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At least 19 recordsLinked to original sources
PubMed2025

Investigations of HLA-F and HLA-G 3'UTR Polymorphisms in Preeclampsia and Fetal Growth Restriction Indicate a Possible Role of HLA-F-HLA-G Haplotypes and Diplotypes.

HLA-F and HLA-G may be involved in the pathogeneses of preeclampsia and fetal growth restriction (FGR). However, the functions of HLA-F and HLA-G in placental dysfunction remain unclear. The aim was to investigate differences in the prevalence of specific HLA-F and HLA-G gene allelic polymorphisms, genotypes, haplotypes, and diplotypes between controls and cases with preeclampsia or FGR. In total, blood samples from 365 pregnant females (controls, n = 192; preeclampsia, n = 164; FGR, n = 19) in their second and third trimester, and corresponding cordial blood samples (reflecting newborns, n = 160) were obtained after delivery. Genomic DNA was sequenced with a focus on the specific gene polymorphisms in the HLA-F gene locus, especially the single nucleotide polymorphisms (SNPs) rs1362126 (G/A), rs2523405 (T/G) and rs2523393 (A/G), as well as the rs371194629 (14-bp ins/del) in the 3'UTR of HLA-G. Haplotype and diplotype distributions were obtained using PHASE v2.1, and linkage disequilibrium analyses were performed. SNPs in the HLA-F gene locus and the 3'UTR of HLA-G were not associated with the risk of preeclampsia or FGR. The SNPs did not correlate with fetal-placental weight ratio, deviation of birth weight at gestational age, and placental weight. However, a trend towards an absence of certain HLA-F-HLA-G extended diplotypes in preeclampsia was observed. The current study does not support associations of the investigated HLA-F SNPs with preeclampsia or FGR. However, further studies are needed to evaluate the possible role of certain fetal HLA-F-HLA-G extended haplotypes and diplotypes in preeclampsia.

Humans↗
PubMed2025

Extensive Analysis of Genetic Diversity in HLA-DMA, HLA-DMB, HLA-DOA and HLA-DOB: Characterisation of 236 Novel Alleles.

HLA-DMA, -DMB, -DOA and -DOB are non-classical HLA Class II genes that play a crucial role in the selection of highly stable HLA Class II/peptide complexes on antigen-presenting cells. Although the genes were initially thought to have a limited diversity with less than 13 alleles per gene documented in the IPD-IMGT/HLA Database in 2022, recent studies suggest a potential impact of certain alleles on the outcome of hematopoietic cell transplantation. To gain a deeper understanding of allelic diversity, we sequenced HLA-DMA, -DMB, -DOA and -DOB of 1880 potential stem cell donors from Germany, Poland, Great Britain and Chile, achieving full-gene resolution. Remarkably, we identified 3968 previously undescribed sequences, including 28 distinct novel proteins. The observed allele frequencies were consistent across all studied populations with one dominating protein for each gene: HLA-DMA*01:01 (> 77%), HLA-DMB*01:01 (> 63%), HLA-DOA*01:01 (> 97%) and HLA-DOB*01:01 (> 77%). Notably, a much higher diversity was observed in full-genomic resolution. Finally, we submitted 51 distinct novel sequences for HLA-DMA, 58 for HLA-DMB, 80 for HLA-DOA and 47 for HLA-DOB to the IPD-IMGT/HLA Database. This comprehensive reference database update will not only simplify future genotyping of HLA-DMA, -DMB, -DOA and -DOB but will hopefully also enhance our understanding of the complex process of peptide selection and loading to the HLA Class II proteins.

Humans↗
PubMed2026

Innovative CRISPR/Cas9-Based Strategy for Allele-Specific HLA Peptidome Analysis Using a Pan-HLA Antibody.

Human leukocyte antigen (HLA) immunopeptidomics is restricted by the limited availability of allele-specific antibodies and by potential artifacts introduced by HLA overexpression systems. To address these challenges, we developed a CRISPR/Cas9-based strategy that selectively deletes undesired classical class I alleles while preserving a single endogenous allele, thereby enabling allele-resolved peptidome profiling with a pan-HLA class I antibody. As a proof of concept, we edited JY cells to eliminate HLA-B∗07:02 and HLA-C∗07:02 while retaining HLA-A∗02:01 (ΔBC clones). Peptide-HLA complexes were immunoprecipitated from WT and ΔBC clones using either the pan-HLA class I antibody W6/32 or the A∗02:01-specific antibody PA2.1, followed by nanoLC-MS/MS and computational HLA assignment. Deletion of HLA-B and HLA-C alleles caused an expected ∼55% reduction in total class I surface expression. Despite this, W6/32 immunoprecipitation from ΔBC clones recovered a comparable peptide yield to PA2.1 in WT cells. Binding predictions showed that most peptides identified in ΔBC clones using W6/32 were assigned to HLA-A∗02:01, with near-complete loss of HLA-B∗07:02- and HLA-C∗07:02-derived peptides. Sequence logo analysis confirmed the canonical A∗02:01 motif across conditions. The ΔBC W6/32 immunopeptidome exhibited a high degree of overlap (∼88%) with the WT PA2.1 repertoire, supporting the specificity and fidelity of the approach. These findings establish CRISPR-based editing of HLA alleles as a viable strategy for allele-specific immunopeptidome analysis using pan-HLA antibodies, supporting its potential application beyond this proof-of-concept system, reducing reliance on allele-specific reagents and facilitating the study of underrepresented HLA alleles.

