Specific Human Leukocyte Antigen Research Articles

Association of human leucocyte antigen loci with vaccine-induced immune thrombotic thrombocytopenia: Potential role of the interaction between platelet factor 4-derived peptides and MHC-II.

No risk factors have been identified for vaccine-induced immune thrombotic thrombocytopenia (VITT) so far. The aim of this study was to identify human leucocyte antigen (HLA) alleles potentially associated with VITT susceptibility. Specific HLA class II alleles were detected with significantly higher frequency in VITT patients compared with Italian controls: DPB1*17:01, DQA1*05:01, and DRB1*11:04. In silico analysis revealed increased affinity of DRB1*11:04 for a platelet factor 4 (PF4)-derived peptide, ITSLEVIKA, that contains two amino acids present in the specific binding site of anti-PF4 antibodies from VITT patients. Our findings show for the first time a genetic predisposition to developing anti-PF4 antibodies in response to Ad-vector vaccines.

CLINICAL-IMMUNOGENETIC RELATIONSHIP IN CHILDREN WITH CHRONIC TONSILLITIS AND ASSOCIATED DISEASES

General Background: Chronic tonsillitis is a prevalent condition in children, often linked to various immunogenetic factors that influence its pathogenesis and associated diseases. Specific Background: The role of HLA (Human Leukocyte Antigen) system A and B loci in chronic tonsillitis remains inadequately understood, particularly regarding their clinical significance and the immunogenetic correlations with related conditions. Knowledge Gap: While prior studies have examined the genetic factors associated with chronic tonsillitis, there is a lack of comprehensive research focusing on the specific HLA loci and their implications for clinical outcomes in affected children. Aims: This study aims to determine the indicators of HLA A and B loci in children with chronic tonsillitis and to explore the clinical-immunogenetic correlations with associated diseases. Results: The findings demonstrate significant associations between specific HLA alleles and the severity of chronic tonsillitis, highlighting potential immunogenetic predispositions that influence disease progression and comorbidities. Novelty: This research introduces a novel perspective by linking HLA system indicators directly to clinical outcomes, thereby providing new insights into the immunogenetic mechanisms underlying chronic tonsillitis in children. Implications: The identification of these immunogenetic factors could enhance the understanding of chronic tonsillitis pathophysiology and inform personalized treatment strategies, ultimately improving patient management and outcomes in pediatric populations.

HLA Genetic Variants in COVID-19 Susceptibility: Assessing Diversity in Indian and Global Populations

Background: The rapid spread of the SARS-CoV-2 virus has had a global impact on various ethnic groups. In order to assess the genetic predisposition of the Indian population towards COVID-19, a comparative analysis was conducted using the Human Leukocyte Antigen (HLA) to investigate the frequencies of polymorphisms directly or potentially associated with COVID-19 susceptibility, severity, immune response, and fatal outcomes in comparison to other major populations. Objectives: The objective of this study is to evaluate the genetic predisposition of the Indian population to COVID-19 by analyzing the frequencies and associations of Human Leukocyte Antigen (HLA) polymorphisms. In addition, by delineating the role of specific HLA variants in the Indian context, the study seeks to enhance our understanding of genetic factors influencing COVID-19 impact and contribute to personalized approaches for disease management and prevention across diverse ethnic groups. Methods: We collected allelic information for DRB1 gene from 653 populations globally, as documented in The Allele Frequency Net Database (AFND). Data on COVID-19 susceptibility, severity, mortality, and protective factors were obtained from a previous global study. This study aimed to compare the specific frequencies of HLA-DRB1* in different ethnic groups, including other Indian populations with COVID-19-associated alleles and protective factors. Results: HLA-DRB1*01 was identified as a significant determinant of COVID-19 susceptibility among patients in 28 states of Mexico, whereas DRB1*08 in Saudi Arabian populations, DRB1*09:01 in Japanese populations, and DRB1*15:01 in Italian populations also showed this association. Likewise, DRB1*04 in the Iranian population played a role in disease severity, and DRB1*08 in the Italian population was associated with mortality in COVID-19 patients. In addition, alleles DRB1*01:01 and DRB1*04:01 were found to exhibit a protective role in Northeast England, whereas DRB1*04 demonstrated protective effects in Saudi Arabian populations. Conclusion: The involvement of HLA in COVID-19 requires further investigation, and epidemiological studies should focus on HLA profiles as determinants of the host immune system. Prolonged homozygosity in particular genomic regions could potentially increase susceptibility to COVID-19 infection. Therefore, prudent management strategies are recommended for this pandemic in isolated communities in India and worldwide.

