Search Results (180)

Background/Objectives. Crohn’s disease (CD) is a chronic immune-mediated inflammatory disease that affects the gastrointestinal tract. The management of CD is complex, and treatment requires numerous therapies. One of the best gut-selective biologic drugs with proven efficacy in induction and maintenance therapy in patients with CD is vedolizumab (VDZ). Nevertheless, not all patients with CD respond to VDZ treatment, possibly due to their individual pharmacogenomic profiles. In this study, the association of variants in genes encoding molecules involved in biological pathways targeted by VDZ, ITGA4, ITGB7, and MADCAM1, with VDZ response was analyzed. In addition, Human Leukocyte Antigen (HLA) alleles were investigated. Methods. Whole exome sequencing was performed on 63 CD patients treated with VDZ as first-line biologic therapy. Genetic variants were associated with response to VDZ treatment, estimated as follows: (1) good clinical response (patients assigned to standard maintenance protocol after 14-week induction) or partial (patients assigned to optimized maintenance protocol after 14-week induction); (2) good biochemical response (CRP ≤ 10 mg/L at week 14) or poor (CRP > 10 mg/L at week 14). Results. Two MADCAM1 variants were associated with VDZ response, as defined by CRP values in week 14 of VDZ therapy. The genetic variant MADCAM1 rs758941486 was associated with poor CRP reduction in response to VDZ induction therapy, while MADCAM1 rs1555716175 was associated with optimal CRP reduction. Anti-drug antibody-related HLA-DRB1, DQB1, and DQA1 alleles were not associated with VDZ response. Conclusions. This is a pioneering pharmacogenomics study on the VDZ direct therapeutic targets in bio-naïve CD patients, which opens the door for future research. Full article

Dengue is an arboviral disease of global significance caused by Orthoflavivirus denguei (DENV), which has four antigenically distinct serotypes. The envelope (E) protein plays a critical role in viral entry and eliciting immune responses. This study aimed to compare the biochemical and immunological properties of the E protein across the four DENV serotypes using in silico approaches. E protein reference sequences were retrieved from RefSeq and analyzed with various bioinformatics tools. Sequence alignment revealed identities ranging from 63.08% to 77.69%. Biochemical analysis showed minimal variation in molecular weight and isoelectric point; however, the net charge of DENV-3 E protein was notably lower. Secondary structure predictions indicated a predominance of alpha-helices in DENVs-1/2, while DENVs-3/4 featured more beta-sheets. Post-translational modification analysis revealed mostly casein kinase II phosphorylation sites across all serotypes, with DENV-4 uniquely presenting also tyrosine kinase sites. Amino acids W231/D341 in DENV-1, Q86 in DENVs-2/4, and D87/D339 in DENV-3 showed maximum antigenicity scores in B cell recognition, while the human leukocyte antigen (HLA) alleles B*08:01/B*39:01 and DRB4*01:01, recognized by T cells, presented the highest number of predicted epitopes for the different DENV serotypes. Conservation analysis showed that the major antigenic regions highlighted in this study are highly conserved among contemporary DENV isolates despite the genetic variability observed within each serotype. These findings suggest that subtle structural differences in the E protein may contribute to distinct immunogenic profiles, highlighting candidate regions for future investigation. Full article

