HLA-DRB1 Research Articles

A machine learning approach for identifying variables associated with risk of developing neutralizing antidrug antibodies to factor VIII

A key unmet need in the management of hemophilia A (HA) is the lack of clinically validated markers that are associated with the development of neutralizing antibodies to Factor VIII (FVIII) (commonly referred to as inhibitors). This study aimed to identify relevant biomarkers for FVIII inhibition using Machine Learning (ML) and Explainable AI (XAI) using the My Life Our Future (MLOF) research repository. The dataset includes biologically relevant variables such as age, race, sex, ethnicity, and the variants in the F8 gene. In addition, we previously carried out Human Leukocyte Antigen Class II (HLA-II) typing on samples obtained from the MLOF repository. Using this information, we derived other patient-specific biologically and genetically important variables. These included identifying the number of foreign FVIII derived peptides, based on the alignment of the endogenous FVIII and infused drug sequences, and the foreign-peptide HLA-II molecule binding affinity calculated using NetMHCIIpan. The data were processed and trained with multiple ML classification models to identify the top performing models. The top performing model was then chosen to apply XAI via SHAP, (SHapley Additive exPlanations) to identify the variables critical for the prediction of FVIII inhibitor development in a hemophilia A patient. Using XAI we provide a robust and ranked identification of variables that could be predictive for developing inhibitors to FVIII drugs in hemophilia A patients. These variables could be validated as biomarkers and used in making clinical decisions and during drug development. The top five variables for predicting inhibitor development based on SHAP values are: (i) the baseline activity of the FVIII protein, (ii) mean affinity of all foreign peptides for HLA DRB 3, 4, & 5 alleles, (iii) mean affinity of all foreign peptides for HLA DRB1 alleles), (iv) the minimum affinity among all foreign peptides for HLA DRB1 alleles, and (v) F8 mutation type.

Human leukocyte antigen immunization in transfusion-dependent Moroccan patients with beta-thalassemia major: prevalence and risk factors

IntroductionBeta-thalassemia major patients need a regular blood transfusion to have an initial normal growth. However, these patients have an increased risk of developing alloantibodies. Our main goal was to study HLA alloimmunization in Moroccan Beta-thalassemia patients by confronting it with transfusion and demographic criteria, exploring the involvement of HLA typing profile in the development of HLA antibodies and in turn determining risk factors for their development. MethodsThe study consisted of 53 Moroccan pediatric patients with Beta-thalassemia major. Screening for HLA alloantibodies was performed using Luminex technology Whereas HLA genotyping was done with sequence-specific primers (PCR-SSP). Results: In this study, 50.9% of patients have been identified as positive for HLA antibodies, with 59.3% having both HLA Class I and Class II antibodies. A significant increase frequency of DRB1*11 allele was revealed in non-immunized patients (34.6% vs. 0%, p = 0.001). Our results also revealed that the majority of our HLA immunized patients were women (72.4% vs. 27.6%, p = 0.001), and transfused with more than 300 units of RBC units (66.7% vs. 33.3%, p = 0.02). There were statistically significant differences when comparing these frequencies. ConclusionsThis paper revealed that the transfusion dependent Beta-thalassemia major patients are exposed to risk of developing HLA antibodies following transfusions with leukoreduced RBC units. The HLA DRB1*11 was a protective factor against HLA alloimmunization in our beta-thalassemia major patients.

Multi-omics profiling reveals potential alterations in rheumatoid arthritis with different disease activity levels

BackgroundRheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease, the pathogenesis of which is not clear. Clinical remission, or decreased disease activity, is the aim of treatment for RA. However, our understanding of disease activity is inadequate, and clinical remission rates for RA are generally poor. In this study, we used multi-omics profiling to study potential alterations in rheumatoid arthritis with different disease activity levels.MethodsFecal and plasma samples from 131 rheumatoid arthritis (RA) patients and 50 healthy subjects were collected for 16S rRNA sequencing, internally transcribed spacer (ITS) sequencing, and liquid chromatography-tandem mass spectrometry (LC–MS/MS). The PBMCS were also collected for RNA sequencing and whole exome sequencing (WES). The disease groups, based on 28 joints and ESR (DAS28), were divided into DAS28L, DAS28M, and DAS28H groups. Three random forest models were constructed and verified with an external validation cohort of 93 subjects.ResultsOur findings revealed significant alterations in plasma metabolites and gut microbiota in RA patients with different disease activities. Moreover, plasma metabolites, especially lipid metabolites, demonstrated a significant correlation with the DAS28 score and also associations with gut bacteria and fungi. KEGG pathway enrichment analysis of plasma metabolites and RNA sequencing data demonstrated alterations in the lipid metabolic pathway in RA progression. Whole exome sequencing (WES) results have shown that non-synonymous single nucleotide variants (nsSNV) of the HLA-DRB1 and HLA-DRB5 gene locus were associated with the disease activity of RA. Furthermore, we developed a disease classifier based on plasma metabolites and gut microbiota that effectively discriminated RA patients with different disease activity in both the discovery cohort and the external validation cohort.ConclusionOverall, our multi-omics analysis confirmed that RA patients with different disease activity were altered in plasma metabolites, gut microbiota composition, transcript levels, and DNA. Our study identified the relationship between gut microbiota and plasma metabolites and RA disease activity, which may provide a novel therapeutic direction for improving the clinical remission rate of RA.

