Idiosyncratic Adverse Drug Reactions Adverse Drug Reactions, Handbook of Experimental pharmacology 196, DOI 10.1007/978-3-642-00663-0_17, ©Springer‐Verlag Berlin Heidelberg 2010 Munir Pirmohamed Idiosyncratic adverse drug reactions are unpredictable and thought to have an underlying genetic etiology. With the completion of the human genome and HapMap projects, together with the rapid advances in genotyping technologies, we have unprecedented capabilities in identifying genetic predisposing factors for these relatively rare, but serious, reactions. The main roadblock to this is the lack of sufficient numbers of well-characterized samples from patients with such reactions. This is now beginning to be solved through the formation of international consortia, including developing novel ways of identifying and recruiting patients affected by these reactions, both prospectively and retrospectively. This has been led by the research on abacavir hypersensitivity – its association with HLA-B*5701 forms the gold standard of how we need to identify associations and implement them in clinical practice. Strong genetic predisposing factors have also been identified for hypersensitivity reactions such as are associated with carbamazepine, allopurinol, flucloxacillin, and statin-induced myopathy. However, for most other idiosyncratic adverse drug reactions, the genetic effect sizes have been low to moderate, although this may partly be due to the fact that only small numbers have been investigated and limited genotyping strategies have been utilized. It may also indicate that genetic predisposition will be dependent on multiple genes, with complex interactions with environmental factors. Irrespective of the strength of the genetic associations identified with individual idiosyncratic adverse drug reactions, it is important to undertake functional investigations to provide insights into the mechanism(s) of how the drug interacts with the gene variant to lead to a phenotype, which can take a multitude of clinical forms with variable severity. Such investigations will be essential in preventing the burden caused by idiosyncratic reactions, both in healthcare and in industry.


Title 11 : Pharmacogenetics of toxic epidermal necrolysis Expert Opin. Pharmacother. (2010) 11(13):2153-2162 Ming Ta Michael Lee, Shuen-Iu Hung, Chun-Yu Wei & Yuan-Tsong Chen Importance of the field: Toxic epidermal necrolysis (TEN) and Stevens—Johnson Syndrome (SJS) are two of the most severe drug-induced cutaneous reactions. Advances in genome technologies have allowed researchers to identify genetic markers associated with this drug-associated event and these have provided a potential tool for prevention.
Areas covered in this review: Current updates of genetic biomarkers that have been identified as being associated with TEN/SJS induced by several drugs, and the associations of these markers in different populations, are discussed.
What the reader will gain: The strong association of HLA-B1502 and carbamazepine (CBZ)-induced TEN/SJS have been reported by several independent studies. This association was mostly observed in patients of Southeast Asian ancestry; it was not observed in populations with low HLA-B1502 allele frequency. Studies also suggest that drugs with a similar chemical structure to CBZ might also induce TEN/SJS in patients with HLA-B1502. In addition to CBZ, HLA-B5801 was also found to associate with allopurinol-induced TEN/SJS. This strongly suggests that the associations of these markers with TEN/SJS are drug specific.
Take home message: The strong association between CBZ and HLA-B1502 has prompted the US Food and Drug Administration to update the label for CBZ to include genetic information and to recommend genetic testing before prescribing CBZ. Patients with Asian ancestry or who are from regions prevalent in HLA-B1502 should be screened before CBZ treatment.


*Title 12 : Pilot association study of oxcarbazepine-induced mild cutaneous adverse reactions with HLA-B1502 allele in Chinese Han population Seizure. 2011 Mar;20(2):160-2. Epub 2010 Dec 18 Hu FY, Wu XT, An DM, Yan B, Stefan H, Zhou D BACKGROUND:** Recent study demonstrated that HLA-B1502 was a common risk allele in aromatic antiepileptic drugs (AEDs) induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. However, the association of AEDs-induced mild maculopapular eruption (MPE) with HLA-B1502 remains unclear until recently. In the present study, we conducted a pilot study to detect a possible association of oxcarbazepine (OXC)-induced MPE with HLA-B*1502 allele in Chinese Han population.
METHODS: We enrolled 90 subjects involving 9 patients with OXC-induced MPE and two groups of controls, 9 OXC-tolerant and 72 normal controls. High-resolution HLA genotyping was performed by specific kit. The results of HLA genotyping are expressed as positive or negative for HLA-B*1502 allele. Differences in genotype frequencies between groups were assessed by the Fisher's exact test.
RESULTS: Four cases were detected as positive for HLA-B1502 amongst 9 patients. However, only 1 subject was positive amongst 9 tolerant controls, and 6 subjects were positive amongst 72 normal controls. The difference in HLA-B1502 allele frequencies between the MPE group and normal controls was statistically significant (OR: 8.8; 95% CI: 1.853-41.790; P=0.011). In addition, we also observed an increased frequency of HLA-B*1502 allele in patients (44.44%) compared with tolerant controls (11.11%), although it failed to reach statistical significance (P=0.294).
CONCLUSIONS: Our findings indicate that HLA-B1502 allele may contribute to the genetic susceptibility to OXC-induced MPE in Chinese Han population. In order to safer AEDs use, we recommend that HLA-B1502 allele should be tested for patients with OXC-induced MPE before changing to other AEDs, and AEDs with similar chemical structure should be avoided in individuals who test positive for HLA-B*1502 allele. It should be pointed out that, however, our results may well be just by chance owing to the small sample size and should be further confirmed in future studies.


