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HLA-B*15:359 differs from HLA-B*15:01:01:01 by one nucleotide substitution in exon 3., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The novel allele HLA-B*15:693 has 5 nucleotide differences compared with HLA-B*15:18:07., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-B*15:358 differs from HLA-B*15:02:01:01 by one nucleotide substitution at position 685 in exon 4., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Two novel HLA alleles HLA-B*15:699 and HLA-C*03:677 were detected during routine HLA typing by next generation sequencing., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Two novel Class I HLA-B alleles HLA-B*13:194 and HLA-B*15:694 are described., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Genetic screening for HLA-B*15:02 before prescribing carbamazepine is standard practice to prevent severe cutaneous adverse reactions in Asian populations. These reactions are associated not only with this allele but also with closely related HLA-B75 serotype markers-HLA-B*15:11 and HLA-B*15:21-which are prevalent in several Asian countries. However, a reliable method for identifying HLA-B75 serotype markers is still not available. We developed an in-house quantitative PCR (qPCR) for HLA-B75 screening and validated it using 303 anonymized DNA samples. Due to inadequate quality control, the qPCR results for 11 samples were excluded. We analyzed the sensitivity and specificity of the test using 93 HLA-typed samples. The concordance between the qPCR method and an established screening method was assessed using 199 HLA-screened samples tested for HLA-B*15:02 at Songklanagarind Hospital, Songkhla, Thailand. All discordant results were confirmed by Sanger sequencing. The qPCR method demonstrated a sensitivity of 100% (95% confidence interval = 83.16%-100.00%) and a specificity of 100% (95% confidence interval = 95.07%-100.00%). Concordance analysis revealed a 96.5% agreement between methods (192/199; 44 positive and 148 negative results). All discordant results were due to HLA-B75 markers not being HLA-B*15:02 (two samples with HLA-B*15:11 and five samples with HLA-B*15:21). In conclusion, this qPCR method could be useful for identifying HLA-B75 carriers at risk of carbamazepine-induced reactions in Asian populations where carriers of HLA-B*15:02, HLA-B*15:11, or HLA-B*15:21 are common., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

