Investigating the Immune Basis of Green Tea Extract Induced Liver Injury in Healthy Donors Expressing HLA-B*35:01.

Epigallocatechin-3-O-gallate (EGCG) is the major component of green tea extract, commonly found in dietary supplements, and has been associated with immune-mediated liver injury. The purpose of this study was to investigate the immunogenicity of EGCG in healthy donors expressing HLA-B*35:01, and characterize EGCG responsive T-cell clones. We have shown that EGCG can prime peripheral blood mononuclear cells and T-cells from donors with and without the HLA-B*35:01 allele. T-cell clones were CD4+ve and capable of secreting Th1, Th2, and cytolytic molecules. These data demonstrate that EGCG can activate T-cells in vitro, suggesting a significant role in the pathogenesis of green tea extract induced liver injury.

[Correlational verification of drug-induced liver injury with HLA-B*35:01 allele due to Polygonum multiflorum].

In order to verify the correlation between Polygonum multiflorum-induced liver injury and HLA-B*35 : 01 alleles, six hospitalized patients diagnosed with Polygonum multiflorum-induced liver injury (PM-DILI) were selected, and their clinicopathological data were collected. Simultaneously, blood HLA-B* 35 : 01 allele detection was performed. Among the six PM-DILI cases, 4 were male, aged 38.83 ± 10.13 years old. The types of liver injury were hepatocellular injury types in all, and the severity of liver injury in five cases was grade 3. The histological presentations were acute hepatitis and acute cholestatic hepatitis. PM-DILI cases were all HLA-B*35:01 carriers, with a carrier rate of 100%. This finding indicates that PM-DILI is significantly correlated with HLA-B*35:01 alleles. Therefore, HLA-B*35 : 01 alleles can be used as an important predictive indicator for PM-DILI.

Risk and association of HLA with oxcarbazepine-induced cutaneous adverse reactions in Asians.

OBJECTIVE: To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in Asian populations (Chinese and Thai). METHODS: We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate of HLA-B*15:02 and HLA-A*31:01 of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)-induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database. RESULTS: We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6 drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all ≦5%) and no mortality. There was a significant association between HLA-B*15:02 and OXC-SJS (p = 1.87 × 10-10; odds ratio 27.90; 95% confidence interval [CI] 7.84-99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values of HLA-B*15:02 for OXC-SJS/TEN were 0.73% and 99.97%, respectively. HLA-A*31:01 was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p = 0.003; relative risk 0.212; 95% CI 0.077-0.584). CONCLUSIONS: Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further.

Clinical features of and genetic predisposition to drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a single Korean tertiary institution patients-investigating the relation between the HLA -B*4403 allele and lamotrigine.

PURPOSE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but fatal adverse mucocutaneous reactions to certain drugs. Recent studies suggest that ethnicity and genetic predisposition may play a crucial role in the manifestation of the reaction. In this study, we described the role of human leukocyte antigen (HLA)-B alleles in the development of clinical characteristics and treatment outcomes of SJS/TEN in a single Korean tertiary hospital. METHODS: We retrospectively reviewed the medical records (from March 1, 2010 to February 28, 2014) of 30 patients diagnosed with SJS and/or TEN. RESULTS: The main causative drugs were anticonvulsants (26.7 %) and allopurinol (26.7 %), followed by antibiotics (16.7 %), acetazolamide (10.0 %), acetaminophen (10.0 %), and herbal medication (6.7 %). The mean latencies of these drugs were variable. Liver damage was the most common symptom (observed in 63.3 % of the patients). Of the five patients with lamotrigine-induced SJS/TEN, three expressed the HLA-B*4403 allele (60.0 %). Of the seven patients with allopurinol-induced SJS/TEN, five expressed the HLA-B*5801 allele (71.4 %). CONCLUSIONS: The major SJS/TEN-inducing drugs were found to be allopurinol and anticonvulsants (such as lamotrigine). We speculated that Korean individuals expressing the HLA-B*4403 allele may be highly susceptible to lamotrigine-induced SJS/TEN.

Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing.