Title 13 : Genetic Markers and Danger Signals in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Allergology International. 2010;59:325-332 Wen-Hung Chung and Shuen-Iu Hung Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse reactions, which could be induced by a variety of drugs. It was proposed that human leukocyte antigen (HLA)-restricted presentation of antigens (drugs or their metabolites) to T lymphocytes initiates the immune reactions of SJS/TEN. However, the genetic susceptibility and the exact pathogenesis were not clear until the recent studies. We first identified that HLA-B1502 is strongly associated with carbamazepine (CBZ)-induced SJS/TEN and HLA-B5801 with allopurinol-SJS/TEN in Han Chinese. The same associations had been validated across different human populations. For the downstream danger signals, Fas-Fas ligand (FasL) and perforin/granzyme B had been advocated as cytotoxic mediators for keratinocyte death in SJS/TEN. However, expression levels of these cytotoxic proteins from the skin lesions were too low to explain the distinct and extensive epidermal necrosis. Our recent study identified that the granulysin, a cytotoxic protein released from cytotoxic T cells or natural killer (NK) cells, is a key mediator for disseminated keratinocyte death in SJS/TEN. This article aims to provide an overview of both of the genomic and immunologic perspectives of SJS/TEN. These studies give us a better understanding of the immune mechanisms, biomarkers for disease prevention and early diagnosis, as well as providing the therapeutic targets for the treatments of SJS/TEN.


2009
*Title 1 : Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B1502 allele in Thai population Epilepsia. 2009 Apr;50(4):971. Chaichon Locharernkul, Jakrin Loplumlert, Chusak Limotai, Wiwat Korkij, Tayard Desudchit, Siraprapa Tongkobpetch, Oratai Kangwanshiratada, Nattiya Hirankarn, Kanya Suphapeetiporn, and Vorasuk Shotelersuk Purpose:** Previous studies found a strong association between HLA-B1502 and carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS) in Han Chinese, but not in Caucasian populations. Even in Han Chinese, the HLA-B1502 was not associated with CBZ-induced maculopapular eruptions (MPE). This study seeks to identify whether HLA-B*1502 is associated with CBZ- or phenytoin (PHT)-induced SJS or MPE in a Thai population.
Methods: Eighty-one Thai epileptic patients between 1994 and 2007 from the Chulalongkorn Comprehensive Epilepsy Program were recruited. Thirty-one subjects had antiepileptic drug (AED)-induced SJS orMPE (6 CBZ-SJS, 4 PHT-SJS, 9 CBZMPE, 12 PHT-MPE), and 50 were AED-tolerant controls.
Results: For the first time, a strong association between HLA-B1502 and PHT-induced SJS was found (p = 0.005). A strong association was also found between the HLA-B1502 and CBZ-induced SJS (p = 0.0005), making Thai the first non-Chinese population demonstrating such an association. Some patients, who were HLA-B1502 and suffered from CBZ-induced SJS, could be tolerant to PHT and vice versa. This suggests that HLA-B1502 may be a common attribute required for a Thai patient to develop SJS from these two AEDs; other different elements, however, are also needed for each AED. In addition, no association between HLA-B alleles and CBZ- or PHT-induced MPE was found. Conclusions: CBZ- and PHT-induced SJS, but not MPE, is associated with HLA-B*1502 allele in Thai population.


*Title 2 : Association of HLA-B1502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians Indian J Dermatol Venereol Leprol November-December 2009 Vol 75 Issue 6 Timir Y. Mehta, Laxman M. Prajapati, Bharti Mittal, Chaitanya G. Joshi, Jayesh J. Sheth, Dinesh B. Patel, Dinkar M. Dave, Ramesh K. Goyal Background:** Stevens-Johnson Syndrome (SJS) and toxic epidermal are severe cutaneous reactions caused by certain drugs, including antiepileptic carbamazepine. A strong association has been reported between human leucocyte antigen HLA-B1502 and carbamazepine-induced SJS in Han Chinese patients. European studies suggested that HLA-B1502 is not a universal marker but it ethnic-specific for Asians.
Aim: To study the association between HLA-B*1502 and carbamazepine-induced in Indian patients.
Methods: Eight individuals who fulfilled the diagnostic criteria of SJS induced by carbamazepine were identified and HLA-B molecular typing was performed. HLA-B genotyping was carried out by polymerase chain reaction using sequence-specific primers.
Results: Out of eight patients studied for genotyping, six patients were found to have the HLA-B*1502 allele.
Conclusion: This study suggests an association betweem HLA-B*1502 and carbamazepine-induced SJS in Indian patients.