HLA-C Peptide Repertoires as Predictors of Clinical Response during Early SARS-CoV-2 Infection.

The human leukocyte antigen (HLA) system plays a pivotal role in the immune response to viral infections, mediating the presentation of viral peptides to T cells and influencing both the strength and specificity of the host immune response. Variations in HLA genotypes across individuals lead to differences in susceptibility to viral infection and severity of illness. This study uses observations from the early phase of the COVID-19 pandemic to explore how specific HLA class I molecules affect clinical responses to SARS-CoV-2 infection. By analyzing paired high-resolution HLA types and viral genomic sequences from 60 patients, we assess the relationship between predicted HLA class I peptide binding repertoires and infection severity as measured by the sequential organ failure assessment score. This approach leverages functional convergence across HLA-C alleles to identify relationships that may otherwise be inaccessible due to allelic diversity and limitations in sample size. Surprisingly, our findings show that severely symptomatic infection in this cohort is associated with disproportionately abundant binding of SARS-CoV-2 structural and non-structural protein epitopes by patient HLA-C molecules. In addition, the extent of overlap between a given patient's predicted HLA-C and HLA-A peptide binding repertoires correlates with worse prognoses in this cohort. The findings highlight immunologic mechanisms linking HLA-C molecules with the human response to viral pathogens that warrant further investigation.

Abstract C020: Identification of KRAS-specific TCRs from human peripheral blood

Abstract Mutant KRAS is the predominant driver oncogene in pancreatic cancer accounting for approximately 90% of KRAS mutations. However, these mutant KRAS peptides exhibit weak binding affinity to most human leukocyte antigens (HLAs), impeding their recognition by the immune system and the subsequent generation of a corresponding T cell response. Identification of KRAS-mutant specific T cells would be useful to track tumor-specific T cell responses in patients and could also be used for adoptive transfer of TCR-transduced cells. Current efforts to identify KRAS-specific T cells have been limited by their restriction to specific HLA haplotypes or the provision of only a few T cell receptor (TCR) sequences. In this study, we developed a facile means of detecting KRAS-specific T cells from peripheral blood at frequencies as low as 1 in 1,000,000. We employ an α41BB agonist-selective lentivirus system combined with a KRAS peptide pool to facilitate the high-throughput discovery of KRAS-specific TCRs in peripheral blood mononuclear cells (PBMCs) derived from both patients with pancreatic cancer and healthy donors. Through in vitro stimulation and single-cell TCR analysis, we identified a series of T cell expansions sharing the same clonotype, indicating a response to KRAS-mutant peptide stimulation. We have quantified CD4 and CD8 KRAS-specific TCRs from patients with a diverse range of HLA haplotypes. Citation Format: Jiao Shen, Blake E. Smith, Winiffer Conce Alberto, Ellen J. Kim, Michael L. Dougan, Harshabad Singh, Michael E. Birnbaum, Stephanie K. Dougan. Identification of KRAS-specific TCRs from human peripheral blood [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C020.

Deciphering the Genetic Landscape: Exploring the Relationship Between HLA-DQA1, HLA-DQB1, and HLA-DRB1 Genes in Diabetes Mellitus

Abstract: Diabetes mellitus (DM) is a complex and multifactorial metabolic disorder with a significant genetic component. The human leukocyte antigen (HLA) genes, specifically HLA-DQA1, HLA-DQB1, and HLA-DRB1, have been implicated in the susceptibility and pathogenesis of DM. This review delves into the intricate interplay of these HLA genes, seeking to unravel the genetic tapestry that contributes to the development and progression of diabetes. We begin by providing an overview of the HLA system and its critical role in immune regulation. Subsequently, we explore the current state of knowledge regarding the association between HLA-DQA1, HLA-DQB1, and HLADRB1 polymorphisms and susceptibility to both type 1 and type 2 diabetes. Emphasis is placed on recent advancements in genetic research methodologies, including genomewide association studies and next-generation sequencing, that have provided deeper insights into the genetic architecture of DM. The review also scrutinizes the functional implications of specific HLA alleles in modulating immune responses and the potential mechanisms by which they contribute to the autoimmune processes observed in type 1 diabetes. Additionally, we examine the role of HLA genes in the context of insulin resistance and beta-cell dysfunction in type 2 diabetes, shedding light on the shared and distinct genetic underpinnings of these two major forms of DM. Furthermore, we discuss the clinical implications of HLA genotyping in predicting disease risk, prognosis, and personalized treatment strategies. The integration of genetic information into clinical practice holds promise for precision medicine approaches in diabetes management.