HLA-B*15:659 differs from HLA-B*15:02:01:01 by one nucleotide in exon 2., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-B*15:02:15 differs from HLA-B*15:02:01:01 by one nucleotide in exon 2., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Genetic differences among individuals could affect the clinical presentations and outcomes of COVID-19. Human Leukocyte Antigens are associated with COVID-19 susceptibility, severity, and prognosis. This study aimed to identify HLA-B and -C genotypes among 69 Egyptian patients with COVID-19 and correlate them with disease outcomes and other clinical and laboratory data. HLA-B and -C typing was performed using Luminex-based HLA typing kits. Forty patients (58%) had severe COVID-19; 55% of these patients died, without reported mortality in the moderate group. The alleles associated with severe COVID-19 were HLA-B*41, -B*42, -C*16, and -C*17, whereas HLA-B*15, -C*7, and -C*12 were significantly associated with protection against mortality. Regression analysis showed that HLA-B*15 was the only allele associated with predicted protection against mortality, where the likelihood of survival increased with HLA-B*15 (P < 0.001). Patient survival was less likely to occur with higher total leukocytic count, ferritin, and creatinine levels. This study provides interesting insights into the association between HLA class I alleles and protection from or severity of COVID-19 through immune response modulation. This is the first study to investigate this relationship in Egyptian patients. More studies are needed to understand how HLA class I alleles interact and affect Cytotoxic T lymphocytes and natural killer cell function., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the association between endoplasmic reticulum aminopeptidase (ERAP)1 and ERAP2 single-nucleotide polymorphisms (SNPs) and human leukocyte antigens (HLA)-B27+ or HLA-B15+ patients with spondyloarthritis (SpA)., Methods: 104 patients with SpA according to Assessment of Spondyloarthritis International Society criteria were included in the study. HLA typing was performed by PCR. The polymorphisms were determined by real-time PCR on genomic DNA using customised probes for SNPs rs27044, rs17482078, rs10050860 and rs30187 in ERAP1 , and rs2910686, rs2248374 and rs2549782 in ERAP2 ., Results: 70 of the104 patients with SpA were HLA-B27+ and 34 were HLA-B15+. The distribution of ERAP1 and ERAP2 SNPs between the HLA-B15+ and HLA-B27+ patients with SpA did not reveal differences. Likewise, no differences in the frequencies of ERAP1 SNP haplotypes and alleles HLA-B15 or HLA-B27 were found. Interestingly, however, the frequencies of three particular haplotypes formed by ERAP2 SNPs rs2549782/rs2248374/rs2910686 varied between HLA-B15+ and HLA-B27+ patients: the ERAP2 SNPs haplotype TGT was more common in HLA-B15+ patients with SpA (OR 2.943, 95% CI 1.264 to 6.585; P=0.009), whereas the ERAP2 SNP haplotypes TGC and CAT were more associated with HLA-B27+ patients with SpA: (OR 4.483, 95% CI 1.524 to 13.187; p=0.003) and (OR 9.014, 95% CI 1.181 to 68.807; p=0.009), respectively., Conclusion: An association was found between HLA-B15+ patients with SpA and haplotype TGT of ERAP2 SNPs. On the other hand, HLA-B27+ patients with SpA were associated with ERAP2 haplotypes TGC and CAT. These associations could be related to the clinical presentation of the disease, specifically with a peripheral or axial predominance, respectively., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The HLA-B15 typing by serological approaches defined the serological subgroups (or splits) B62, B63, B75, B76, B77 and B70 (B71 and B72). The scarcity of sera with specific anti-HLA antibodies makes the serological typing method difficult to discriminate a high variety of HLA antigens, especially between the B15 antigen subgroups. Advancements in DNA-based technologies have led to a switch from serological typing to high-resolution DNA typing methods. DNA sequencing techniques assign B15 specificity to all alleles in the HLA-B*15 allele group, without distinction of the serological split equivalents. However, the presence of antibodies in the patient defined as split B15 antigens urges the identification of HLA-B*15 allele subtypes of the donor, since the presence of donor-specific antibodies is an important contraindication for organ transplantation. Although the HLA dictionary comprises information regarding the serological subtypes of HLA alleles, there are currently 394 B15 antigens out of 516 in the IPD-IMGT/HLA database (3.38.0) without any assigned serological subtype. In this regard, we aimed to identify specific amino acid patterns for each B*15 serological split, in order to facilitate the assignment of B*15 alleles to serological equivalents after high-resolution molecular typing. As a result, serological specificities of 372/394 not yet assigned alleles could be predicted based on amino acid motifs. Furthermore, two new serological types were identified and added, B62-Bw4 and B71-Bw4.

We report a discordance between complement-dependent cytotoxicity and next-generation sequencing molecular typing revealing HLA-B*15:47:01 allele with undefined serological equivalent confirmed by high-level immunization against the B15 serotype. Due to the high-level immunization against HLA-B15 and B70 antigens, we considered the HLA-B*15:47:01 allele to be B Blank and not as B15 or B70 serological specificity., (© 2019 John Wiley & Sons Ltd.)

Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αβTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αβTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αβTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.

Controversies exist with regard to in vivo approaches to delayed immunologically mediated adverse drug reactions, such as exanthem (maculopapular eruption), drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and fixed drug eruptions. In particular, widespread differences exist between regions and practice on the availability and use of intradermal and patch testing, the standard drug concentrations used, the use of additional drugs in intradermal and patch testing to help determine cross-reactivity, the timing of testing in relation to the occurrence of the adverse drug reaction, the use of testing in specific phenotypes, and the use of oral challenge in conjunction with delayed intradermal and patch testing to ascertain drug tolerance. It was noted that there have been advances in the science of delayed T cell-mediated reactions that have shed light on immunopathogenesis and provided a mechanism of preprescription screening in the case of HLA-B*57:01 and abacavir hypersensitivity and HLA-B*15:02 and carbamazepine Stevens-Johnson syndrome/toxic epidermal necrolysis in Southeast Asian subjects. Future directions should include the collaboration of large international networks to develop and standardize in vivo diagnostic approaches, such as skin testing and patch testing, combined with ex vivo and in vitro laboratory approaches., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

HLA-B*15:476 differs from HLA-B*15:01:01:01 by one nucleotide substitution at codon 299 in exon 5., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

T-cell receptor (TCR) immunotherapy uses T cells engineered with new TCRs to enable detection and killing of cancer cells. Efficacy of TCR immunotherapy depends on targeting antigenic peptides that are efficiently presented by the best-suited major histocompatibility complex (MHC) molecules of cancer cells. However, efficient strategies are lacking to easily identify TCRs recognizing immunodominant peptide-MHC (pMHC) combinations utilizing any of the six possible MHC class I alleles of a cancer cell. We generated an MHC cell library and developed a platform approach to detect, isolate, and re-express TCRs specific for immunodominant pMHCs. The platform approach was applied to identify a human papillomavirus (HPV16) oncogene E5-specific TCR, recognizing a novel, naturally processed pMHC (HLA-B*15:01) and a cytomegalovirus-specific TCR targeting an immunodominant pMHC (HLA-B*07:02). The platform provides a useful tool to isolate in an unbiased manner TCRs specific for novel and immunodominant pMHC targets for use in TCR immunotherapy.