Title 3 : FDA, researchers focus on genetics of drug hypersensitivity Am J Health-Syst Pharm—Vol 66 May 1, 2009 Kate Traynor The anticonvulsant drug carbamazepine is likewise associated with serious skin hypersensitivity reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis, in patients who have the HLA-B1502 allele. Labeling for the drug carries warnings against using it in patients with this genetic marker. FDA in November announced that it is investigating data on whether HLA-B1502 is associated with SJS and other skin reactions in people treated with another anticonvulsant, phenytoin.


Title 4 : Genetic basis for idiosyncratic reactions to antiepileptic drugs Current Opinion in Neurology 2009, 22:144–149 Diego Franciotta, Patrick Kwan and Emilio Perucca Purpose of review: In recent years, there has been an explosion of genetic research in epilepsy, including a search for genetic markers of adverse reactions to antiepileptic drugs. This article will focus on recent findings concerning genetic factors affecting susceptibility to idiosyncratic reactions to antiepileptic drugs.
Recent findings: Recent studies have investigated the role of genetic factors in the development of antiepileptic drug-induced cutaneous reactions, carbamazepine and valproate-induced liver toxicity, vigabatrin-induced visual field defects, and antiepileptic drug-induced teratogenicity. The greatest progress has been an improved definition of the role of human leukocyte antigen-related genes as predictors of the risk of serious antiepileptic drug-induced cutaneous reactions. This has led to the recommendation that patients of Asian ancestry be tested for the HLA-B*1502 allele, in order to identify those at high risk of developing Stevens–Johnson syndrome and toxic epidermal necrolysis after administration of carbamazepine and, possibly, phenytoin and other antiepileptic drugs.
Summary: Future research will probably lead to discovery of additional genetic predictors of susceptibility to adverse reactions to antiepileptic drugs. Identification of genetic markers should, in turn, allow unravelling of the molecular mechanisms underlying these reactions. Ultimately, these advances should lead not only to improved personalization of therapy but also to development of safer drugs.


Title 5 : Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis 2008 Nature Publishing Group http://www.nature.com/naturemedicine Wen-Hung Chung, Shuen-Iu Hung, Jui-Yung Yang, Shih-Chi Su, Shien-Ping Huang, Chun-Yu Wei,See-Wen Chin, Chien-Chun Chiou, Sung-Chao Chu, Hsin-Chun Ho, Chih-Hsun Yang, Chi-Fang Lu, Jer-Yuarn Wu, You-Di Liao & Yuan-Tsong Chen Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions characterized by massive epidermal necrosis, in which the specific danger signals involved remain unclear. Here we show that blister cells from skin lesions of SJS-TEN primarily consist of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand concentrations, and depleting granulysin reduced the cytotoxicity. Granulysin in the blister fluids was a 15-kDa secretory form, and injection of it into mouse skin resulted in features mimicking SJS-TEN. Our findings demonstrate that secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS-TEN and highlight a mechanism for CTL- or NK cell—mediated cytotoxicity that does not require direct cellular contact.


*Title 6: Oxcarbazepine-induced Stevens–Johnson syndrome in a patient with HLA-B1502 genotype** Journal compilation © 2008 European Academy of Dermatology and Venereology Y-C Chen, C-Y Chu, C-H Hsiao Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two of the severe cutaneous adverse drug reactions that are potentially life threatening. The strong association between the HLA-B1502 allele and carbamazepine-induced SJS (CBZ-SJS) has been documented in Han Chinese in one previous study. Oxcarbazepine (OXC), a 10-keto analogue of CBZ, is considered to be much safer than CBZ due to its different metabolic pathway. Herein, we describe a Chinese male diagnosed as having oxcarbazepine-induced SJS (OXC-SJS) with also positive HLA-B1502 allele. We also estimated the incidence of developing SJS/TEN in patients receiving CBZ and OXC.


Title 7 : The clinical impact of pharmacogenetics on the treatment of epilepsy Epilepsia, 50(1):1–23, 2009 Wolfgang Lo¨scher, Ulrich Klotz, Fritz Zimprich, and Dieter Schmidt Drug treatment of epilepsy is characterized byunpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLA-B 1502, are at a higher risk for Stevens-Johnson syndrome when using carbamazepine, are helpful to increase our knowledge how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individuals with epilepsy.