Human leukocyte antigen B (HLA-B) is a gene that encodes a cell surface protein involved in presenting antigens to the immune system. The variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in response to carbamazepine treatment. We summarize evidence from the published literature supporting this association and provide recommendations for the use of carbamazepine based on HLA-B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this article is to provide information to allow the interpretation of clinical HLA-B*15:02 genotype tests so that the results can be used to guide the use of carbamazepine. The guideline provides recommendations for the use of carbamazepine when HLA-B*15:02 genotype results are available. Detailed guidelines regarding the selection of alternative therapies, the use of phenotypic tests, when to conduct genotype testing, and cost-effectiveness analyses are beyond the scope of this document. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are published and updated periodically on the PharmGKB website at (http://www.pharmgkb.org).

Characterization of 236 novel alleles at the HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 loci from China Marrow Donor Program.

Two hundred and thirty-six novel human leukocyte antigen (HLA) alleles are described from volunteer donors of the China Marrow Donor Program: 71 HLA-A alleles, 79 HLA-B alleles, 43 HLA-C, 16 HLA-DRB1 alleles, 26 HLA-DQB1 and 1 HLA-DPB1. Two hundred and thirteen (90.3%) of the 236 novel alleles are single nucleotide substitution variants when compared with their most homologous allele. Seventy-eight of these single nucleotide variants are silent substitutions. The remaining novel alleles differ from their most similar allele by two to four nucleotide substitutions. Some of the novel alleles encode amino acid changes at positions not previously reported to be polymorphic, such as codons 57, 62, 67, 41 and 52 in HLA-A alleles; codons 133, 156, 201 and 215 in HLA-B alleles; codons 74, 208 and 225 in HLA-C; codons 25, 32 and 72 in HLA-DRB1; codons 20, 39 and 77 in HLA-DQB1.

Genetic variability in autochthonous Basques from Guipuzcoa: a view from MHC microsatellites.

Five short tandem repeats (STRs) located at human chromosome 6 were analysed in 97 autochthonous Basques from Guipuzcoa (northern Spain), with the aim of assessing the genetic relationships of Basques at a European scale, based on the variability of the major histocompatibility complex (MHC) region, and comparing the phylogenetic information obtained from STRs, and from HLA class I genes (HLA-A and HLA-B) for the same set of European populations. The integrative approach was focused on D6S265 and D6S2792, according to availability of population databases. F(ST) genetic distances obtained from STRs and from HLA loci were very similar, thereby describing a comparable pattern of genetic structuring among the European populations. These findings were supported by results of the Mantel test of matrix correspondence (r = 0.796, P = 0.0022) and by significant correlations between the first two F(ST) eigenvectors of STRs and HLA genes. Coinciding with previous phylogenetic studies, Basques showed substantial genetic differentiation within the European context, probably as a result of the impact of random genetic drift and high inbreeding levels for extended periods of isolation even from adjacent populations. Analysis of the geographical distribution of the allele frequencies revealed a great number of latitudinal frequency clines in both the MHC STRs and the HLA class I genes, which supports the notion of the post-glacial resettlement of Europe being a crucial factor in the genetic make-up of Europeans. Our results indicate that analysing the genetic variability of MHC microsatellites could be a suitable strategy in evaluating the role of evolutionary forces such as natural selection (because of genetic hitchhiking effect), genetic drift and gene flow in the maintenance of polymorphism at the MHC region, because STRs can efficiently complement the genetic information obtained from HLA genes.

HLA genes in populations of the Aleutian islands.

We typed a subset of the Aleut population for HLA loci (HLA-A, HLA-B, HLA-DRB1, HLA-DQB1) to obtain an HLA profile, which was compared to other Eurasian and Amerindian populations for studying Aleut origin and its significance on the peopling of the Americas. Allele frequencies at the four loci were identified in an Aleut sample using standard indirect DNA sequencing methods. Genetic distances with Amerindians and Eurasians were obtained by comparing Aleut allele frequencies with a worldwide population database (13,164 chromosomes). The most frequently extended HLA haplotypes were also calculated. We also generated Aleut relatedness dendrograms and calculated correspondence relatedness in a multidimensional scale. Both neighbor-joining dendrograms and correspondence analysis separated Aleuts from Eskimos and Amerindians. Aleuts are closer genetically to Europeans, including Scandinavians and English. Our results are concordant with those obtained by Y-chromosome analysis, suggesting that most male Aleut ancestors of our sample came mainly from Europe.