HLA-A*31:01 and HLA-B*15:02 have been widely reported to confer genetic susceptibility to carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCARs). Accordingly, the screening for these alleles has been highly recommended to prevent SCAR prior to introducing CBZ therapy. Although a number of methods are available for screening of HLA-A*31:01 or HLA-B*15:02 alleles separately, developing an assay that can detect both these alleles would be more clinically practical, cost-effective and less time-consuming. Therefore, in this study, a multiplex polymerase chain reaction (PCR) using TaqMan Probe was designed and validated to be able to detect HLA-A*31:01 and HLA-B*15:02. In comparison with Luminex-SSO/SBT/SSB, the multiplex PCR assay for detection of HLA-A*31:01 and HLA-B*15:02 had a perfect agreement in the validation group of 125 samples. The method was able to detect the target genes at the DNA concentration of 0.037 ng/μL. The unit cost of this assay is less than $5 USD with total time of 110 minutes., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The novel HLA-B*15:416 allele differs from HLA-B*15:01:01:01 by a single nucleotide substitution at codon 114., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-B*15:01:23 has 1 synonymous nucleotide change from HLA-B*15:01:01:01 at nucleotide 393 (codon 107 glycine)., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We report the full-length sequences of 4 alleles of the HLA-B*15 gene family., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We report the full-length sequence of 4 HLA-B*15 alleles, B*15:07:01:01, B*15:27:01, B*15:32:01 and B*15:58., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

One nucleotide replacement at residue 221 of HLA-B*15:18:01:01 results in a new allele, HLA-B*15:414., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: HLA-B*15:02 is a known biomarker for carbamazepine (CBZ)-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) in some ethnic populations. The US FDA recommends B*15:02 screening for Asian and other populations with a high prevalence of B*15:02 prior to treatment with CBZ to prevent drug-related SJS/TEN., Materials and Methods: A total of 1607 blood samples were collected from volunteer blood donors who were ethnic minorities living in the Yunnan province of southwestern China, including 153 Yi, 193 Naxi, 167 Miao, 156 Lisu, 166 Derung, 211 Bai, 184 Hani, 198 Dai, and 179 Zhuang. The genetic diversity of the HLA-B*15:02 genes in the ethnic minority samples was examined using sequence based typing at high resolution., Results: The allele frequencies of HLA-B*15:02 in the Yi, Naxi, Miao, Lisu, Derung, Bai, Hani, Dai, and Zhuang populations were 4.25%, 4.4%, 5.09%, 5.77%, 6.33%, 7.82%, 8.15%, 9.6%, and 15.36%, respectively. The frequencies of HLA-B*15:02 carriers in the Yi, Naxi, Miao, Lisu, Derung, Bai, Hani, Dai, and Zhuang populations were 8.5%, 8.8%, 9.58%, 10.9%, 12.65%, 15.64%, 16.3%, 18.69%, and 28.49%, respectively., Conclusion: The HLA-B*15:02 allele frequencies indicated that the prevalence of B*15:02 was different among the different ethnic populations. Because the number of carriers of B*15:02 was high in some ethnic populations, larger studies are required to confirm these findings. The Zhuang population had the highest frequency of B*15:02 in this study. More attention should be paid to CBZ-induced SJS/TEN in Chinese minority populations., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Phenytoin (PHT) is a common cause of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Although HLA-B*15:02 is associated with PHT-induced SJS/TEN (PHT-SJS/TEN) in Han Chinese and Thais, the genetic basis for susceptibility to PHT-induced SCARs (PHT-SCAR) in other populations remains unclear. We performed a case-control association study by genotyping the human leukocyte antigen (HLA)-B alleles of 16 Malay PHT-SCAR patients (13 SJS/TEN and 3 DRESS), 32 PHT-tolerant controls and 300 healthy ethnicity-matched controls. A novel genetic biomarker, HLA-B*15:13, showed significant association with PHT-SJS/TEN (53.8%, 7/13 cases) (odds ratio (OR) 11.28, P=0.003) and PHT-DRESS (100%, 3/3 cases) (OR 59.00, P=0.003) when compared with PHT-tolerant controls (9.4%, 3/32 controls). We also confirmed HLA-B*15:02 association with PHT-SJS/TEN (61.5%, 8/13 cases vs 21.9%, 7/32 controls; OR 5.71, P=0.016) when compared with PHT-tolerant controls. These alleles may serve as markers to predict PHT-SCAR in Malays.

Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction characterized by necrosis of the epidermis. Its incidence is approximately 1 per million a year and average mortality rate is high at 25-50%. TEN has a flu-like prodrome, followed by atypical, targetoid erythematous or purpuric macules on the skin. These macules coalesce to form flaccid blisters that slough off as areas of epidermal necrosis. Drugs such as allopurinol, sulfonamides, and carbamazepine are the most common causes. The human leukocyte antigen (HLA)-B*15:02 in Asians being administered carbamazepine and the HLA-B*58:01 antigen in patients of all ethnicities being administered allopurinol are known to be high-risk factors. Rapid diagnosis, discontinuation of the causative drug, and supportive treatment are essential for better prognosis and improvement of sequelae. Till now, systemic corticosteroids and intravenous immunoglobulins have been used as the most common active interventions; however, no gold standard has been established. In Japan, physicians follow a unique diagnostic criteria and treatment guideline to improve the diagnosis rate and streamline treatments. This may be a contributing factor for the lower mortality rate (14.3%). The efficacy of systemic corticosteroids, immunoglobulins, and plasmapheresis may have been beneficial as well. In Japan, TEN is defined as an epidermal detachment of over 10% of the body surface area (BSA), while the globally accepted definition established by Bastuji-Garin describes it as an epidermal detachment of over 30% of the BSA. In Japanese individuals, HLA-A*02:06, HLA-A*02:07, HLA-A*31:01 and HLA-B*51:01 may be linked to higher risks of TEN., (Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

HLA-B*15:374 has one nucleotide change from HLA-B*15:02:01 at nucleotide 553 bp where G → A in exon 3., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

One nucleotide replacement in codon 41 of HLA-B*15:02:01 results in a novel allele, HLA-B*15:399., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-B*15:379 differs from HLA-B*15:03:01:01 by a c.T539G substitution in exon 3., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-B*15:226N has one nucleotide change from HLA-B*15:08:01 where 87Q is changed to a stop codon., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-B*15:04:04 differs from HLA-B*15:04:01 by one nucleotide at codon 238 (gat > gac)., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

One nucleotide replacement at residue 47 of HLA-B*15:18:01:01 results in a new allele, HLA-B*15:388., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: In HLA-matched allogeneic hematopoietic stem cell transplantation (alloSCT), donor T cells recognizing minor histocompatibility antigens (MiHAs) can mediate desired antitumor immunity as well as undesired side effects. MiHAs with hematopoiesis-restricted expression are relevant targets to augment antitumor immunity after alloSCT without side effects. To identify therapeutic MiHAs, we analyzed the in vivo immune response in a patient with strong antitumor immunity after alloSCT., Experimental Design: T-cell clones recognizing patient, but not donor, hematopoietic cells were selected for MiHA discovery by whole genome association scanning. RNA-sequence data from the GEUVADIS project were analyzed to investigate alternative transcripts, and expression patterns were determined by microarray analysis and qPCR. T-cell reactivity was measured by cytokine release and cytotoxicity., Results: T-cell clones were isolated for two HLA-B*15:01-restricted MiHA. LB-GLE1-1V is encoded by a nonsynonymous SNP in exon 6 of GLE1 For the other MiHAs, an associating SNP in intron 3 of ITGB2 was found, but no SNP disparity was present in the normal gene transcript between patient and donor. RNA-sequence analysis identified an alternative ITGB2 transcript containing part of intron 3. qPCR demonstrated that this transcript is restricted to hematopoietic cells and SNP-positive individuals. In silico translation revealed LB-ITGB2-1 as HLA-B*15:01-binding peptide, which was validated as hematopoietic MiHA by T-cell experiments., Conclusions: Whole genome and transcriptome analysis identified LB-ITGB2-1 as MiHAs encoded by an alternative transcript. Our data support the therapeutic relevance of LB-ITGB2-1 and illustrate the value of RNA-sequence analysis for discovery of immune targets encoded by alternative transcripts. Clin Cancer Res; 22(16); 4185-96. ©2016 AACR., (©2016 American Association for Cancer Research.)