Background: Dysregulated G protein-coupled receptor (GPCR) signaling is increasingly implicated as an important driver for oncogenesis. Uveal melanoma (UM) represents a highly metastatic intraocular malignancy primarily driven by activating mutations in G protein family members Gαq/11. Although Tebentafusp, the first FDA-approved bi-specific T-cell engager for UM, improves survival, its activity is restricted to specific human leukocyte antigen (HLA) alleles, highlighting the need to identify broadly expressed targetable proteins for immunotherapeutic strategies. Here we aimed to define surfaceome and phospho-signaling signatures associated with oncogenic Gαq-signaling. Methods: Heterologous and UM in vitro systems were used to interrogate Gαq-driven changes. HEK293T cells were transfected with wild-type Gαq or the oncogenic Gαq (R183Q) mutant, with surface marker profiles quantified by flow cytometry. Complementary immunophenotyping was performed in the Gαq-mutant UM cell line MP46 and Gα11-mutant line MP41. Kinase phosphorylation was assessed in control and Gαq mutant conditions followed by effect size estimation (Hedges’ g), Welch’s t-test, principal component analysis, and Spearman correlation-based network analysis of surface and phosphoprotein readouts. Results: Hyperactive Gαq in HEK293T cells induced graded remodeling of surface protein profiles, including reduced CD56 (NCAM) and CD49c (ITGA3) expression. Similarly, in UM models, MP46 versus MP41 had limited expression of CD56 and CD49c. Moreover, phospho kinase profiling and network analysis identified altered surface-phosphoprotein relationships, including a CD56-p70 S6 kinase association. Conclusions: These data provide new insights into Gαq-driven modulators of UM phenotype of relevance for studies of tumor–microenvironment interaction and metastasis. Full article

Human leukocyte antigen (HLA) loci are highly polymorphic genome regions, with allele frequencies varying significantly across different populations. Population HLA frequency databases may contain biases and make cross-study comparison complicated due to varying data curation protocols, genotyping methodologies, resolution, and inconsistencies in the selection criteria for population samples. This study presents HLA allele frequencies of class I (HLA-A, -B, -C) and class II (HLA-DRB1, -DQB1, -DQA1), as well as their combined haplotypes obtained from over 18,000 whole genome sequencing samples of the Russian population. The cohort was stratified based on PCA and admixture components, providing frequencies for 14 different ethnic groups. For 12 groups cohort size allowed us to reach average saturation of 96% of allele frequencies in groups. Moreover, we demonstrated the utility of composed statistics for disease population study using type 1 diabetes (T1D) as an example. Genetically defined population clusters with similar aggregated genetic risk for T1D demonstrated substantial differences in frequencies of risk and protective HLA alleles. Obtained frequency data were made publicly available through the Allele Frequency Net Database improving previously sparse coverage in HLA frequencies data for the East Europe and North Asia regions. Full article

Background/Objectives: Genetic variation in human leukocyte antigen (HLA) genes may contribute to inter-individual differences in infectious-disease susceptibility and clinical outcomes. This study aimed to determine the genotype frequency of HLA Class I and Class II loci in patients with COVID-19 in Saudi Arabia and to examine their associations with survival and clinical severity. Methods: A prospective observational study was conducted at King Faisal Specialist Hospital and Research Centre (KFSH&RC), Riyadh, Saudi Arabia, from January 2022 to December 2023. Genomic DNA was extracted, and polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) testing was performed to screen HLA genetic variation. Patients were grouped by survival status (recovered or deceased) and clinical severity: Stage A (asymptomatic), Stage B (mild), Stage C (moderate), and Stage D (severe). Results: In total, 123 patients with COVID-19 were included; 102 (82.9%) recovered and 21 (17.1%) died. ICU admission was more frequent among deceased patients than among recovered patients (95.2% versus 51.0%, p = 0.0001). At the locus level, HLA-DPB1 represented the largest proportion of HLA calls (21%). In call-position-specific allele-group analyses, B*15 in Allele 1 (14.3% versus 1.0%, p = 0.016), C*06 in Allele 2 (42.9% versus 18.6%, p = 0.023), DRB1*10 in Allele 1 (19.0% versus 4.9%, p = 0.045), and DQB1*05 in Allele 1 (33.3% versus 11.8%, p = 0.021) were significantly more frequent among deceased patients, whereas DQB1*03 in Allele 1 was significantly more frequent among recovered patients (45.1% versus 14.3%, p = 0.013). Severity analyses showed call-position-specific differences involving C*15, C*06, B*14, B*39, B*53, and DQB1*03. Vaccination status did not differ significantly by survival status or across the four clinical severity stages. Conclusions: Selected HLA Class I and Class II allele groups may be associated with COVID-19 survival and clinical severity patterns in this Saudi cohort. These findings should be interpreted cautiously given the cohort size and call-position-specific nature of the analyses. Full article

