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PubMed2025

HLA-B Alleles With Shared Peptide Binding Specificities Define Global Risk of Co-trimoxazole-Induced Severe Cutaneous Adverse Drug Reactions.

BACKGROUND: Co-trimoxazole is a leading global cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Co-trimoxazole-induced SCAR are associated with HLA class I alleles including HLA-B&#x2217;13:01 and HLA-B&#x2217;38:02 in Southeast Asian (SEA) populations. However, the global generalizability of these associations is unknown but critical for population-appropriate risk stratification and diagnosis. OBJECTIVE: To determine HLA risk factors associated with co-trimoxazole-induced SJS/TEN and DRESS in populations from the United States and South Africa. METHODS: We performed high-resolution HLA typing on dermatologist-adjudicated co-trimoxazole-induced patients with SCAR in the United States (n = 63) and South Africa (n = 26) compared with population controls. Peptide binding and docking analyses were performed using MHCcluster2.0 and CB-Dock2. RESULTS: In a multiple logistic regression model, HLA-B&#x2217;44:03 (corrected P [Pc] < .001; odds ratio [OR] = 4.08), HLA-B&#x2217;38:01 (Pc < .001; OR = 5.66), and HLA-C&#x2217;04:01 (Pc = .003; OR = 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the United States. HLA-B&#x2217;44:03 was also associated with co-trimoxazole-induced DRESS in South Africa (Pc = .019; OR = 10.69). Distinct HLA-B variants with shared peptide binding specificities (SPBS) and HLA-C&#x2217;04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the United States, respectively. The SEA risk allele HLA-B&#x2217;13:01, with SPBS to HLA-B&#x2217;44:03, was identified in just one of 63 US patients with SCAR. CONCLUSIONS: HLA alleles with SPBS to SEA-related risk alleles, including HLA-B&#x2217;44:03 (SPBS with HLA-B&#x2217;13:01) and HLA-B&#x2217;38:01 (SPBS with HLA-B&#x2217;38:02) but also HLA-C&#x2217;04:01, predisposed to co-trimoxazole-induced SCAR in the United States and South Africa. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR.

Humans↗
PubMed2026

HLA Allele and Haplotype Frequencies Among Registered Unrelated Donors in the Western Region of Saudi Arabia.

The Saudi stem cell donor registry (SSCDR) has successfully recruited over 92,000 unrelated potential stem cell donors through nationwide campaigns. The Western region of Saudi Arabia is characterized by its unique ethnic diversity, shaped by centuries of immigration and pilgrimage. This study aimed to determine the distribution of HLA alleles and haplotypes among donors from this region. A total of 1112 donors registered with SSCDR were included, all recruited during campaigns conducted in the Western region between 2019 and 2021. Participants provided ancestry information to confirm their city of origin. High-resolution HLA typing for loci A, B, C, DRB1 and DQB1 was performed using sequence-based typing (SBT). Allele and haplotype frequencies were estimated for each subgroup using Arlequin 3.5 software. Distinct haplotype patterns were observed across cities. The most common haplotypes in the 1112 potential stem cell donors in the Western Region of Saudi Arabia were HLA-A*02:01&#x223c;C*07:02&#x223c;B*07:02&#x223c;DRB1*15:01&#x223c;DQB1*06:02 and HLA-A*02:01&#x223c;C*06:02&#x223c;B*50:01&#x223c;DRB1*07:01&#x223c;DQB1*02:01 in Jeddah; A*23:01&#x223c;C*06:02&#x223c;B*50:01&#x223c;DRB1*07:01&#x223c;DQB1*02:01 in Al-Madinah; HLA-A*26:01&#x223c;C*07:02&#x223c;B*08:01&#x223c;DRB1*03:01&#x223c;DQB1*02:01, HLA-A*30:01&#x223c;C*06:02&#x223c;B*13:02&#x223c;DRB1*07:01&#x223c;DQB1*02:01 and HLA-A*02:01&#x223c;C*06:02&#x223c;B*50:01&#x223c;DRB1*07:01&#x223c;DQB1*02:01 in Makkah; HLA-A*02:01&#x223c;C*15:02&#x223c;B*51:01&#x223c;DRB1*13:01&#x223c;DQB1*06:03 and HLA-A*02:01&#x223c;C*07:02&#x223c;B*07:02&#x223c;DRB1*15:01&#x223c;DQB1*06:02 in Al-Baha; and HLA-A*31:01&#x223c;C*15:02&#x223c;B*51:01&#x223c;DRB1*13:01&#x223c;DQB1*06:03 in Taif. HLA data are available in the Allele Frequencies Net Database (AFND: 3854, 3855, 3856, 3857 and 3858) under the population name 'Saudi Western Region'. In western Saudi Arabia, HLA allele and haplotype distributions demonstrate marked city-specific variation. Our research identifies DR7-, DR13- and DR15-based haplotypes as the most prevalent across the region. These findings are critical for optimizing unrelated donor searches for patients lacking compatible familial matches. Understanding these local frequencies allows for more targeted recruitment and better matching probabilities in stem cell registries.