In this report we describe a case of somatic mutation in the HLA-B gene in the tumour cells of a patient with acute myelogenous leukaemia (AML). Routine human leukocyte antigen (HLA) typing of patient by serology and molecular methodologies rendered discrepant results regarding the expression of a B*15:01 antigen. Sequencing-based typing of a patient's sample including a very high percentage of blast cells revealed the presence of one nucleotide insertion at exon 3, position 440, codon 123. This insertion resulted in a reading frame shift and a premature stop codon at position 152. The mutation was absent in a sample obtained when the patient was in remission. This case report points out the relevance of the sample source for HLA typing in patients with haematological malignancies., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The novel allele B*15:02:11, was identified in a Chinese individual by sequence-based typing., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Currently, there are three published HLA-B*15:02 screening methods for prevention of carbamazepine-induced severe drug reactions in Asian populations. To analyze available HLA-B*15:02 screening methods, we compared four screening methods, including a multiplex PCR method, a nested PCR method, a LAMP method and our new in-house PCR-dot blot hybridization method. These methods were reviewed regarding their sensitivity, specificity, false positivity and technical considerations. Possible false positive (FP) alleles and genotypes were checked regarding the primers and probes designs, using the IMGT/HLA database. Expected FP rates in Asian populations were predicted using the Allele Frequencies Net Database. All methods had a sensitivity of more than 99.9%, although giving FP results to certain very rare alleles and genotypes. The multiplex PCR method was the only test that gave FP results to certain genotypes of HLA-B*15:13, the allele which is prevalent in Southeast Asian populations. In conclusion, the nested PCR, LAMP and our in-house methods could be applied in various Asian populations, but the multiplex PCR, or any test with FP to HLA-B*15:13, should be applied with caution in the Southeast Asian populations.

HLA-B*15:326 has one base substitution at position 176G>A in exon 2 compared with HLA-B*15:01:01:01., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

One nucleotide substitution at residue 86 of HLA-B*15:27:01 results in a new allele, HLA-B*15:327., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

One nucleotide substitution at residue 531 of HLA-B*15:01:01:01 results in a new allele, HLA-B*15:01:37., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-B*15:263 differs from HLA-B*15:18:01 by a single nucleotide exchange at position 824, C>G (codon 251 TCT>TGT)., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Study Aims: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are fatal adverse cutaneous drug reactions which may be induced by phenytoin (PHT) or lamotrigine (LTG). The objective of this study was to analyze the association of human leukocyte antigen (HLA)-B*1502 and PHT or LTG induced SJS/TEN., Patients and Methods: All the participants were epileptic patients and the SJS/TEN were induced by PHT or LTG. The presence or absence of the HLA-B*1502 allele of all the patients was determined. ISI Web of Knowledge, PubMed, ScienceDirect, EMBASE, and Cochrane Register of Controlled Trials (CENTRAL) data were searched for the literature published before April 2014. Meta-analysis was performed using Review Manager 5.2 software., Results: From 256 citations, 6 English studies were included that involved 480 epilepsy patients. Meta-analysis showed that odd ratio (OR) of PHT and LTG were 5.65 [95% CI: 2.76-11.57] and 4.51 [95% CI: 1.57-12.98], respectively. Funnel plot analysis showed symmetry, indicting less possible publication bias and the results were partly reliable., Conclusion: There is a significant association between HLA-B*1502 and PHT or LTG-induced SJS/TEN., (© Georg Thieme Verlag KG Stuttgart · New York.)