Impact of HLA Alleles on COVID-19 Severity in Kidney Transplant Recipients: A Single-Center Study.

Introduction The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted global health, particularly affecting vulnerable populations, such as organ transplant recipients. Human leukocyte antigens (HLAs) play a critical role in immune response regulation, and understanding their association with COVID-19 can provide insights into disease susceptibility and severity. This study aims to explore the association between HLA allele variability and COVID-19 susceptibility and severity among kidney transplant recipients. Methods In 2023, we conducted a study on 73 kidney transplant recipients who tested positive for COVID-19 via polymerase chain reaction. This study included assessments of clinical status, immunosuppressive drug levels, HLA allele frequencies, and donor-recipient tissue compatibility. Molecular analyses were performed using sequence-specific oligonucleotide typing, and statistical analysis was conducted using IBM SPSS Statistics, version 20.0 (IBM Corp., Armonk, NY). Results Among the participants, 31 were hospitalized and 42 were treated as outpatients. Significant differences were observed in HLA allele distributions, particularly the HLA-A*11 allele, which was more prevalent in outpatient-treated patients, suggesting a potential protective effect. No significant age differences were observed between hospitalized and outpatient groups. Serum tacrolimus levels were notably higher in outpatients. Statistical analyses revealed significant associations between certain HLA groups and the severity of COVID-19 infection. Conclusions This study highlights the importance of HLA allele compatibility in influencing the clinical outcomes of COVID-19 in kidney transplant recipients. The findings suggest that specific HLA alleles may reduce susceptibility or moderate the severity of COVID-19, indicating a need for broader genetic studies across diverse populations to validate these observations and improve management strategies for transplant recipients during pandemics.

In Silico Identification of Peanut Peptides Suitable for Allergy Immunotherapy in HLA-DRB1*03:01-Restricted Patients.

Peanut allergy, a prevalent and potentially severe condition affecting millions worldwide, has been linked to specific human leukocyte antigens (HLAs), suggesting increased susceptibility. Employing an immunoinformatic strategy, we developed a "logo model" based on amino acid frequencies in the peptide binding core and used it to predict peptides originating from 28 known peanut allergens binding to HLA-DRB1*03:01, one of the susceptibility alleles. These peptides hold promise for immunotherapy in HLA-DRB1*03:01 carriers, offering reduced allergenicity compared to whole proteins. By targeting essential epitopes, immunotherapy can modulate immune responses with minimal risk of severe reactions. This precise approach could induce immune tolerance with fewer adverse effects, presenting a safer and more effective treatment for peanut allergy and other allergic conditions.

Genetic testing and human leukocyte antigen in patients with hypertrophic cardiomyopathy and connective tissue diseases.

Hypertrophic cardiomyopathy (HCM) is caused by myocardial hypertrophy, often due to mutations in cardiac sarcomere protein genes such as beta-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3). However, a significant proportion of HCM cases lack identified genetic mutations, and genotype-phenotype correlations remain unclear. Concurrently, potential associations between HCM and human leukocyte antigen (HLA) types, as well as connective tissue diseases, have been proposed. In this single-center study, we aimed to investigate the genetic and HLA profiles of patients with obstructive hypertrophic cardiomyopathy (HOCM) and connective tissue diseases, particularly focusing on the prevalence of genetic variants and HLA types. We conducted a detailed analysis of five patients with HOCM and connective tissue diseases and sarcoidosis, identifying rare variants in causative genes for HCM in two cases and observing specific HLA types that were relatively common. Notably, 15% of all HOCM cases presented with connective tissue diseases, mainly rheumatoid arthritis. These findings underscore the complexity of HCM etiology and suggest potential implications for both diagnostic strategies and therapeutic approaches in patients with concomitant inflammatory conditions.

The Impact of Donor-Recipient Human Leukocyte Antigen Matching on Bronchiolitis Obliterans-Free Survival Among Lung Transplant Recipients With Connective Tissue Diseases.