Title 8 : The future (or lack of future) of personalized prescription in psychiatry Pharmacological Research 59 (2009) 81–89 Jose de Leon Rapid technological advances in genetics have created conceptual chaos regarding the genetics of drug response. Terms for differing concepts are used interchangeably: pharmacogenetics with pharmacogenomics, personalized medicine with personalized prescription. Biomarker has many definitions. The author prefers the concept of personalized prescription and uses it with implications beyond pharmacogenetics by considering all scientific information valid for prescribing medication. Genetics may not be crucial for all drugs. In this comprehensive view, clinicians must consider genetic, environmental and personal variables when prescribing medication and incorporate some basic pharmacological principles: (1) safety and efficacy, (2) pharmacokinetics and pharmacodynamics, (3) therapeutic window and prescriber’s role, and (4) idiosyncratic and dose-related adverse drug reactions. Personalized prescription in the clinical environment can be expressed in two main ways: as personalized selection of the drug and as personalized dosing. The future, or lack of future, of personalized drug selection and of personalized dosing in psychiatry is reviewed. Currently, the author thinks that, in psychiatry, pharmacogenetic tests have some potential in two areas: (1) excluding some drugs for some unusual patients (HLA-B*1502 genotyping in Asians for carbamazepine), and (2) using pharmacokinetic genes for personalizing dosing in narrowtherapeutic window drugs. In the short term, there is dubious potential for other pharmacogenetic tests and no potential for pharmacogenetic testing to ascertain the best drug for each patient. Personalized dosing hasimmediate application if one understands it as the use of our current scientific knowledge of genetic, environmental and personal variables to determine dosing; its sole requirement is well-trained psychiatrists.


2008
Title 1 : A European study of HLA-B in Stevens–Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs Pharmacogenetics and Genomics 2008, Vol 18 No 2 Christine Lonjou, Nicolas Borot, Peggy Sekula, Neil Ledger, Laure Thomas, Sima Halevy, Luigi Naldi, Jan-Nico Bouwes-Bavinck, Alexis Sidoroff, Claudia de Toma, Martin Schumacher, Jean-Claude Roujeau, Alain Hovnanian, Maja Mockenhaupt and for the 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-B*
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.
Conclusion: 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 2 : Association of HLA-B1502 allele and carbamazepineinduced severe adverse cutaneous drug reaction among Asians, a review** Neurology Asia 2008; 13 : 15 – 21 Kheng Seang Lim, Patrick Kwan, Chong Tin Tan Strong association between HLA B1502 and carbamazepine-induced Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) was demonstrated among Han Chinese in 2004. Studies from Europe showed that the HLA B1502 is not a universal marker for SJS/TEN, but is ethnicity specific for Asians. Reports across Asia has shown that the prevalence of HLA B1502 is high among Han Chinese (5-15%), Malays (12-15%), and Thais (8-27%), but low among Japan, Korea, Sri Lanka, and most ethnic groups in India. Other than Han Chinese, the association between HLA B1502 and carbamazepine-induced SJS-TEN is also seen among the Thais and Malay. There is urgent need for further studies to determine the prevalence of SJS/TEN, and HLA B1502 in the various ethnic groups in Asia, and its association with carbamazepine-induced SJS-TEN in each of these ethnic groups. In view of the significant morbidity and mortality in SJS-TEN, facilities should be developed to allow for screening of HLA B1502 before carbamazepine is prescribed to the Hans Chinese, Malays and Thais. For those who experience no adverse cutaneous reaction after 3 months use of carbamazepine, the risk of SJS/TEN is low, and the drugs can be continued.


*Title 3 : Carbamazepine, HLA-B1502 and risk of Stevens-Johnson syndrom and toxic epidermal necrolysis: US FDA recommendations** Pharmacogenomics (2008) 9(10), 1543-1546 P Brent Ferrell Jr & Howard L McLeod Recently, the USA FDA has made a labeling change to the drug information contained in carbamazepine. Owing to recent data implicating the HLA allele B*1502 as a marker for carbamazepineiinduced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese, the FDA recommends genotyping all Asians for the allele. this allele is seen in high frequency in many Asian popuations other than Han Chinese, but there are few data on whether the allele is a marker for this severe outcome in anyone other than han Chinese. In fact, the association has not been found in Caucasian patients. We review the data that prompted this recommendation, list data for other ethnic groups, both Asian and non-Asian, and briefly discuss the implication of this recommendation for clinical practice.