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families.

The main genetic predisposition to type 1 diabetes (T1D) is known to be conferred by the HLA-DRB1, -DQA1 and -DQB1 genes in the major histocompatibility complex (MHC). Other genetic factors within this complex are known to contribute, but their identity has often been controversial. This picture is shared with several other autoimmune diseases (AIDs). Moreover, as common genetic factors are known to exist between AIDs, associations reported with other AIDs may also be involved in T1D. In this study, we have used these observations in a candidate gene approach to look for additional MHC risk factors in T1D. Using complementary conditional methods (involving conditional logistic regression and family-based haplotype tests) and analyses of linkage disequilibrium (LD) patterns, we confirmed association for alleles of the HLA-A and HLA-B genes and found preliminary evidence for a novel association of a single-nucleotide polymorphism (rs2259571) in the AIF1 gene, independent of the DRB1-DQA1-DQB1 genes and of each other. However, no evidence of independent associations for a number of previously suggested candidate polymorphisms was detected. Our results illustrate the importance of a comprehensive adjustment for LD effects when performing association studies in this complex.

[Connective tissue dysplasia, magnesium, and nucleotide polymorphisms].

Undifferentiated connective tissue dysplasia (UCTD) is one of most common diseases of the connective tissue. High frequency of UCTD in population along with the fact that it can provoke a number of other diseases make UCTD an important object of the modern biomedical research in the areas of cardiology, neurology, rheumatology and pulmonology. Modern diagnostics and determination of the predisposition to UCTD allow elaboration of personalized therapy. In particular, Mg-containing supplements and medications can be effectively used in the therapy of UCTD. In one of our previous works we have analyzed possible molecular mechanisms of UCTD etiology as well as therapeutic action of magnesium. The use of data on nucleotide polymorphisms as complementation of standard medical diagnostics is one of perspective trends of the post-genomic medical research. The present work suggest a number of nucleotide polymorphisms that can be used in genetic association analyses of the UCTD as of well as therapeutic efficiency of magnesium treatment. Selection and analysis of the polymorphisms was done on the base of molecular mechanisms we had proposed earlier, comprehensive analysis of published data and also with the use of an integral approach to analysis of the functional effects of the nucleotide polymorphisms and corresponding amino acid substitutions.

HLA-B*5701 screening for susceptibility to abacavir hypersensitivity.

The introduction of highly active antiretroviral therapy (also known as combination therapy) has transformed the nature of HIV infection from a severe and ultimately fatal disease to that of a manageable chronic condition. HIV drugs are highly efficacious, but their use comes at the cost of a range of drug-related adverse events, including severe drug hypersensitivity reactions (HSRs) that have been most notably associated with abacavir and nevirapine therapy. This article discusses the issues of pharmacogenetic screening, in the light of the strong genetic association of the HLA-B*5701 allele and the susceptibility to developing abacavir HSRs. It also presents the screening's impact on clinical practice and discusses the practical considerations that influence the introduction and cost-effectiveness of such screening.

Monozygotic twins concordant for intestinal Behçet's disease.

Although Behçet's disease (BD) is a multisystem disorder of unknown causes, both genetic and environmental factors have been suggested. This is the second reported case of monozygotic twins concordant for Behçet's disease and the first such report of intestinal Behçet's disease. Patient 1 was a 17-year-old man with fever, recurrent oral aphthae, and skin eruptions. He developed hematochezia and was given corticosteroid empirically. One month after he was discharged, he again developed oral ulcerations, fever, and hematochezia. Colonoscopy was performed again, showing aphthous ulcerations in the entire colon, and deep oval ulcers with marginal elevation around the ileocecal valve, which are characteristics of intestinal Behçet's disease. He was treated with colchicine and azathioprine in combination with salazosulfapyridine (SASP) and prednisolone (PSL) and achieved remission. Patient 2 was the twin brother of patient 1. He was admitted because of oral aphthous ulcerations, fever, pustules on his face and body, and genital ulcers. Two weeks later he developed hematochezia. Colonoscopic and barium enema findings were similar to those of his brother. SASP, PSL, colchicines, and azathioprine were also required to achieve remission. Both of the patients were diagnosed with intestinal Behçet's disease. Their monozygosity was confirmed by detailed genetic typing, and HLA-B51 was negative.