The development of connective tissue disease-associated lung diseases (CTD-LD) occurs in association with specific human leukocyte antigens (HLA). For CTD-LD patients who require lung transplant, it is unknown whether utilization of donor organs expressing these same HLA impacts posttransplant outcomes. Using the Scientific Registry of Transplant Recipients, we assessed whether CTD-LD lung transplant recipients in the United States have worse bronchiolitis obliterans (BOS)-free survival based on the degree of donor HLA matching. This included overall degree of donor-recipient HLA matching, donor-recipient matching at DR loci, and recipient matching with specific donor HLA antigens associated with the development of pulmonary disease in their condition. Among 1413 patients with CTD-ILD, highly HLA-matched donor-recipients did not have worse adjusted survival (hazard ratio [HR]=0.93, 95% confidence interval [CI]=0.58-1.51, p=0.77). Recipients who were fully matched at HLA DR did not have worse survival (HR=0.82, 95% CI=0.56-1.19, p=0.29). Finally, among individual CTD-LD, including rheumatoid arthritis, systemic sclerosis, the idiopathic inflammatory myopathies, and systemic lupus erythematous, transplant with a donor expressing HLA antigens associated with lung manifestations in these conditions was not associated with worse BOS-free survival. Among transplant recipients with CTD-LD, HLA donor-recipient matching, including at the DR loci, does not result in worse BOS-free survival. Based on these findings, there is no reason to treat these as unacceptable antigens when considering donor offers for CTD-LD candidates.

Analysis of HLA Alleles in Different Cohorts of Patients Infected by L. infantum from Southern Spain.

Leishmaniasis is an infectious disease caused by protozoa of the genus Leishmania, which is endemic in certain areas of Europe, such as southern Spain. The disease manifests in various clinical phenotypes, including visceral, cutaneous, mucosal, or asymptomatic leishmaniasis. This diversity in clinical outcomes may be influenced by the host immune response, with human leukocyte antigen (HLA) molecules playing a crucial role in determining susceptibility and progression of the infection. This study explores the association between specific HLA variants and Leishmania infantum infection. We recruited four cohorts: a control group, asymptomatic individuals, patients with symptomatic disease, and cohabitants of infected individuals. HLA typing was performed for all participants, followed by an association analysis with infection status and disease progression. Our findings indicate that the HLA-B*38 and HLA-C*03 alleles are associated with protection against L. infantum infection. These results contribute to a better understanding of the disease's progression, offer potential for new therapeutic approaches such as vaccines, and expand the existing knowledge in the literature.

Association of HLA alleles with cephalosporin allergy in the Taiwanese population

Cephalosporin antibiotics are widely used in clinical settings, but they can cause hypersensitivity reactions, which may be influenced by genetic factors such as the expression of Human leukocyte antigen (HLA) molecules. This study aimed to investigate whether specific HLA alleles were associated with an increased risk of adverse reactions to cephalosporins among individuals in the Taiwanese population. This retrospective case–control study analyzed data from the Taiwan Precision Medicine Initiative (TPMI) on 27,933 individuals who received cephalosporin exposure and had HLA allele genotyping information available. Using logistic regression analyses, we examined the associations between HLA genotypes, comorbidities, allergy risk, and severity. Among the study population, 278 individuals had cephalosporin allergy and 2780 were in the control group. Our results indicated that certain HLA alleles, including HLA-B*55:02 (OR = 1.76, 95% CI 1.18–2.61, p = 0.005), HLA-C*01:02 (OR = 1.36, 95% CI 1.05–1.77, p = 0.018), and HLA-DQB1*06:09 (OR = 2.58, 95% CI 1.62–4.12, p < 0.001), were significantly associated with an increased risk of cephalosporin allergy reactions. Additionally, the HLA-C*01:02 allele genotype was significantly associated with a higher risk of severe allergy (OR = 2.33, 95% CI 1.05–5.15, p = 0.04). This study identified significant associations between HLA alleles and an increased risk of cephalosporin allergy, which can aid in early detection and prediction of adverse drug reactions to cephalosporins. Furthermore, our study highlights the importance of HLA typing in drug safety and expanding our knowledge of drug hypersensitivity syndromes.

HLA Genotyping in Children With Celiac Disease Allows to Establish the Risk of Developing Type 1 Diabetes.