Adverse drug reactions (ADRs) remain a major clinical challenge and a leading cause of morbidity and mortality worldwide. Among them, severe cutaneous adverse drug reactions (SCARs), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), represent life-threatening immune-mediated hypersensitivity responses strongly associated with specific human leukocyte antigen (HLA) alleles. Despite well-established pharmacogenetic associations, current diagnostic strategies remain largely retrospective and lack predictive capability for novel drug–HLA risk pairs. Here, we present an integrative network-informed machine learning framework for predicting HLA-associated SCAR risk by combining pharmacogenomic features, drug chemical structure, and topological descriptors derived from drug–drug and drug–symptom interaction networks. An Extreme Gradient Boosting (XGBoost) classifier trained on integrated HLA allele and drug features, labeled using curated HLA–SCAR associations, achieved an accuracy of 0.860 ± 0.005, an F1-score of 0.689 ± 0.010, with an area under the receiver operating characteristic curve (AUROC) of 0.922 ± 0.003 and an area under the precision–recall curve (AUPRC) of 0.768 ± 0.007. Notably, several predicted positive associations absent from the training data corresponded to biologically plausible and literature-supported cases, including carbamazepine—HLA-B*15:11, supporting the model’s ability to generalize beyond known associations. Molecular docking provides structural evidence for the predicted associations, highlighting allele-specific binding patterns underlying these results. Overall, our results demonstrate that network-informed machine learning provides a proactive and integrative approach to SCAR risk prediction and may support early risk stratification and personalized drug safety assessment in precision medicine. Full article

To date, Lyme vaccine development has largely overlooked the vaccinee’s human leukocyte antigen (HLA) genetic makeup on which antibody production critically depends. Here, we evaluated in silico the predicted binding affinities of 192 HLA-II alleles with all 15-mer peptide sequences of five Borrelia burgdorferi proteins to identify peptides with strong binding affinity, as they would be the best candidates for antibody production in response to vaccination. We found the following: (a) 226 of the 1067 peptides tested (21.2%) were found to bind strongly to HLA-II molecules; (b) decorin-binding protein A had the greatest number of strongly binding peptides; and (c) 69 HLA-II alleles (primarily of the DRB1 gene) bound with strong affinity to peptides from Borrelia burgdorferi proteins. Finally, we tested for possible susceptibility to autoimmunity by any one of the 226 peptides above by searching for their occurrence in ~84,000 proteins of the human proteome and found overlap with only two 8-mer peptide sequences (embedded within the 226 15-mer peptides), neither of which was characterized by strong binding to HLA-I, suggesting a reduced likelihood of autoimmunity. These findings emphasize the importance of a personalized vaccine approach based on the vaccinee’s human leukocyte antigen genetic makeup and offer specific vaccine-candidate peptides that are predicted to maximize vaccine effectiveness and safety. The results of this computational study provide novel directions for future development of Lyme vaccines. Full article