Humans↗
PubMed2026

Next-Generation Sequencing-Based High-Resolution Typing of HLA-A, -B, -C and HPA Genes in Jilin Province: Building a Platelet Donor Database and Identifying Novel Alleles.

To systematically analyse HLA-A, -B and -C and human platelet antigen (HPA) genotypes of platelet donors in Jilin Province using next-generation sequencing (NGS) technology, a comprehensive donor database was established. Additionally, potential novel alleles were identified, providing a scientific basis for enhancing the safety of clinical blood transfusions. DNA fragments from 200 platelet donor samples in Jilin Province were amplified using locus-specific primers. Comprehensive sequencing of HLA and HPA genes was performed via NGS. Bioinformatics analysis was employed to process genotyping results and screen for novel genetic variants. Newly discovered alleles were validated by Sanger sequencing to ensure accuracy and reliability. HLA genotyping achieved three-field allele resolution, revealing the highest-frequency alleles are as follows: HLA-A*11:01:01, HLA-B*13:02:01, HLA-C*01:02:01 and C*03:04:01. A novel allele B*49:91 (mutation: E2 24T>C) was identified. For the HPA systems (HPA-1, -2, -3, -5, -6, -15, -21), high heterozygosity was observed in HPA-3 and HPA-15, while no bb homozygosity was detected in HPA-1, -2, -5, -6 or -21. The application of NGS in constructing a platelet HLA/HPA gene database enables high-resolution genotyping, laying a critical foundation for precise platelet matching. This significantly reduces the risk of platelet transfusion refractoriness (PTR) and facilitates the discovery of novel allelic variants. The database provides essential theoretical and practical guidance for future donor screening and personalised transfusion strategies.

Humans↗
PubMed2025

Genetic Landscape of Opsoclonus-Myoclonus-Ataxia Syndrome in Children.

BACKGROUND: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare neurological disorder, with involuntary rapid saccadic conjugate eye movements as one of characteristics, primarily affecting the cerebellum. While the exact pathogenesis remains unclear, genetic and autoimmune factors have been suggested to contribute to its development. METHODS: We enrolled patients diagnosed with OMAS before the age of 18 years at a pediatric neuroimmunology clinic in Boston, United States, using the 2004 Genoa Criteria. Whole genome sequencing was conducted for the patients and their biological parents in all cases, with one case including an unaffected twin sibling. RESULTS: De novo germline variants (DNVs) in probands were identified and validated and analyses of structural variants, recessive variants in neuroimmune-associated genes, and high-resolution human leukocyte antigen (HLA) typing were performed. Our study included 42 patients, 23 of whom had neuroblastoma. We found 12 confirmed DNVs in protein-coding regions in nine patients (29.0% of 31 from 30 trios and 1 quartet). Ten patients (23.8% of 42) had rare homozygous or compound heterozygous variants known to alter protein function, affecting 11 genes. Notably, the major histocompatibility complex, class II, DR beta 1 (HLA-DRB1) &#x2217;01 allele was observed in 27 out of 84 (32.1%) alleles in the patients, significantly higher than that in the general population (chi-square test, P < 0.0001). In one case, a potential genetic modifier of OMAS with severe cerebellar atrophy was identified, associated with a protein-truncating DNV in the CACNA2D2 gene. CONCLUSIONS: This first genome sequencing study reveals potential genetic contributors to OMAS, implicating polygenic predisposition-with HLA-DRB1&#x2217;01 as a possible factor-combined with nongenetic risk factors like neuroblastoma.

Humans↗
PubMed2025

Association Between HLA-DRB1 Serotype and HLA-DQB1 Allele Mismatches and Acute Rejection in Kidney Transplantation.