Title 4 : Currents in Contemporary Ethics Journal of law, medicine & ethics: race, pharmaceuticals, and medical technology • fall 2008 Perry W. Payne, Jr. The term “personalized medicine” increasingly has come to mean the use of genetic testing in prescribing pharmaceutical products. The scientific basis of this approach to medicine is that, because of genetic variations, humans differ in their response to treatments. This observation is the cornerstone of pharmacogenetics and pharmacogenomics. Ethical problems sometimes arise when this principle is applied on a group basis. For example, if humans could be divided into two genetic groups, a group with genotype A and a group with genotype B, members of each group might respond differently to a particular drug. The group with genotype A might have an adverse reaction to a drug. The group with genotype B might have a therapeutic response to the drug. Personalized medicine focuses on ensuring that individuals likely to respond positively to a drug receive it, and individuals likely to respond negatively are not given the drug. Although often defined as a way of individually tailoring treatments, personalized medicine is better characterized as a way of tailoring treatments to groups of people with some shared genetic trait or traits. Hence, personalized medicine may be viewed as “subgroup medicine.”


Title 5 : A European study of HLA-B in Stevens–Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs Pharmacogenetics and Genomics 2008, 18:99–107 Christine Lonjou, Nicolas Borot, Peggy Sekula, Neil Ledger, Laure Thomas, Sima Halevy, Luigi Naldi, Jan-Nico Bouwes-Bavinck, Alexis Sidoroff, Claudia de Toma, Martin Schumacher, Jean-Claude Roujeau, Alain Hovnanian, Maja Mockenhaupt and for the 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.


Title 6 : HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis Pharmacogenomics (2008) 9(11), 1617-1622 Nahoko Kaniwa, Yoshiro Saito, Michiko Aihara, Kayoko Matsunaga, Masahiro Tohkin, Kouichi Kurose, Jun-ichi Sawada, Hirokazu Furuya, Yukitoshi Takahashi, Masaaki muramatsu, Shigeru Kinoshita, Masamichi Abe, Hiroko Ileda, mariko Kashiwagi, Yixuan Song, Mayumi Ueta, Chie Sotozono, Zenro Ikezawa & Riuychi Hasegawa; on behalf of the JSAR research group Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe adverse drug reactions with mucosal and cutaneous disorders, and very often accompanied by high fever and systemic complications. Some investigators have proposed that SJS and TEN are variations of the same disease expressed with different severity, although this is controversial. Although SJS and TEN incidence is very low (0.4-6 per million per year), more than 100 different causative drugs have been reported. The disease are probably T-cell-mediated delayed allergic reactions, and typically begin within 1-3 weeks after exposure to a drug. Recently, an extremely strong association (odd ration: ~2504) between human leukocyte antigen (HLA)-B1502 and carbamazepine-induced SJS/TEN in Han Chinese in Taiwan was reported. Another Taiwanese study showed that HLA-B5801 was detected in all Han Chinese patients with SJS/TEN or drug-induced hypersensitivity (DIHS) induced by allopurinol. The involvement of HLA-B1502 was also confirmed in SJS/TEN caused by other aromatic epileptic agents such as phenytoin in Han Chinese or Thai population. However, such a strong association between HLA-B1502 and carbamazepine-induced SJS/TEN was not detected in Caucasian patients. These reports suggested that HLA involvement in severe cutanrous adverse reactions may be drug-specific as well as ethnic group-specific. Thus, we started a retrospective case-control study to explore genetic biomarkers related to SJS and TEN in Japanese patients living in Japan.


Title 7 : OF RACE, ETHNICITY, AND RASH: THE GENETICS OF ANTIEPILEPTIC DRUG-INDUCED SKIN REACTIONS Epilepsy Currents, Vol. 8, No. 5 (September/October) 2008 pp. 120–121 John W. Miller, MD, PhD Serious allergic cutaneous reactions, especially Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are among the most feared complications of antiepileptic drug (AED) therapy. SJS and TEN are characterized by a blistering exanthema with mucosal involvement and skin detachment. TEN is defined by more extensive skin involvement than SJS (>30%) and has a higher mortality rate, 25% or more. The risk of these rare conditions colors many epilepsy treatment decisions, influencing the choice of an AED and the speed at which it is initiated. For this reason, the emerging evidence that genetic factors strongly predict occurrence of SJS and TEN will most certainly lead to changes in clinical practice.


Title 8 : Pharmacogenetic Determinants of Immediate and Delayed Reactions of Drug Hypersensitivity Current Pharmaceutical Design, 2008, 14, 2770-2777 J.L. Guéant, R.M. Guéant-Rodriguez, I. Aimone Gastin, J.A. Cornejo-García, M. Viola, A. Barbaud, P.M. Mertes, M. Blanca and A. Romano 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 β-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 FcεRIβ gene). Delayed Tcell-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 FcεRIβ 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 9 : Pharmacogenetic information derived from analysis of HLA alleles Pharmacogenomics (2008) 9(2), 207-214 Hiroyuki Gatanaga, Haruhito Honda & Shinichi Oka 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 centain drugs and allow personalized treatment, although the patients should be monitored closely even if they are negative for HLA alleles associated with hypersensitivity.