Background/Objectives: This observational study investigated associations between human leukocyte antigen (HLA) polymorphisms and imaging-defined hepatic steatosis (non-alcoholic fatty liver disease—NAFLD) and liver fibrosis in patients with rheumatoid arthritis (RA). Methods: Steatosis was assessed by transient elastography (FibroScan) and defined as controlled attenuation parameter (CAP) ≥ 275 dB/m; fibrosis was defined as liver stiffness measurement ≥ 8 kPa. We tested 11 frequent HLA alleles (HLA-A*02, HLA-B*07, HLA-B*08, HLA-B*27, HLA-B*35, HLA-B*44, HLA-B*51, HLA-DRB1*11, HLA-DRB1*14, HLA-DRB1*15, and HLA-DRB1*16). Associations were evaluated using multivariable logistic regression (individual and omnibus models) adjusted for age, body mass index (BMI), triglycerides, and glucose. Results: A total of 176 patients with rheumatoid arthritis were enrolled. NAFLD/steatosis was present in 35.2% of patients (n = 62), and fibrosis in 10.8% (n = 19). No HLA allele was significantly associated with steatosis or fibrosis after correction for multiple testing. BMI and triglycerides were independently associated with steatosis (BMI OR 1.22, 95% CI 1.12–1.34; triglycerides OR 1.48, 95% CI 1.04–2.18). For fibrosis, HLA-DRB1*15 showed the strongest trend-level association (OR ~2.6–2.9) but did not remain significant after correcting for multiple testing. Conclusions: In this RA cohort, metabolic factors (particularly BMI and triglycerides) were the dominant predictors of CAP-defined steatosis. No robust association between the tested HLA markers and steatosis or fibrosis was identified. Trend-level signals—most notably HLA-DRB1*15 for fibrosis—should be considered hypothesis-generating and warrant replication in larger, adequately powered cohorts. Full article

Background/Objectives: Ischemic sudden cardiac death (SCD) is a devastating event that often occurs in apparently healthy individuals. Genetic susceptibility may play a key role in the pathogenesis of such ischemic events. This study aimed to investigate the correlations between Human Leukocyte Antigen (HLA) alleles, genotypes, and haplotypes and SCD to identify potential risk factors. This study also investigated three Single-Nucleotide Polymorphisms (SNPs) in the MYBPC3 gene and their association with SCD. Methods: We conducted an exploratory study between 2022 and 2024 in North-Western Transylvania (Romania) on 81 autopsy-confirmed SCD cases, compared with 162 controls for HLA typing, and with 96 controls for SNPs. HLA analysis of the HLA-DRB1 and HLA-DQB1 genes was performed using low-resolution SSP-PCR. The three SNPs in the MYBPC3 gene: rs142317339 (C > T), rs148808089 (G > A), and rs11570076 (G > A) were performed using a Real-Time PCR System. Results: The HLA-DRB1*07 allele has reduced odds of SCD, after adjustment for age and sex, and the HLA-DRB1*08 allele showed a trend toward increased odds. No statistically significant associations were detected at the allele or genotype level for HLA-DQB1. Haplotype-based analyses further revealed that genetic susceptibility is driven predominantly by low-frequency protective haplotypes rather than by common risk haplotypes, with several combinations conferring strong or moderate protection (HLA-DRB1*07~HLA-DQB1*03, HLA-DRB1*07~HLA-DQB1*02, and HLA-DRB1*15~HLA-DQB1*05). No statistically significant association was found between the three SNPs studied in the two groups, and their frequencies were very low. Conclusions: Specific HLA-DRB1 and HLA-DQB1 alleles and haplotypes may be associated with protection against SCD, supporting a possible immunogenetic role in SCD and the identification of genetic risk markers. Full article

Background: The human leukocyte antigen (HLA) is crucial for antigen presentation and vaccine efficacy. This study examined the association between HLA polymorphisms and the immune response to hepatitis B vaccination in children with acute lymphoblastic leukemia (ALL). Methods: 101 pediatric ALL patients at Shanghai Children’s Medical Center affiliated with Shanghai Jiaotong University School of Medicine who tested negative for hepatitis B surface antibody (anti-HBs) and were not infected with hepatitis B received three doses of the hepatitis B vaccine. Anti-HBs titers were measured before and after vaccination. Participants were divided into high- and low-response groups based on post-vaccination anti-HBs titers. Sequence-specific primer polymerase chain reaction (PCR-SSP) was used to genotype HLA-A, -B, -Cw, -DRB1, and -DQB1 alleles. Results: Pre-vaccination anti-HBs titers were 3.38 ± 2.97 mIU/mL, and the post-vaccination seroconversion rate was 100% with mean titers of 429.61 ± 303.13 mIU/mL (p < 0.001). Following immunization, the low-response group (11.88%) had an anti-HBs titer of 56.47 ± 28.38 mIU/mL, while the high-response group (88.12%) had an anti-HBs titer of 479.93 ± 287.70 mIU/mL. There were significant differences in allele frequencies of B*3501 and Cw*0303 between the two response groups (p < 0.05). Binary logistic regression analysis showed that the B*3501 allele was negatively correlated with the anti-HBs response level (p < 0.05). Conclusions: HLA-B*3501 may be associated with lower antibody response levels in children with ALL who completed the full hepatitis B vaccination series. All these children demonstrated protection against the hepatitis B virus (HBV). We will subsequently validate the association between HLA-B*3501 and the level of hepatitis B vaccine immune response in children with ALL through expanding the sample size or conducting a multicenter study. Full article