The purpose of this single-center case-control study was to investigate the association between HLA serotype mismatch (MM), compared to other HLA MM modalities, and the occurrence of acute rejection (AR) within the first year after deceased donor kidney transplantation. The study included 198 transplants in 99 pairs of recipients of kidneys from the same donor, where one recipient experienced AR and the other survived the first year without AR. Donors and recipients were typed with NGS for 11 HLA loci at high resolution. HLA MM categories included allele groups, alleles, serotypes, amino acids, EMMA, eplet and PIRCHE-II. Additionally, we investigated Cytomegalovirus LIL peptide (CMV LIL) MM. Recipients with AR presented higher frequencies of pre-transplant HLA-ABDR DSA (20.2% vs. 6.1%, p&#x2009;=&#x2009;0.005) and CMV LIL MM (24.2% vs. 10.1%, p&#x2009;=&#x2009;0.01). Univariate and multivariate Cox proportional hazards regression for matched-pair analyses were used to test the association between HLA MM and AR. Univariate analyses indicated significant association with DRB1 ST, HLA-DQB1 AG, HLA-DQB1 AL, EMMA C, EMMA DQB1, Eplet ABC and Eplet DQ MM. Different models were tested in multivariate analyses, all including pre-transplant HLA-ABDR DSA and CMV LIL MM. The models were compared using the Akaike Information Criterion (AIC). The best estimate for AR prediction (AIC&#x2009;=&#x2009;97.6) was the model that included pre-transplant HLA-ABDR DSA (HR&#x2009;=&#x2009;11.97; p&#x2009;=&#x2009;0.003), CMV LIL MM (HR&#x2009;=&#x2009;367.2; p&#x2009;<&#x2009;0.001), HLA-DRB1 serotype MM (9.65; p&#x2009;=&#x2009;0.002) and HLA-DQB1 allele MM (HR&#x2009;=&#x2009;3.54; p&#x2009;=&#x2009;0.033). In conclusion, this original report demonstrates an association between the HLA-DRB1 serotype MM and AR, highlighting that serotypes are clinically relevant.

Humans↗
PubMed2025

Analysis of HLA Allelic and Haplotypic Frequencies in a Cohort of Bone Marrow Donors in Catalonia: Impact of Next-Generation Sequencing on Donor Registry Quality.

In haematopoietic stem cell transplantation (HSCT), the volunteer unrelated donor (VUD) has become the most common strategy in Europe, as improved outcomes are achieved through HLA compatibility at allelic-level resolution. In this context, the implementation of next-generation sequencing (NGS) in histocompatibility typing laboratories has significantly enhanced the quality of bone marrow registries, enabling a high level of resolution at a lower cost and improved performance. In this study, we analyse a large cohort of 21,787 bone marrow donors in Catalonia and present the observed HLA allelic and haplotypic frequencies, along with their linkage disequilibria. HLA-A, -B, -C, -E and -G were genotyped at full resolution, while -DRB1, -DQB1, -DQA1, -DPA1 and -DPB1 were genotyped at high resolution. We identified 236 new officially named HLA alleles, both coding and non-coding regions. This study highlights that the implementation of high-throughput HLA typing has led to an increase in the number of registered donors and an improvement in quality, which has been reflected in a rise in the number of effective donors.

Humans↗
PubMed2025

Guidelines From the French-Speaking Society for Histocompatibility and Immunogenetics (SFHI) for Harmonisation of HLA Genotyping in Autoimmune Diseases, Drug Hypersensitivity and Pharmacogenetics.

HLA molecules play a central role in the adaptive immune response. Their high polymorphism influences individual susceptibility to various autoimmune diseases and certain drug-induced hypersensitivities. In France, HLA genotyping is classified as a medical genetics procedure and is strictly regulated. The Soci&#xe9;t&#xe9; Francophone d'Histocompatibilit&#xe9; et d'Immunog&#xe9;n&#xe9;tique (SFHI) has established national guidelines outlining clinically validated indications, required resolution levels and interpretation criteria based on robust data. These guidelines are particularly relevant for common clinical contexts, including autoimmune diseases and pharmacogenetic testing. Well-established associations include HLA-DQB1*02/DQA1*05 (DQ2) and HLA-DQB1*03:02/DQA1*05 (DQ8) with celiac disease, HLA-B*27 with spondyloarthritis, HLA-DQB1*06:02 with type 1 narcolepsy, HLA-A*29 with Birdshot chorioretinopathy and several pharmacogenetic risk alleles such as HLA-B*57:01 (abacavir), HLA-B*15:02 and HLA-A*31:01 (carbamazepine) and HLA-B*58:01 (allopurinol). In immunotherapy, the efficacy of tebentafusp has been shown to depend on HLA-A*02:01 positivity. HLA alleles must be interpreted as relative risk factors, not absolute predictors. Critical analysis of HLA-related scientific literature requires consideration of the genotyping technique, typing resolution, allele frequencies within the studied population and environmental factors. High-resolution typing is essential in pharmacogenetics and recommended in selected autoimmune disorders. Interpretation should be conducted by qualified medical biologists, integrating clinical context, allelic diversity and recent technological advances, particularly next-generation sequencing. HLA genotyping represents a valuable tool in diagnosis and risk assessment, with increasing importance in the era of personalised medicine.