Title 10 : Polymorphisms of HLA genes in Western Javanese (Indonesia): close affinities to Southeast Asian populations Journal compilation 2008 Blackwell Munksgaard Tissue Antigens 73, 46–53 R. Yuliwulandari, K. Kashiwase, H. Nakajima, J. Uddin, T. P. Susmiarsih, A. S. M. Sofro2 & K. Tokunaga 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%), HLAB1502 (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.


2007
*Title 1 : Association between HLA-B1502 Allele and Antiepileptic Drug-Induced Cutaneous Reactions in Han Chinese** Epilepsia, 48(5):1015–1018, 2007 Celeste B.L. Man, Patrick Kwan, Larry Baum, Evelyn Yu, K.M. Lau, Alice S.H. Cheng, and Margaret H.L. Ng Summary: A previous study conducted in Taiwan found a 100% association between HLA-B 1502 allele and carbamazepine-induced Stevens-Johnson syndrome (SJS) in Han Chinese subjects, with an extremely high odds ratio compared with carbamazepine-tolerant subjects (odds ratio=2,504).We examined this association in 24 Hong Kong Han Chinese subjects who had cutaneous adverse reactions induced by different antiepileptic drugs (AEDs). They were matched with 48 AED-tolerant controls. HLA-B∗1502 was associated with severe cutaneous reactions (SCR) induced by AEDs, which included carbamazepine, phenytoin, and lamotrigine (p = 0.001, odds ratio = 17.6), but was not associated with maculopapular exanthema (MPE) (p=0.32). Further studies in larger samples of ethnically matched subjects should be conducted to confirm the findings. Identification of genetic polymorphisms predisposing to development of AED-induced SCR offers the possibility of avoiding these high-risk drugs in genetically susceptible individuals. KeyWords: HLA—Cutaneous reactions—Antiepileptic rugs—Rash—Stevens-Johnson syndrome.


Title 2 : Genetics of Severe Drug Hypersensitivity Reactions in Han Chinese Pichler WJ (ed): Drug Hypersensitivity. Basel, Karger, 2007, pp 55–64 Shuen-Iu Hung; Wen-Hung Chung; Yuan-Tsong Chen Drug hypersensitivity, an immune-related idiosyncratic adverse reaction, was historically referred to as being unpredictable. However, recent studies in Han Chinese have revealed that several types of severe drug hypersensitivity reactions have a strong genetic predisposition and might be predicted, particularly with the use of the genes coding for major histocompatibility complex (MHC), a key molecule for immune response. The genetic predisposition is drug- and phenotype-specific, HLA-B * 1502 is associated with carbamazepine-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and HLA-B * 5801 with allopurinol-SJS/TEN/hypersensitivity syndrome. These genetic associations are not limited to the Han Chinese, and their significance in other ethnic populations depends on the allele frequency of the populations. The genetic studies in Han Chinese support the concept that MHC-restricted presentation of drug is involved in the pathogenesis of immune-mediated severe drug hypersensitivity reactions. These genetic markers have the potential to be used for further development of tests to identify individuals at risk for these drug-related life-threatening conditions, as well as for an increased understanding of the pathogenesis of these clinical syndromes.


*Title 3 : HLA-B1502–bound peptides: Implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome J Allergy Clin Immunol 2007;120:870-7. Chih-Wen Ou Yang, MS, Shuen-Iu Hung, PhD, Chiun-Gung Juo, PhD, Ya-Ping Lin, MS, Wu-Hsiang Fang, MS, I.-Hsuan Lu, MS, Shui-Tein Chen, PhD, and Yuan-Tsong Chen, MD, PhD Background:** Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can involve MHC-restricted presentation of a drug or its metabolites for T-cell activation. HLA-B*1502 tightly associated with carbamazepine (CBZ) induced these conditions in a Han Chinese population.
Objective: We sought to identify HLA-B1502–bound peptides that might be involved in CBZ-induced SJS/TEN. Methods: Soluble HLA-B1502 was used to identify bound peptides in the presence and absence of CBZ by using liquid chromatography–tandem mass spectrometry. Peptide-binding assays were performed to detect the specific interaction between the HLA molecule and the identified peptides. Mass spectra were compared to detect CBZ-modified peptides.
Results: We identified more than 145 peptides bound to HLAB* 1502. In 13 of 15 peptides examined,we functionally confirmed their specificity with binding assays. Preferable uses of these peptides at the anchoring residues P2 and P9 were similar to those observed in other HLA-B alleles in the Han Chinese population. However, the preferable use of serine residues at the nonanchoring position (P) 5, P6, P7, and P8 appeared to be unique for the B*1502 peptides. No specific CBZ-modified peptides were detected when we compared the mass spectra of peptides detected in the presence or absence of the drug.
Conclusion: Noncovalent interaction between a drug and an HLA complex might contribute to cytotoxic T cell–mediated cell death in patients with SJS/TEN. Clinical implications: An understanding of pharmacologic interaction of drugs with an HLA complex might lead to safer drugs that avoid SJS/TEN.