The significance of gut epithelial cell autoantibodies (GECAs), human leukocyte antigen (HLA) alleles, and other scientifically relevant factors has been largely overlooked, despite their potential importance in the medical management of HIV-infected individuals, in understanding the pathogenesis of AIDS, and in improving epidemiological and diagnostic approaches. This review may be considered as a hypothesis-driven narrative paper mostly considering GECAs and some easily detectable genetic markers. Thus, the aim is to highlight these neglected medical and scientific issues. Addressing them may contribute to a deeper understanding of HIV pathology at both the individual and population levels. Autoantibodies against enterocytes (GECAs) are present in the majority of HIV-positive patients. These intestinal epithelial cells are crucial for nutrient absorption and because of their role as antigen-presenting cells (APCs) within the immune system. Furthermore, the number of CD4-positive lymphocytes depends largely on daily antigenic stimulation rather than on thymic function, which becomes residual or inactive after puberty. The fall of CD4+ lymphocyte counts observed in HIV-infected patients may therefore be exacerbated by enterocyte dysfunction/damage, as indicated by the presence of GECAs. These autoantibodies either cause or reflect damage to these important antigen-presenting cells, which may impair intestinal antigen presentation by their surface HLA proteins to the clonotypic T-cell receptor of lymphocytes. Additionally, the association between specific HLA alleles and a CCR5 variant affects HIV disease progression or transmission and should be considered in both adults and mother–infant pairs. In particular, HLA-B35 and HLA-B57 allelic groups have been implicated in influencing both the transmission and progression of HIV infection. Moreover, several aspects of the natural history of HIV infection remain unresolved and controversial, and these issues warrant urgent clarification. For instance, diagnostic tests are not yet standardised globally, and viral abundance in HIV-infected individuals or AIDS patients’ cells may be relatively low. In summary, the neglected facets of HIV infection demand renewed investigation, particularly now that an HIV diagnosis is no longer the devastating prognosis it once was. The objective of this work is to emphasise additional factors that may influence the course of AIDS, such as enterocyte injury reflected by presence of GECAs. Ultimately, we propose that GECAs may impair enterocytes’ HLA (MHC II)-mediated antigen presentation by enterocytes to CD4+ T lymphocytes (through T-cell receptors), thereby diminishing T-cell proliferation, reducing CD4+ cell numbers, and impairing immune function. Full article

Genetic associations with IgA nephropathy (IgAN), particularly in the human leukocyte antigen (HLA) region, vary across ethnic groups. This study investigated the association of HLA alleles with the diagnosis, pathological findings, and prognosis of biopsy-proven IgAN in a Taiwanese population. A case-control study was conducted using data from the Taiwan Precision Medicine Initiative, including 157 patients with biopsy-proven IgAN and 1570 age- and sex-matched controls. Genetic data were obtained from single-nucleotide polymorphism arrays, and HLA imputation was performed. Most single-nucleotide polymorphisms associated with IgAN were located within the HLA region on chromosome 6. Frequencies of several alleles (including C*08:01, DQA1*03:01, and DQB1*04:01) were significantly higher in the IgAN group. Conversely, frequencies of alleles such as B*58:01 and DQB1*02:01 were significantly lower. This study identified novel risk and protective HLA alleles for IgAN in a Taiwanese population. Full article