This study aimed to investigate the prevalence and association of HLA-B*15:02 with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (CBZ-SJS/TEN) in the Indian population in Malaysia, which mostly originated from Southern India. HLA-B alleles in five Indian case patients with CBZ-SJS/TEN and 52 CBZ-tolerant controls, and followed by a pooled sample of seven cases from two centers in Malaysia were analyzed. Positive association for HLA-B*15:02 with CBZ-SJS/TEN was detected in Indians (40% [2/5] vs. 3.8% [2/52], odds ratio [OR] 16.7, p = 0.0349), of which 80% (4/5) of the Indian patients originated from Southern India. A pooled sample of seven cases showed stronger association between HLA-B*15:02 and CBZ-SJS/TEN (57.1% [4/7] vs. 3.8% [2/52], OR 33.3, 95% confidence interval [CI] 4.25-162.21, p = 1.05 × 10(-3)). Subsequent meta-analysis on Indians from Malaysia and India further demonstrated a significant and strong association between HLA-B*15:02 and CBZ-SJS/TEN (OR 38.54; 95% CI 6.83-217.34, p < 1.0 × 10(-4)). Our study is the first on Indians predominantly from Southern India that demonstrated HLA-B*15:02 as a strong risk factor for CBZ-SJS/TEN despite a low population allele frequency. This stressed the importance of testing for HLA-B*15:02, irrespective of the ancestral background, including populations with low allele frequency., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

The evidence of association between HLA-B(∗)1502 and anticonvulsant induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) from the Indian population is scant. Patients with a history of SJS/TEN secondary to carbamazepine or phenytoin were enrolled. The control group comprised of patients who had received carbamazepine/phenytoin for ⩾ 6 months without any adverse cutaneous event. Low-resolution DNA typing for HLA-B and high resolution HLA-B(∗)15 typing was performed. Seventeen patients with history of SJS/TEN secondary to carbamazepine (9) or phenytoin (8) and 50 tolerant controls (carbamazepine-37; phenytoin-13) were enrolled. The mean age of patients and controls was 33.9 ± 11.6 and 28.1 ± 9.9 years, respectively. HLA-B(∗)1502 was observed in 2/9 (22.2%) carbamazepine-SJS/TEN patients and none of the 37 carbamazepine tolerant controls (p = 0.035). HLA-B(∗)1502 was not observed in any of the 8 phenytoin-SJS/TEN patients or the 13 phenytoin tolerant controls. Our data suggests that HLA-B(∗)1502 is a risk factor for carbamazepine induced SJS/TEN. Therefore, HLA-B(∗)1502 testing should be performed prior to initiating carbamazepine in North Indian population., (Copyright © 2014. Published by Elsevier Inc.)

With the advent of Twenty-First century, more and more genome-wide association studies (GWAS) showed that idiosyncratic adverse drug reactions (ADRs) were closely related with human leukocyte antigen (HLA) alleles, such as the associations of abacavir-HLA-B*5701, allopurinol-HLA-B*5801, and carbamazepine-HLA-B*1502, etc. To explore the mechanisms of these idiosyncratic drug reactions, hapten hypothesis, danger signal hypothesis, pharmacological interaction (P-I) concept and autoimmune mechanism are proposed. In this paper, recent GWAS studies on the HLA-mediated adverse drug reactions and underlying mechanism are reviewed in detail.

To investigate the relationship between human leukocyte antigen (HLA) class I and II alleles and treatment-induced anemia in chronic hepatitis C (CHC) patients receiving combination therapy with pegylated interferon-α (PEG-IFN-α) and ribavirin (RBV). One hundred six naïve CHC patients (59 females and 47 males; mean age, 53.08 years) who underwent combination treatment were enrolled. The patients were considered positive for hemoglobin (Hb)-related side effects if the Hb concentrations dropped below 10 g/dl during PEG-IFN-α plus RBV treatment. The HLA-A, -B, -C, -DR, and -DQ loci were investigated by sequence-based genotyping. The effects of the clinical characteristics, virologic variables, and the HLA alleles on treatment-induced anemia were evaluated by a logistic regression analysis. Forty patients (37.7%) had Hb levels below 10 g/dl during the treatment course. Low baseline Hb levels and an advanced liver fibrosis stage were associated with decreases in Hb levels to below 10 g/dl. The occurrence of treatment-related anemia (Hb < 10 g/dl) was significantly associated with HLA-B*15:02 as shown by multivariate analysis (adjusted odds ratio, 8.13; 95% confidence interval: 1.19-55.70; P-value after Holm's procedure, 0.03). HLA-B*15:02 is associated with treatment-induced anemia in Taiwanese CHC patients receiving combination therapy with PEG-IFN-α plus RBV., (© 2012 John Wiley & Sons A/S.)