Title 4 : Human leukocyte antigens and drug hypersensitivity Current Opinion in Allergy and Clinical Immunology 2007, 7:317–323 Wen-Hung Chung, Shuen-Iu Hung and Yuan-Tsong Chen 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 allopurinolinduced 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 B1502 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.
Keywords: drug hypersensitivity, human leukocyte antigen, immune reactions, pharmacogenetics


Title 5 : Various Pharmacogenetic Aspects of Antiepileptic Drug Therapy CNS Drugs 2007; 21 (2): 143-164 Michael W. Mann and Gerard Pons Pharmacogenetics concerns the influence of an individual’s genetic background on the pharmacokinetics and pharmacodynamics of xenobiotics. Much of the pharmacogenetic data in the field of epilepsy deals with the pharmacokinetics of antiepileptic drugs (AEDs). In particular, two polymorphisms of cytochrome P450 2C9 are known to slow down the metabolism of phenytoin to a degree that increases the risk of the neurotoxic adverse effects of 144 Mann & Pons this drug among carriers of these polymorphisms. A significant number of patients with epilepsy do not respond to AEDs and such pharmacoresistance is a major, largely unsolved, problem that is likely to be multifactorial in nature. In this regard, genetic factors may influence transmembrane drug transporter proteins, thereby modifying the intracerebral penetration of AEDs. Monogenic idiopathic epilepsies are rare and frequently associated with ion channel mutations; however, to date, a consistent relationship between changes in channel properties and clinical phenotype has not been established nor has any association between genotype and response to specific treatment options. Polymorphisms of drug targets may represent another genetic facet in epilepsy: a recent study demonstrated for the first time a polymorphism of a drug target (the α-subunit of a voltage-gated sodium channel) associated in clinical practice with differing response to two classic AEDs. Adverse drug reactions and teratogenicity of AEDs remain a major concern. Whole-genome single nucleotide polymorphism profiling might in the future help to determine genetic predisposing factors for adverse drug reactions. Recently, in Han Chinese treated with carbamazepine and presenting with Stevens-Johnson syndrome, a strong association was found with HLA B*1502. If genetically targeted drug development becomes more affordable/cost efficient in the near future, the development of new drugs for relatively rare diseases could become economically viable for the pharmaceutical industry. The synergy of lower trial costs and efficacy-based prescribing may reduce the cost of medical treatment for a particular disease. This hypothetical advantage of the practical use of pharmacogenetics is, however, counterbalanced by several possible dangers, including illicit data mining and the development of a human ‘genetic underclass’ with the risk of exclusion from, for example employment or health insurance, because of an ‘unfavourable’ genetic profile.


2006
Title 1 : A marker for Stevens-Johnson syndrome: ethnicity matters The Pharmacogenomics Journal (2006) 6, 265–268 C Lonjou, L Thomas, N Borot, N Ledger, C de Toma, H LeLouet, E Graf, M Schumacher, A Hovnanian, M Mockenhaupt, J-C Roujeau (for the RegiSCAR group) Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe cutaneous adverse drug reactions, which can be caused by a certain number of specific drugs among which is carbamazepine, an antiepileptic agent. A very strong association of carbamazepine-induced SJS with HLA-B1502 has recently been described in the Han Chinese population. Here in, we report preliminary results from a European study (RegiSCAR) of 12 carbamazepine-induced SJS/TEN cases (nine French and three German). Among these only four had a HLA-B1502 allele. Remarkably, these four patients had an Asian ancestry, whereas the others did not as far as we have ascertained. This shows that although the HLA region may contain important genes for SJS, the HLA-B*1502 allele is not a universal marker for this disease and that ethnicity matters.