Celiac disease (CD) and type 1 diabetes (T1D) often co-occur and share genetic components in the human leukocyte antigen (HLA) class II region. We aimed to study the usefulness of HLA genotyping in predicting the risk of developing T1D in patients with CD and the temporal relationship between these diseases. A cohort of 1,886 Sardinian patients, including 822 with CD, 1,064 with T1D, and 627 controls, underwent HLA class II typing. Seventy-six of 822 patients with CD were also affected by T1D (CD-T1D), and their HLA genotypes were analyzed for specific HLA associations with CD, T1D, and controls. High-risk HLA-DQ genotypes, including HLA-DQ2.5/DQ8, -DQ2.5/DQ2.5, and -DQ2.5/DQ2.3, were strongly associated with CD-T1D with frequencies of 34.5%, 15.9%, and 18.8%, respectively. Conversely, certain HLA genotypes associated with CD seemed to confer protection against T1D development. Therefore, HLA genotyping allows for the identification of those patients with CD who might develop T1D. The frequency of patients with CD preceding T1D is higher in younger children than older ones, with implications for the early childhood approach to diabetes prevention. CD is a condition for future T1D development, and specific HLA genotypes can predict this risk. Early screening for celiac autoimmunity and subsequent HLA typing in CD children could help identify those at high risk of T1D, allowing for proactive interventions and immunotherapies to preserve β-cell function. These findings may support the re-evaluation of HLA typing in children with CD.

HLA investigation in ICI-induced T1D and isolated ACTH deficiency including meta-analysis.

Widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment has led to an increase in the number of reported cases of immunotherapy-related endocrinopathies. This study aimed to analyze and compare human leukocyte antigen (HLA) signatures associated with ICI-induced type 1 diabetes (ICI-T1D) and isolated adrenocorticotropic hormone deficiency (ICI-IAD) in patients with both conditions. HLA signatures were examined for their frequencies of occurrence in 22 patients with ICI-T1D without concurrent IAD, including 16 patients from nationwide reports (ICI-T1D group) and 14 patients with ICI-IAD without concurrent T1D (ICI-IAD group). The HLA signatures were also compared for their respective frequencies in 11 patients with ICI-T1D and ICI-IAD, including eight from nationwide reports (ICI-T1D/IAD group). In the ICI-T1D group, HLA-DRB1*09:01-DQB1*03:03 and DQA1*03:02, which are in linkage disequilibrium with DRB1*09:01-DQB1*03:03 and DRB1*13:02-DQB1*06:04, were susceptible to ICI-T1D, whereas DRB1*15:02-DQB1*06:01 was protective against ICI-T1D. In the ICI-IAD group, DPB1*09:01, C*12:02-B*52:01, and DRB1*15:02-DRB1*06:01, which are in strong linkage disequilibrium, were associated with susceptibility to ICI-IAD. Moreover, DRB1*15:02-DRB1*06:01 was not detected in the ICI-T1D/IAD group. This study revealed specific HLA signatures associated with ICI-T1D and ICI-IAD. Moreover, HLA-DRB1*15:02-DRB1*06:01, an ICI-IAD-susceptible HLA haplotype, coincides with the ICI-T1D-protective HLA haplotype, suggesting that the presence of DRB1*15:02-DRB1*06:01 may protect against the co-occurrence of T1D in patients with ICI-IAD.

Association between specific human leukocyte antigen alleles and development of thyroid immune-related adverse event.

Aim: Inherent variations in human leukocyte antigen (HLA) alleles have been revealed epidemiologically to influence the development of autoimmune diseases. HLA alleles may thus also be associated with the development of immune-related adverse events (irAEs), such as thyroid irAE.Materials & methods: In this case-control study, 71 cancer patients who received immune checkpoint inhibitors were enrolled and HLA-genotyped and the frequency of HLA alleles was compared.Results: A*26:01, DPA1*01:03 and DPB1*02:01 were significantly more frequent in patients with thyroid irAE than in patients without any irAEs (35.0 vs3.2% [p=0.004], 80.0 vs45.2% [p=0.020] and 55.0 vs25.8% [p=0.044], respectively).Conclusion: A*26:01, DPA1*01:03 and DPB1*02:01 appear to be associated with thyroid irAE.