Humans↗
PubMed2025

An In-Depth Review of the Genetics of the Non-Classical HLA Class I Gene HLA-E and Its Effects on Haematopoietic Cell Transplant Outcomes.

HLA-E is a non-classical HLA class I gene with limited reported genetic variability and few published studies into full-gene sequencing or population allele frequencies. Two protein variants, HLA-E*01:01 and HLA-E*01:03, are very common, accounting for 94%-100% of observed alleles in most studies performed to date. Frequently utilised exon-based sequencing strategies have led to the assumption of HLA-E being a near bi-allelic gene; however, recent full-gene sequencing studies have shown a greater degree of genetic variability than initially imagined. We carried out a literature review of HLA-E genotype and ethnicity data, which suggested HLA-E*01:03 is more common in Asian and, in particular, East Asian populations. Furthermore, HLA-E*01:03:02 is more frequently observed than HLA-E*01:03:01 in European and American populations, whereas HLA-E*01:03:01 is found at higher frequencies in Asian populations. It has been proposed that HLA-E may have a role in Haematopoietic Cell Transplantation (HCT) due to its interaction with NK and CD8+ T cells and its non-canonical peptide binding repertoire. Here we also review published literature into the effects of HLA-E genetics on HCT outcomes. Heterogeneity between cohorts muddies the waters; hence, studies report confounding effects of HLA-E genotype and matching on HCT outcomes. The need for further HLA-E sequencing of larger cohorts is evident to gain useful insight into the true genetic variability of HLA-E and its impact on HCT.

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

Protective Effects of HLA-DRB1*08:03 and HLA-DQA1*01:03 Alleles for Alloanti-D Immunisation in the Southern Chinese D-Negative Pregnant Women.

Alloanti-D is still one of the most common causes of severe hemolytic disease of the fetus and newborn in China, as rhesus immunoglobulin (RhIG) prophylaxis is not a routine practice throughout China. HLA plays an important role in the susceptibility to alloimmunisation against red blood cell antigens. This study was designed to identify susceptible and protective HLA alleles for alloanti-D immunisation after pregnancy in the southern Chinese D-negative (D-) pregnant women. In this study, a cohort of 116 true D- pregnant females who had not received prophylactic RhIG prophylaxis, had two or more pregnancies, and did not produce alloanti-D (non-responders group), and 122 true D- pregnant women with alloanti-D immunisation (D responders group), were enrolled. HLA genotyping (HLA-A, -B, -C, -DRB1, -DPA1, -DPB1, -DQA1, and -DQB1) was performed by third generation sequencing with nanopore technology. The phenotypic frequencies of HLA alleles were compared between the D responders group and non-responders group. The results showed that the phenotypic frequencies of HLA-DRB1*08:03 and HLA-DQA1*01:03 alleles in the D responders group were significantly lower than those in the non-responders group: 1.7% versus 13.1% [Odds Ratio (OR): 0.116, 95% CI: 0.026-0.518; pc&#x2009;=&#x2009;0.029] for HLA-DRB1*08:03 allele, and 5.2% versus 18.8% (OR: 0.235, 95% CI: 0.092-0.600, pc&#x2009;=&#x2009;0.019) for HLA-DQA1*01:03 allele. Our findings indicated that the presence of HLA-DRB1*08:03 or HLA-DQA1*01:03 alleles can be considered as a protective factor for alloanti-D immunisation in the southern Chinese D- pregnant women.

Humans↗
PubMed2026

Selective control of HLA-DRB1 and HLA-DQA1 transcription through DR/DQ super enhancer microelements.

MHC-II gene expression requires promoter-proximal and distal organizing elements. A super enhancer located between the HLA-DR and -DQ genes was dissected into five microdomains (regions A-E) to define its mechanism of action. Regions A and B were required for maximal expression of HLA-DQA1. Region A facilitated HLA-DQA1 expression and substituted for region B in its absence, as well as mediating longer-range interactions with distal CTCF sites. Region D modulated HLA-DRB1 through specific 3D chromatin interactions, whereas a local insulator element (XL9) broadly interacted with the SE. Through deletion of HLA-DRB1 proximal-promoter elements, HLA-DQ expression increased by co-opting interactions with region D, indicating that competition between microelements regulates the absolute levels of MHC-II genes. Together, these data define an additional layer of control for MHC-II genes encoded in one of the most polymorphic and disease-associated regions of the human genome.

CP: immunology↗
PubMed2026

The combined impact of HLA and non-HLA mismatch between donors and recipients on kidney transplant survival: a genomic analysis in a prospective cohort.