HLA alleles in isolated populations from North Spain: origin of the Basques and the ancient Iberians.

HLA-A, -B, -DRB1, -DQA1 and -DQB1 alleles have been studied in three relatively isolated populations of northern Spain from Cantabria ( Pas Valleys inhabitants or Pasiegos and Cabuernigos) and from the Basque Country (Arratia Valley inhabitants). These populations have been compared with neighbouring ones and other Mediterraneans by using neighbour-joining dendrograms and plane genetic distances.

HLA-B locus-specific downregulation in human melanoma requires enhancer A as well as a sequence element located downstream of the transcription initiation site.

Human MHC class I molecules are encoded by three different loci (HLA-A, -B, and -C), which are regulated at the transcriptional level through several conserved cis-acting promoter elements. The presence of locus-specific residues throughout the entire promoter region strongly suggests that the various HLA class I loci are differentially regulated. To identify regulatory sequences involved in locus-specific HLA class I gene transcription, a series of truncated HLA-A2 and HLA-B7 promoter-reporter constructs were transfected into melanoma cell lines expressing high and low levels of endogenous HLA-B, but comparable levels of HLA-A. These experiments showed that differential regulation of HLA-B expression in melanoma cell lines is mediated by a previously unidentified co-operative action of enhancer A, located 175 bp upstream of the transcription initiation site (+1), and a specific region of 20 nucleotides located at +13 to +33 bp downstream of the transcription initiation site. Furthermore, we demonstrated binding of transcription factor Yin Yang 1 to the HLA-A +13/+33 bp region, but not to the equivalent HLA-B region. Based on these results, we present a model suggesting that YY1 displaces either activating or repressing transcription factors, thereby making the HLA-A gene resistant to differential regulation.

Behçet's disease, the Silk Road and HLA-B51: historical and geographical perspectives.

Behçet's disease (BD), also known as the Silk Road disease, is a blinding inflammatory disorder of young adults found predominantly between the Mediterranean basin and the Orient, and is strongly associated with the major histocompatibility complex (MHC) antigen HLA-B51. In this article we review the history of Behçet's disease since its first description by Hippocrates, the development of the trading routes collectively known as the Silk Road and the effect of population movement on the distribution of HLA-B51. The global distribution of this antigen among healthy control populations bears a striking similarity both to the ancient trading routes and the distribution of Behçet's disease, suggesting a genetic risk that migrated in parallel with population movement between the Mediterranean and Asia. However, certain indigenous Amerindian peoples have a high prevalence of HLA-B51 but no reported cases of BD. Furthermore, a clear genealogical relationship exists between eastern, but not central, Siberian populations with the Amerindians. Since a high level of recombination within the MHC is known to have occurred in these eastern populations before their migration into Beringia, we suggest that disruption of genetic loci in linkage disequilibria with HLA-B51 may be one reason for the absence of disease in these high HLA-B51-bearing populations. However, a contributory influence of environmental factors is not excluded by this data, and the wide variation that exists in relative risk of HLA-B51 even within Europe would support other non-genetic risk factors on the Silk Road which may be absent, or non-contributory to disease, in the Americas.

HLA and HPA typing in idiopathic thrombocytopenic purpura patients treated with Kami-kihi-to.