Association of Human Leukocyte Antigen (HLA) Class II Alleles of DQB1 (DQB1*03:02) (DQB1*06:02) and DRB1 (DRB1*04:01) with Type-1 Diabetes Patients of Khyber Pakhtunkhwa, Pakistan

Type-1 diabetes (T1D), an autoimmune disease, significantly impacts global health, with varying prevalence across different geographies. This study investigates the association of specific Human Leukocyte Antigen (HLA) Class II alleles, namely DQB1*03:02, DQB1*06:02, and DRB1*04:01, with T1D in the Khyber Pakhtunkhwa (KP) population of Pakistan. Conducted as a 1:1 matched case-control study, this research involved 33 T1D patients and an equal number of age- and gender-matched healthy controls. Our findings reveal a weak association of alleles DRB1*04:01 and DQB1*03:02 with T1D (OR = 2.065 and 1.393, respectively, p &gt; 0.05). DQB1*06:02 allele, which is considered to have a protective effect against T1D was more prevalent in control as compared to cases (93.9% vs 90.9%), however, the association was non-significant (OR 0.645, p &gt; 0.05). These insights contribute to understanding genetic influences on T1D in the KP region and underscore the need for further research with larger, diverse cohorts to refine the genetic markers of T1D risk and protection

An exploratory study on prediction of risk for abemaciclib-induced interstitial lung disease or hepatotoxicity by specific human leukocyte antigen alleles.

3087 Background: Interstitial lung disease (ILD) and hepatotoxicity have been observed in a small population of patients treated with abemaciclib. It has been reported that the antitumor effect of cyclin-dependent kinases 4 and 6 inhibitors including abemaciclib is contributed by not only inducing tumor cell cycle arrest but also promoting antitumor immunity. Based on our experience of higher incidence of severe toxicities in the clinical study of abemaciclib combined with nivolumab, we speculated that abemaciclib-related toxicity might also be mediated by immune system. This study sought to identify specific human leukocyte antigen (HLA) alleles associated with abemaciclib-induced ILD or hepatotoxicity. Methods: Of 236 abemaciclib-treated patients with advanced breast cancer in the previous observational study, 83 patients were enrolled by obtaining additional informed consent for collecting blood and pharmacogenetic investigation. Genomic DNA was extracted from peripheral whole blood, and HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, and -DPB1were genotyped to four-digit resolution by next generation sequencing method. Exploratory marker identification evaluated the HLA alleles with frequency of ≥ 10% in cases. The significance level was adjusted by Bonferroni’s correction for multiple testing. Results: One hundred seventeen alleles ( HLA-A,13 alleles; -B, 26 alleles; -C, 16alleles; -DRB1,24 alleles; -DQA1, 14 alleles; -DQB1, 13 alleles; -DPB1, 11 alleles) were detected. Of 28 alleles with frequency of ≥ 10% in cases with development of ILD [significance level = .00178 (0.05 divided by 28)], there was no significant association between HLA allele carriages and development of ILD in 16 cases and 67 controls. Of 28 alleles with frequency of ≥ 10% in cases with grade ≥ 2 alanine aminotransferase (ALT) elevation [significance level = .00178 (0.05 divided by 28)], HLA-DQA1*05:05 allele carriage was found to be significantly associated with ALT elevation in 13 cases with grade ≥ 2 and 47 controls with grade 0. HLA- DQA1*05:05 was present in 30.8% of cases and in 0.0% of controls ( P=.00147; odds ratio, 45.0; 95% CI, 2.23 to 907). Suggestive associations of ALT elevation were observed with HLA-DPB1*05:01 allele carriage ( P=.00930; odds ratio, 11.5; 95% CI, 1.38 to 95.7) and HLA-A*31:01 allele carriage ( P=.01522; odds ratio, 5.86; 95% CI, 1.46 to 23.4). Conclusions: Evaluated 28 HLA alleles were not associated with development of ILD. HLA-DQA1*05:05 allele was identified as a promising marker candidate that can predict patients with a higher risk of abemaciclib-induced hepatotoxicity. Further study is necessary to confirm the association in an independent population for managing liver safety risk during abemaciclib treatment. This result also implicates an immune-mediated mechanism for abemaciclib-related hepatotoxicity. Clinical trial information: UMIN000046611.

Elucidating the Mechanisms Underlying Interindividual Differences in the Onset of Adverse Drug Reactions.

