Association of HLA-B*1502 and *1511 allele with antiepileptic drug-induced Stevens-Johnson syndrome in central China / 华中科技大学学报（医学）（英德文版）

Previous studies have demonstrated a strong association between carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS) and HLA-B*1502 in Han Chinese. Here, we extended the study of HLA-B*1502 susceptibility to two different antiepileptic drugs, oxcarbazepine (OXC) and phenobarbital (PB). In addition, we genotyped HLA-B*1511 in a case of CBZ-induced SJS with genotype negative for HLA-B*1502. The presence of HLA-B*1502 was determined using polymerase chain reaction with sequence-specific primers (PCR-SSP). Moreover, we genotyped HLA-B*1502 in 17 cases of antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs), in comparison with AEDs-tolerant (n=32) and normal controls (n=38) in the central region of China. The data showed that HLA-B*1502 was positive in 5 of 6 cases of AEDs-induced SJS (4 CBZ, 1 OXC and 1 PB), which was significantly more frequent than AEDs-tolerant (2/32, 18 CBZ, 6 PB and 8 OXC) and normal controls (3/38). Compared with AEDs-tolerant and normal controls, the OR for patients carrying the HLA-B*1502 with AEDs-induced SJS was 6.25 (95% CI: 1.06-36.74) and 4.86 (95% CI: 1.01-23.47). The sensitivity and specificity of HLA-B*1502 for prediction of AEDs-induced SJS were 71.4%. The sensitivity and specificity of HLA-B*1502 for prediction of CBZ-induced SJS were 60% and 94%. HLA-B*1502 was not found in 11 children with maculopapular exanthema (MPE) (n=9) and hypersensitivity syndrome (HSS) (n=2). However, we also found one case of CBZ-induced SJS who was negative for HLA-B*1502 but carried HLA-B*1511. It was suggested that the association between the CBZ-induced SJS and HLA-B*1502 allele in Han Chinese children can extend to other aromatic AEDs including OXC and PB related SJS. HLA-B*1511 may be a risk factor for some patients with CBZ-induced SJS negative for HLA-B*1502.

The associations between idiosyncratic adverse drug reactions and HLA alleles and their underlying mechanism / 药学学报

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.

Sequence analysis and identification of two novel HLA alleles HLA-B*9536 and HLA-B*4612 / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To identify two novel HLA alleles HLA-B*9536 and B*4612, in an individual.</p><p><b>METHODS</b>DNA was extracted from whole blood by Invitrogen DNA extraction kit. The amplification for HLA-B exons 2-4 of the proband was performed separately with allele group specific primers and the PCR products were directly sequenced for exons 2-4 in both direction.</p><p><b>RESULTS</b>There were two novel HLA-B alleles in the proband. The sequences of the two alleles have been submitted to GenBank (EU081878 and EU081879). The two alleles have been officially named as B*9536 and B*4612 by the WHO Nomenclature Committee. The sequence of exons 2-4 of HLA-B*9536 showed one nucleotide difference in exon 3 at position 544 (G to A) comparing with the closest allele B*1505, which resulted in an amino acid change from Ala to Thr at codon 158. In the HLA-B*4612 allele, there was one nucleotide change in exon 3 at position 363 (G to A), when compared to the closest allele B*4601, which lead to an amino acid change from Arg to Ser at codon 97.</p><p><b>CONCLUSION</b>Two novel HLA-B alleles were identified in one individual and have been officially named by the WHO Nomenclature Committee.</p>

Identification of a novel HLA allele HLA-B*9526 / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>A novel human leukocyte antigen-B (HLA-B) allele, B*9526, was identified and analyzed by sequencing-based method in a Chinese donor.</p><p><b>METHODS</b>HLA typing was performed by PCR-sequence-specific oligonucleotide (SSO). Molecular cloning and DNA sequencing were used to identify the sequence of the potential novel allele and the difference between this new allele and other known alleles were analyzed.</p><p><b>RESULTS</b>HLA genotyping of one sample gave different results. The sequencing result showed HLA-B alleles of the proband as B*5403 and a novel allele. The nucleotide sequence of the novel allele was different from all known B alleles and harbored one nucleotide change from the closest matching allele B*1507 at nucleotide 425 (A to G) in exon 3, resulting in an amino acid change from Y (TAC) to C (TGC) at codon 142.</p><p><b>CONCLUSION</b>A novel HLA allele was identified and officially designated as HLA-B*9526 by WHO Nomenclature Committee for Factors of the HLA System.</p>

HLA-B*15 gene polymorphism of registered bone marrow from donors in north Chinese Han population typed by PCR-SBT / 中国实验血液学杂志

To investigate the characteristics of the allele distribution of HLA-B*15 gene family in Chinese Han population and to study its influence on the selection of clinical transplantation donor, population of a 815 Han in north China from Shaanxi sub-registry of Chinese National Marrow Donor Project was randomly selected and out of them 206 HLA-B*15 positive samples according to the previous known low-resolution typing results were acquired. HLA-B*15 gene polymorphisms of above-mentioned samples and other 17 individuals were analyzed for the first time by polymerase chain reaction sequence-based typing (PCR-SBT) at high-resolution level. The structure differentiation of all HLA-B*15 alleles were analyzed by HLA three-dimensional structure modeling and software Swiss-PdbViewer. The results showed that the distribution of HLA-A, -B, -DRB1 gene of randomly selected 815 samples accorded with Hardy-Weinberg equilibrium and the gene frequency of HLA-B*15 was 0.1379. There were a total of 16 kinds of alleles of HLA-B*15 gene family to be obtained, which belonged to 7 kinds of serologic specificities. HLA-B*1501, B*1511, B*1502 and B*1518 were the major alleles with a frequency of 0.0485, 0.0215, 0.0178 and 0.0160 respectively, and the constituent ratio of their accumulated frequencies was 75.11%. The each frequency of the other 12 kinds of B*15 alleles was lower than 0.0100. Among the homozygote of 10 samples at low/medial-resolution level, there were only 4 samples to be pur sang homozygote of HLA-B*15xx, --at high-resolution level, and all the homozygote were constituted by respective dominating alleles. HLA three-dimensional structure modeling demonstrated that within the same specificity, gentle structure differentiation not only existed, such as B*1501, 1505, 1507, 1525, 1527, 1532 (each RMSD<or=0.02 nm), but also presented significant structure differentiation, such as B*1502, 1511, 1521 and B*1503, 1546 (each RMSD=0.29 nm). However, some alleles belonged to different specificities showed similar structure with RMSD<or=0.02 nm. It is concluded that the characteristics of HLA-B*15 gene polymorphism defined by PCR-SBT with the largest sample size up to now is unique in north Chinese Han population. The study will be helpful to find suitable donors for patients and establish the important foundation for further studying transplantation immunity and population genetics in this area. To select the optimal donor, it is necessary for gene family with high polymorphism like HLA-B*15 to type accurately at high-resolution level.