We performed human leukocyte antigen (HLA) and human platelet antigen (HPA) in patients with Kami-kihi-to-responsive idiopathic thrombocytopenic purpura. The HLA-A2, A61 and Cw1 were significantly increased in responders compared with nonresponders, as were HLA DRB1 *0901, DRB1 *1502, and DPB1 *0501. In contrast, HLA DPB1 *0201 and DPB1 *0901 were significantly decreased in responders. The a/b genotype of HPA-2 and a/a genotype of HPA-3 were markedly increased in nonresponders, and anti-GPIb antibody was also increased. These results suggest that HLA, HPA, and anti-GP antibody studies may predict the response of idiopathic thrombocytopenic purpura to Kami-kihi-to.

The search for HLA-matched donors: a summary of HLA-A*, -B*, -DRB1/3/4/5* alleles and their association with serologically defined HLA-A, -B, -DR antigens.

This report summarizes data obtained from several large studies including the WHO HLA Nomenclature Committee, the International Cell Exchange, UCLA, the British Society for Histocompatibility and Immunogenetics Rare Cell Exchange and the National Marrow Donor Program and individual laboratories aimed at identifying a serologic type for specific HLA-A,-B,-DRB allelic products. Alleles that are poorly characterized at the serologic level are indicated and an approach is suggested for obtaining the information needed to clarify their serologic typing. The tables provided will be useful in guiding searches for an unrelated donor in which patient and/or potential donors are typed either by serology or by DNA-based methods and will provide a "dictionary" of potential equivalents between HLA "types" obtained by the two methods.

Frequencies of HLA-A24 and HLA-DR4-DQ8 are increased and that of HLA-B blank is decreased in chronic toxic oil syndrome.

The cause of toxic oil syndrome (TOS) has not yet been definitively determined, but some genetic susceptibility factors (certain HLA antigens and female sex) have been identified in 236 patients. Similarities with genetic factors for scleroderma and hydralazine-induced lupus (i.e. in TOS female sex and HLA-A24, Pcorrected = 0.00001 and DR4, Pcorrected = 0.04, respectively) may provide a clue to the responsible xenobiotic and its pathogenesis, and may also help in understanding the basis of the related eosinophilia-myalgia syndrome associated with tryptophan ingestion. In this paper it is also established that a human class I antigen (HLA-A24) and, independently, an HLA class II haplotype (DR4-DQ8, Pcorrected = 0.04) and arginine 52 in the alpha-DQ chains (Pcorrected = 0.03) are associated with TOS susceptibility, similarly to insulin-dependent diabetes. This further supports the classification of TOS as an autoimmune disease. Also, the increased frequency of a particular set of low-frequency HLA class I antigens in chronic TOS patients (i.e. B27, B37, B38 and B49) and the probable decrease in the frequency of HLA-B homozygotes in surviving patients (Pcorrected = 0.008) may provide an objective model to explain the maintenance of the HLA polymorphism: less frequent HLA alleles may be more advantageous in the event of unexpected human contact with unusual xenobiotics (not only microbes); however, other mechanisms working together to preserve and generate HLA polymorphism may coexist.

HLA-antigens in oral submucous fibrosis.

HLA-typing was carried out on 122 areca nut chewers who attended hospitals for complaints unrelated to the habit. The subjects were South Africans of Indian extraction. The study did not include haplotypes. Palpable fibrous bands in the mouth indicated oral submucous fibrosis. The subjects were divided into 4 groups based on specific oral symptoms and signs. Groups A and B were without fibrous bands. Group A (47 subjects) included those with one or no symptoms while group B (28 subjects) suffered from 2 to 7 oral symptoms. Group C (17 subjects) had oral symptoms and represented early or mild oral submucous fibrosis and exhibited at least one discrete palpable fibrous band. Group D (30 subjects) were classic oral submucous fibrosis cases with multiple bands. The high occurrence of oral submucous fibrosis in this study group (39%) is similar to the occurrence in comparable age groups reported earlier in South Africa and is conceivably due to the higher age range of the subjects and their relatively long exposure to the areca nut. We were unable to demonstrate a specific pattern of HLA-antigen frequencies in chewers with or without the disease. Furthermore, there were no differences between the study population and the controls. It is concluded that there is not necessarily a HLA-associated susceptibility in oral submucous fibrosis.