Humans↗
PubMed2025

HLA-Typing of Donor-Origin Cells Enriched From Urine Cell Culture of Kidney Transplanted Recipients.

The incomplete or lack of histocompatibility information constitutes a barrier for the early detection and management of de novo donor-specific antibodies (DSA). To improve the quantity and quality of DNA materials for HLA typing, we developed a non-invasive culture-based method, using DNA extracted from enriched donor-derived kidney stem cells (DKSC) selectively cultured from the urine of kidney transplant receipients (KTR) to allow high-resolution typing by next-generation sequencing. This prospective proof-of-concept study evaluated the feasibility and performance of this approach. DKSC were enriched from the urine of 60 KTRs. DNA extracted from culture-enriched DKSC showed significantly higher concentration and better quality than unbound cells, and with identical short tandem repeat (STR) and 100% concordance compared to that obtained from peripheral blood. Our results suggest that cultured-enriched DKSC are non-invasive and useful for determining HLA and other genes for KTRs where donor information is limited or lacking.

Humans↗
PubMed2025

Quantifying HLA transcripts by genotype in chimeric mixtures at single-cell resolution.

Gene products from the highly variable major histocompatibility locus, including HLA, are essential for self-recognition and immune surveillance of malignancy. Following allogeneic hematopoietic cell transplantation (alloHCT), genetic and epigenetic alterations in HLA can drive disease recurrence, making precise HLA assessment critical for determining future therapy. However, current methods lack the sensitivity to quantify HLA transcripts at the single-cell level, limiting their clinical utility. We introduce scrHLA-typing, a novel technique that accurately identifies and quantifies HLA transcripts in single cells using long-read sequencing. When applied to samples from patients with post-transplant relapse, scrHLA-typing successfully detected HLA allele-specific expression, across a range of levels of donor-recipient chimerism, at clinically actionable levels. By characterizing allele expression in residual leukemia cells, our assay identified differences in expression patterns among patients. This capability highlights scrHLA-typing's potential to improve risk stratification and guide the selection of appropriate salvage therapies, enhancing personalized treatment strategies after relapse.

Journal Article↗
PubMed2026

FuFiHLA: a tool for full-field HLA typing from long-read data.

MOTIVATION: Allele typing for Human Leukocyte Antigen (HLA) genes has many important clinical applications. Popular short-read typing can only accurately distinguish alleles at the coding sequence level, which potentially limit our understanding of the effect of variants in non-coding region. Long read data has been proved to be useful in typing HLA alleles in full resolution, but only a few tools are publicly available and with significant limitations in practical application. RESULTS: We developed FuFiHLA, a lightweight open-source software, to type HLA alleles. Currently it supports typing alleles of six HLA genes (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, and HLA-DQB1) from long reads. Evaluation using 233 PacBio HiFi WGS samples from HPRC shows that FuFiHLA achieves 99.6% accuracy in the full field allele typing and QV as 51.8 for consensus allele sequence construction. Additional testing on four Nanopore R10 reads demonstrates slightly reduced accuracy in the fourth field. AVAILABILITY: FuFiHLA is available at https://github.com/jingqing-hu/FuFiHLA under MIT License.

Humans↗
PubMed2025

Comparative HLA Alleles and Haplotypes of Bone Marrow Volunteers Recruiting in the Asian and European Parts of Russia.

HLA typing of 9126 haematopoietic stem cell donors living in the Asian and European parts of Russia and identifying themselves as Russians was performed using NGS technology in 2-field resolution at the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci. The study of donors in the Asian part of Russia disclosed 77 alleles at the HLA-A locus, 111 at the HLA-B locus, 58 at the HLA-C locus, 54 at the HLA-DRB1 locus, and 26 at the HLA-DQB1 locus. Donors of the European part of Russia are characterised by the following allelic diversity: 87 alleles at the HLA-A locus, 136 at the HLA-B locus, 72 at the HLA-C locus, 67 at the HLA-DRB1 locus, and 37 at the HLA-DQB1 locus. The most common five-locus haplotype in both populations is HLA-A*01:01&#x2009;~&#x2009;HLA-C*07:01&#x2009;~&#x2009;HLA-B*08:01&#x2009;~&#x2009;HLA-DRB1*03:01&#x2009;~&#x2009;HLA-DQB1*02:01. Throughout the study, 26 new alleles were revealed.

Humans↗