BACKGROUND: Kidney transplantation outcomes are strongly influenced by immunological compatibility between donor and recipient. While genetic mismatches in the human leukocyte antigen (HLA) region have long been recognised as key determinants of graft survival, increasing evidence, including our own previous work, suggests that non-HLA alloimmunity also plays a critical role. METHODS: We sequenced exomes of deceased kidney donor and recipient pairs in the prospective kidney transplant cohort at the Vienna General Hospital, recruited between January 1, 2012, and June 15, 2023. Out of 1209 pairs, 1187 passed quality control for analysis. Non-HLA mismatch was computed by considering non-synonymous single nucleotide polymorphisms specifically encoding trans-cell membrane or secreted proteins in the kidney (nsSNP-tcmsk). Using adjusted Cox proportional hazards models, we replicated results from our earlier work in recipients with primary graft function after 90 days, and extended the analysis to the combination of nsSNP-tcmsk with eplet mismatch to assess their associations with graft loss in the full cohort. FINDINGS: Of 20,421 human proteins, 2371 were considered for the nsSNP-tcmsk score. In our replication analysis we estimated for nsSNP-tcmsk a hazard ratio (HR) of 1.33 (95% CI 1.02-1.74) for graft loss per increase of one interquartile range. The nsSNP-tcmsk and eplet mismatch were uncorrelated (Spearman correlation coefficient 0.02, p = 0.47). A composite score of nsSNP-tcmsk and eplet mismatch was associated with graft loss with a HR of 1.76 (95% CI 1.20-2.57) corresponding to an absolute difference in 7-year restricted mean survival time between the first and fourth quartiles of 0.52 years (95% CI 0.16-0.87 years). INTERPRETATION: The impact of non-HLA donor-recipient mismatch on transplant loss is of the same magnitude as established mismatch scores in the HLA region. Together, these scores may be further validated as guiding markers for the required strength of maintenance immunosuppression. FUNDING: Vienna Science and Technology Fund, NIH/NIAID.

Humans↗
PubMed2026

Trimethoprim/sulfamethoxazole-triggered drug-induced hypersensitivity syndrome in an HLA B*13:01-positive kidney transplant recipient: a case report with implications for HLA-severe cutaneous adverse reaction associations in transplant care.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe cutaneous adverse reaction (SCAR) with a reported mortality rate of approximately 2-10%. DIHS/DRESS typically develops 2-8 weeks after exposure to an offending drug. An important focus of contemporary SCAR research is the growing evidence that specific human leukocyte antigen (HLA) alleles confer a markedly increased risk of drug-specific hypersensitivity reactions. We report a case of a kidney transplant recipient who developed DIHS/DRESS after prolonged trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis and carried the HLA-B13:01 allele. HLA-B13:01 is a strong genetic risk factor for TMP/SMX-induced DIHS/DRESS, particularly in Southeast Asian populations. Herein, we highlight the potential clinical relevance of pre-transplant HLA typing in predicting SCAR risk in transplant recipients. TMP/SMX-associated DIHS/DRESS may be under-recognized in transplant settings, where awareness of HLA-associated risk remains limited despite robust evidence from non-transplant populations. Transplant clinicians should be aware that DIHS/DRESS can occur outside the typical latency period, especially during immunosuppressant tapering, highlighting the need to integrate pharmacogenomic risk assessments into transplant care.

Humans↗
PubMed2026

HLA and non-HLA genetic analyses reveal suggestive variants associated with statin-induced liver injury.

BACKGROUND: Statins are widely prescribed for cardiovascular risk reduction and are generally well tolerated. However, they can cause drug-induced liver injury (DILI), and the genetic factors contributing to statin-DILI remain poorly understood. METHODS: HLA association and genome-wide association (GWAS) studies were conducted to identify genetic variants associated with statin-DILI. High-confidence cases (n=71) were identified from the Drug-Induced Liver Injury Network (DILIN) and compared with statin-exposed controls without liver injury (n=551) from the Indiana Biobank. Association testing was performed across ancestries and within ancestry, adjusting for age, sex, and three principal components of genotypes. Top variants were further evaluated in non-statin DILI cases and unexposed controls. In addition, we investigated the frequency of candidate variants among a comprehensive list of pharmacogenetic variants related to statins. RESULTS: HLA-DQA1*03:01 was significantly associated with increased risk of statin-DILI (OR=3.49, 95% CI 2.21-5.51, p-value=1.27&#xd7;10-7), with enrichment observed across multiple ancestry groups, particularly non-Hispanic Black and Hispanic individuals. From the GWAS, three loci showed suggestive associations (p-value <5&#xd7;10-06) with statin-DILI, including rs35197737 in RGS1 (OR=5.03, 95% CI 1.11-3.66, p=1.14&#xd7;10-7), rs75629598 in FRMD4A (OR=4.4, 95% CI=2.33-8.12, p=3.97&#xd7;10-6), and rs7658630 in the intergenic region on chromosome 4 (OR=4.86, 95% CI 2.66-8.85, p=2.68&#xd7;10-7). No pharmacogenetic variants revealed statistical significance. CONCLUSION: We identified HLA and non-HLA genetic variants associated with statin DILI. Future studies with larger sample sizes should confirm these observations.

Humans↗