Idiosyncratic drug toxicities (IDTs) pose a significant challenge; they are marked by life-threatening adverse reactions that emerge aftermarket release and are influenced by intricate genetic and environmental variations. Recent genome-wide association studies have highlighted a strong correlation between specific human leukocyte antigen (HLA) polymorphisms and IDT onset. This review provides an overview of current research on HLA-mediated drug toxicities. In the last six years, HLA-transgenic (Tg) mice have been instrumental in advancing our understanding of these underlying mechanisms, uncovering systemic immune reactions that replicate human drug-induced immune stimulation. Additionally, the potential role of immune tolerance in shaping individual differences in adverse effects highlights its relevance to the interplay between HLA polymorphisms and IDTs. Although HLA-Tg mice offer valuable insights into systemic immune reactions, further exploration is essential to decipher the intricate interactions that lead to organ-specific adverse effects, especially in organs such as the skin or liver. Navigating the intricate interplay of HLA, which may potentially trigger intracellular immune responses, this review emphasizes the need for a holistic approach that integrates findings from both animal models and molecular/cellular investigations. The overarching goal is to enhance our comprehensive understanding of HLA-mediated IDTs and identify factors shaping individual variations in drug reactions. This review aims to facilitate the development of strategies to prevent severe adverse effects, address existing knowledge gaps, and provide guidance for future research initiatives in the field of HLA-mediated IDTs.

Correlation of patient HLA class I genotypes with severe immune-related adverse events: A retrospective study in Chinese population.

10586 Background: Immune checkpoint inhibitors (ICIs) are effective in multiple tumors. However, about 10% of immune-related adverse events (irAEs) are severe and can have serious or even life-threatening consequences for patients. We investigated whether Human leukocyte antigen (HLA) genes predispose to and thus hold a predictive role of developing of severe irAEs in Chinese population. Methods: In a case/control study, we collected data from patients with metastatic cancer treated with ICIs and developed severe irAEs (Grade ≥3 and required hospitalization). Patients treated with ICIs without any irAEs were used as controls. Data was collected from15th Nov, 2019 until 10th Oct, 2023. HLA typing was performed via next generation sequencing. Results: We enrolled 83 patients with severe irAEs and 286 patients treated with ICIs without any irAEs. We found HLA-B*15:27 (OR=9.1, X21,95 = 7.2, P = 0.008) and HLA-C*04:01 (OR=2.5, X21,95 = 7.0, P =0.008) were significantly associated with severe overall irAEs risk. When assessing irAE individually, a significant association between HLA-B*13:02 and serious myocarditis (OR = 3.4, X21,95 = 6.2, P =0.01) as well as striking enrichment for HLA-A*02:03 haplotypes in severe adrenal insufficiency (OR = 10.0, X21,95 = 19.1, P&lt;0.0001) were observed. Conclusions: Specific HLA alleles were associated with severe irAEs. Consideration of pre-prescription HLA typing and vigilance for serious reactions to ICIs are warranted.

The John Charnley Award: The Impact of Human Leukocyte Antigen Genotype on Bacterial Infection Rates and Successful Eradication in Total Hip Arthroplasty

BackgroundGenetics play an important role in several medical domains; however, the influence of human leukocyte antigen (HLA) genotype on the development of periprosthetic joint infection (PJI) in total hip arthroplasty (THA) remains unknown. The primary aim of this study was to determine if HLA genotype is associated with the development of bacterial PJI in THA. Secondarily, we evaluated the association between HLA genotype and PJI treatment success. MethodsA retrospective, matched, case-control study was performed using prospectively collected data from a single institution. A total of 49 patients who underwent primary THA were included, with a mean follow-up of 8.5 years (range, 4.2 to 12.9). The 23 cases (PJI) and 26 controls (no PJI) were matched for age, sex, follow-up, body mass index, primary diagnosis, and comorbidities (P > .05). High-resolution genetic analysis targeting 11 separate HLA loci was performed in all patients using serum samples. The HLA gene frequencies and carriage rates were determined and compared between cohorts. A subgroup analysis of PJI treatment success (18) and failure (5) was performed. Statistical significance was set at P = .10 for genetic analysis and at 0.05 for all other analyses. ResultsThere were 4 HLA alleles that were significantly associated with the development of PJI. The 3 at-risk alleles included HLA-C∗06:02 (odds ratio 5.25, 95% CI [confidence interval] 0.96 to 28.6, P = .064), HLA-DQA1∗04:01 (P = .096), and HLA-DQB1∗04:02 (P = .096). The single protective allele was HLA-C∗03:04 (odds ratio 0.12, 95% CI 0.01 to 1.10, P = .052). There were no specific HLA alleles that were associated with treatment success or failure. ConclusionsThis study suggests that there are at-risk and protective HLA alleles associated with the development of PJI in THA. To our knowledge, this is the first study to demonstrate an association between patient HLA genotype and the development of PJI. A larger study of the subject matter is necessary and warranted.