The human leucocyte antigen (HLA) system is well known for its association with certain diseases such as ankylosing spondylitis, celiac disease and many others. More recently, severe and even fatal drug hypersensitivity reactions linked to particular HLA alleles have been discovered. The significance of these discoveries has led the European Medicines Agency (EMA) and its member state agencies to recommend HLA gene testing before initiation of drug treatment. To date, the following drugs have been identified as causing significant drug hypersensitivity reactions in patients who have the following HLA alleles: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02/A*31:01 and finally allopurinol and HLA-B*58:01. This review will outline and discuss these three drugs and their associated HLA alleles as well as examine the pathogenesis of the drug hypersensitivity reactions., (© 2011 Blackwell Publishing Ltd.)

Using PCR with sequence-specific primers (SSP) and subsequent sequencing of exons 2 and 3, we identified an example of B*15:33 in a likely north-western European Caucasoid volunteer haemopoietic stem cell (HSC) donor. This was only the second example submitted to the IMGT/HLA database since B*15:33 was first described in 1996. B*15:33 differs from B*15:01:01:01 by three nucleotides resulting in two amino acid differences with B*15:01 (131S>R, 138T>K). This allele encodes a typical HLA-B62 specificity--as confirmed using 17 local antisera from parous women and 19 monoclonal antibodies directed towards B15, B62 and B63 specificities. Importantly, it also reacted as a Cw5/Cw8 specificity when tested against 21 Cw5, Cw5/Cw8 and Cw8 antisera. This Cw5/Cw8 reactivity is probably due to the B*15:33 specificity having lysine at position 138 which is possessed by numerous C*05 and many C*08 products. B*15:33 is likely to have derived from a HLA-B/C inter-locus gene conversion event. HLA-B*15:33 is clearly rare--this single example was found during the HLA PCR-SSP-based typing of 57,079 potential HSC donors. This indicates an allele frequency of <0.00001 in blood donors resident in Wales. An Epstein-Barr virus transformed B-cell line from the HLA-B*15:33 donor is available., (© 2011 Blackwell Publishing Ltd.)

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are rare but severe adverse cutaneous drug reactions that are to be considered medical emergencies. The average reported mortality rate for SJS is 1-5%, and up to 25-35% for TEN. TEN and SJS are characterized by more or less extensive painful erythematous and erosive lesions of the skin, conjunctiva and mucous membranes resulting from massive apoptosis of epithelial cells, and are considered to be two ends of a spectrum of severe epidermolytic adverse cutaneous drug reactions, differing only by their extent of skin detachment. Drugs including allopurinol, antibiotics, anticonvulsants and NSAIDs of the oxicam type are the main cause of SJS/TEN in most cases. Recent evidence supports a genetic susceptibility to SJS and TEN as exemplified by the strong association observed in Han Chinese between the human leukocyte antigen HLA-B*1502, and SJS induced by carbamazepine. Diagnosis relies mainly on clinical signs together with the histological analysis of a skin biopsy showing typical full-thickness epidermal necrolysis due to extensive keratinocyte apoptosis. Differential diagnoses include autoimmune bullous dermatoses, acute generalized exanthematous pustulosis, disseminated fixed bullous drug eruption and staphyloccocal scalded skin syndrome. Due to the high risk of mortality, management of patients with SJS/TEN requires rapid diagnosis, evaluation of the prognosis using SCORTEN, rapid identification and interruption of the culprit drug, specialized supportive care ideally in an intensive care unit, and the consideration of immunomodulatory agents such as high-dose intravenous immunoglobulin., (Copyright © 2012 S. Karger AG, Basel.)

We describe the association of the HLA-B*1502 allele in 27 epilepsy patients (19 Malays, 8 Chinese) treated with carbamazepine (CBZ) at the UKM Medical Center (UKMMC), 6 with CBZ-Steven Johnson Syndrome (CBZ-SJS), 11 with CBZ-induced rash, 2 with suspected phenytoin-induced rash and 8 negative controls. Our study showed that 10 (6 Malay, 4 Chinese) patients were positive for HLA-B*1502. Out of the 10 patients, six were confirmed to have CBZ-SJS (p = 0.0006), while four patients developed a skin rash. However there were 6 Malay patients and 1 Chinese patient that developed a skin rash after CBZ administration who were not positive for the allele, indicating that there might be more that one allele associated with CBZ-induced hypersensitivity. Another 2 patients were suspected of having phenytoin-induced rash, instead of CBZ, and these patients did not have HLA-B*1502. In conclusion, this study confirmed the association of HLA-B*1502 with CBZ-SJS among Malaysian epilepsy patients, however there might be other genes that could be responsible for the CBZ-induced rash.