Title 2 : Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions Pharmacogenetics and Genomics 2006, 16:297–306 Shuen-Iu Hung, Wen-Hung Chung, Shiou-Hwa Jee, Wen-Chieh Chen, Yun-Ting Chang, Woan-Ruoh Lee, Shu-Ling Hu, Meng-Tse Wu, Gwo-Shing Chen, Tak-Wah Wong, Pa-Fan Hsiao, Wei-Hsuan Chen, Han-Yu Shih, Wu-Hsiang Fang, Chun-Yu Wei, Yi-Hui Lou, Yau-Li Huang, Juei-Jueng Lin and Yuan-Tsong Chen The anticonvulsant carbamazepine (CBZ) frequently causes cutaneous adverse drug reactions (cADRs), including maculopapular eruption (MPE), hypersensitivity syndrome (HSS), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We reported that SJS/TEN caused by CBZ is strongly associated with the HLA-B1502 gene in Han Chinese. Here, we extended our genetic study to different types of CBZ-cADRs (91 patients, including 60 patients with SJS/TEN, 13 patients with hypersensitivity syndrome and 18 with maculopapular exanthema versus 144 tolerant controls). We used MALDI-TOF mass spectrometry to screen the genetic association of 278 single nucleotide polymorphisms (SNPs), which cover the major histocompatibility complex (MHC) region, tumor necrosis factor-alpha, heat shock protein and CBZ-metabolic enzymes, including CYP3A4, 2B6, 2C8, 2C9, 1A2 and epoxide hydrolase 1. In addition, we genotyped 20 microsatellites in the MHC region and performed HLA-typing to construct the recombinant map. We narrowed the susceptibility locus for CBZ-SJS/TEN to within 86 kb flanking the HLA-B gene on the extended B1502 haplotype, and confirmed the association of B1502 with SJS/TEN [Pc = 1.6 10–41, odds ratio (OR)= 1357; 95% confidence interval (CI) =193.4–8838.3]. By contrast to CBZ-SJS/TEN, HLA-B1502 association was not observed in the MPE or HSS groups: MPE was associated with SNPs in the HLA-E region and a nearby allele, HLA-A3101 (Pc =2.2 10–3, OR= 17.5; 95% CI= 4.6–66.5), and HSS with SNPs in the motilin gene (Pc = 0.0064, OR= 7.11; 95% CI= 3.1–16.5) located terminal to the MHC class II genes. No SNPs in genes involved in CBZ metabolism were associated with CBZ-induced cADRs. Our data suggest that HLA-B1502 could contribute to the pathogenesis of CBZ-SJS/TEN, and that genetic susceptibility to CBZ-induced cADRs is phenotypespecific.


Title 3 : HLA-B locus in Caucasion patients with carbamazepine hypersensitivity Pharmacogenomics J. 2006; 7(6), 813-818 Ana Alfirevic, Andrea L Jorgensen, Paula R Williamson, David W Chadwick, B Kevin Park, Munir Pirmohamed Background: A strong pharmacogenetic association has been reported in Chinese patients between human leukocyte antigen (HLA)-B*1502 and carbamazepine (CBZ)-induced Steven-Johnson syndrome (SJS).
Methods: We have genotyped the HLA-B alleles in 56 Caucasian patients with varying severities of CBZ hypersensitivity and 43 controls on CBZ without adverse effects.
Results: None of our patients (including two with blistering skin rashes) were positive for the HLA-B1502 allele. HLA-B0702 allele may protect against severe CBZ hypersensitivity but warrants further study. Of secondary interest, the correlation between HLA-B*0801 and HLA-DR3, DQ2 and TNF-308 alleles (on the ancestral haplotype 8.1) is consistent with our previous findings.
Conclusion: HLA-B*1502 does not seem to be a marker for all forms of CBZ-induced hypersensitivity in a Caucasian population.


2005
Title 1 : HLA-B genotyping to detect carbamazepine induced Steven-Johnson Syndrome: implications for personalizing medicine Personalized Medicine. 2005; 2(3)225-237. Hung SI, Chung WH, Chen YT Preventing severe adverse drug reactions by identifying people at risk with a simple genetic test is the goal of many pharmacogenomic studies. Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are related, life-threatening cutaneous adverse reactions, most often caused by medication. The overall incidence and the commonly offending drugs vary among different ethnic populations. Susceptibility to such idiosyncratic reactions is thought to be genetically determined and immune mediated. Finding a strong genetic association between a particular human leukocyte antigen (HLA)-B allele and the reaction to a specific drug provides evidence that the pathogenesis of the severe cutaneous adverse drug reactions involves major histocompatibility complex-restricted presentation of a drug or its metabolites for T-cell activation. In the case of carbamazepine-induced SJS/TEN, the tight association of the HLA-B*1502 allele (sensitivity 100%, specificity 97% and odds ratio 2504) provides a plausible basis for further development of such a test to identify individuals at risk of developing this life-threatening condition.


2004
Title 1 : Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004 Apr 1;428(6982):486 Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JY, Chen YT. Department of Dermatology, Chang Gung Memorial Hospital, Taipei, Taiwan. Stevens-Johnson syndrome and the related disease toxic epidermal necrolysis are life-threatening reactions of the skin to particular types of medication. Here we show that there is a strong association in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B*1502, and Stevens-Johnson syndrome induced by carbamazepine, a drug commonly prescribed for the treatment of seizures. It should be possible to exploit this association in a highly reliable test to predict severe adverse reaction, as well as for investigation of the pathogenesis of Stevens-Johnson syndrome. PMID: 15057820 [PubMed - indexed for MEDLINE]