Drug-induced liver injury (DILI) remains one of the most challenging adverse drug reactions in clinical practice, particularly in its idiosyncratic form, which is not dose-dependent and is largely driven by host-specific immune and genetic factors. Recent genomic studies have revealed strong associations between certain human leukocyte antigen (HLA) alleles and susceptibility to DILI, supporting an immunogenetic mechanism in which drug or metabolite–protein adducts act as neoantigens, triggering aberrant T-cell activation and hepatocellular injury. This review summarizes current evidence on the contribution of HLA polymorphisms to the pathogenesis of idiosyncratic DILI, highlighting allele-specific risk patterns, such as HLA-B*57:01 associated with flucloxacillin, HLA-DRB1*15:01–DQB1*06:02 in amoxicillin–clavulanate, and HLA-B*35:02 in minocycline-induced liver injury. Furthermore, ethnic variability and allele-haplotype interactions are discussed as potential modulators of susceptibility and clinical phenotype. By integrating genetic and immunological insights, the identification of HLA signatures offers promising tools for precision medicine, enabling earlier identification of at-risk individuals and improved prevention of severe hepatotoxic reactions. Full article

The sodium iodide symporter (NIS) is a key protein in thyroid function responsible for iodine uptake, and it may be involved in the pathogenesis of autoimmune thyroiditis. However, it is also expressed in the salivary glands, the primary target of autoreactive cells in Sjögren’s syndrome (SS). Given the common link between the two diseases, we computationally investigated whether the epitopes of NIS can trigger an immune response leading to SS in Hashimoto’s thyroiditis (HT) patients genetically predisposed to both diseases. The TepiTool 2016, ABCpred 2006, and DiscoTope 2.0 servers were used to predict T-cell and B-cell epitopes by inputting the FASTA sequences and 3D structures of NIS, thyroid peroxidase (TPO) and Ro60 Y RNA-binding protein (Ro60), which served as reference antigens for HT and SS, respectively. T-cell epitopes were selected based on their binding to a panel of human leukocyte antigen (HLA) alleles associated with both SS and HT. We identified a total of 376 linear T-cell epitopes, 64 linear B-cell epitopes and 68 conformational B-cell epitopes of NIS. Compared to TPO, NIS T-cell epitopes showed significantly lower affinity for HLA alleles (p < 0.0001), while no significant difference was found compared to Ro60. While linear B-cell epitopes of NIS, TPO, and Ro60 showed similar binding affinity, conformational epitopes of NIS were predicted to have higher immunogenicity than Ro60 (p = 0.04), while no significant difference was found compared to TPO. These pivotal findings, discovered by the methods of computer modeling, suggest that NIS can potentially activate T cells and B cells in patients with genetic predisposition to SS and HT and need to be confirmed by further laboratory studies. Full article

The human leukocyte antigen (HLA) system plays a crucial role in regulating the immune response and is significant in organ transplantation, disease association studies, and population genetics. But does it influence longevity? The present study aims to explore the frequency of HLA alleles in a cohort of 100 individuals in the 65–90 age bracket from Romania, providing insights into genetic diversity and potential implications in longevity. High-resolution HLA typing was performed using next-generation sequencing (NGS) technology, allowing for precise identification of HLA alleles with a high degree of accuracy. The results reveal significant genetic diversity within the cohort, with prevalent alleles such as HLA-A*02:01:01:01, HLA-B*08:01:01:01, and DRB1*01:01:01:01 potentially influencing disease susceptibility and longevity. The study reveals the genetic diversity of HLA alleles in elderly Romanians, highlighting prevalent alleles that could be linked to longevity and disease resistance. Different results from previous research are attributed to the high-resolution analysis and small cohort size. Further studies with larger samples are needed to confirm findings and uncover their implications for healthy aging and healthcare. Full article