Artificial Intelligence (AI) based approach for identifying biomarkers associated with neutralizing antidrug antibodies to Factor VIII used in Hemophilia A treatment

Abstract Lack of clinically validated markers associated with the development of neutralizing antibodies (inhibitors) to the replacement protein-drug, Factor VIII (FVIII) is a major challenge in managing Hemophilia A (HA). By utilizing Machine Learning (ML) and Explainable AI (XAI) we identified and ranked relevant variables (biomarkers) that could be predictive for developing inhibitors to FVIII drugs in hemophilia A patients. The dataset used for the study was derived from the My Life Our Future (MLOF) repository and included variables such as age, race, ethnicity, mutations in the F8 gene and the Human Leucocyte Antigen Class II (HLA-II) type. We computed the number of foreign FVIII derived peptides, based on the alignment of the endogenous FVIII and infused drug sequences, and the foreign-peptide HLA-II molecule binding affinity (using the NetMHCIIpan algorithm). The complete dataset with the added variables was trained and validated using multiple ML classification models to identify the top performing model, which was chosen for further processing with XAI via SHAP (SHapley Additive exPlanations) to identify the variables critical for the prediction of FVIII inhibitor development in a hemophilia A patients. The top five variables for predicting inhibitor development based on SHAP values are: (i) the baseline activity of the FVIII protein, (ii) mean affinity of all foreign peptides for HLA DRB 3, 4, & 5 alleles, (iii) mean affinity of all foreign peptides for HLA DRB1 alleles, (iv) the maximum affinity among all foreign peptides for HLA DRB1 alleles, and (v) F8 mutation type. This research was supported by funds from the Hemostasis Branch/Division of Plasma Protein 344 Therapeutics/Office of Tissues and Advanced Therapies/Center for Biologics Evaluation and Research 345 of the U.S. Food and Drug Administration and in part by an appointment to the Research Participation 346 Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute 347 for Science and Education through an interagency agreement between the U.S. Department of Energy 348 and the U.S. Food and Drug Administration. The MLOF program was developed as a partnership 349 between NHF, ATHN, Bloodworks Northwest, and Bioverativ and supported financially by 350 Bioverativ, NHF, Bloodworks Northwest, and ATHN.

Impact of donor age and relationship on outcomes of peripheral blood haploidentical hematopoietic cell transplantation

Here we describe a retrospective analysis of outcomes in 299 patients who underwent peripheral blood haplo-HCT with PTCy from July 2009 through May 2021 and their association with donor characteristics. Patients had mostly acute leukemias and high or very high DRI. Multivariate analyses were conducted examining OS, NRM, relapse, cytokine release syndrome, acute and chronic GVHD. Donor characteristics included age, sex, relationship, ABO status, CMV status, and HLA match grade. Our analysis revealed increasing donor age was associated with higher NRM (compared to age <30; age 30–44 HR, 1.65; P = 0.110, age >44 HR, 1.80; P = 0.056) but lower relapse risk (compared to age <30; age 30–44 HR, 0.61; P = 0.034, age > 44 HR, 0.71; P = 0.132). There were no differences in CRS, aGVHD or cGVHD. We found no difference in outcomes based on the donor-recipient relationship. No differences were found based on HLA match grade or DRB1 match status. Increasing donor age was associated with lower relapse risk but higher NRM, resulting in no difference in OS based on donor age. Other donor factors including relationship (parent/sibling/child/ maternal), CMV status, donor sex, HLA match grade, and DRB1 status were not associated with outcomes.

Worldwide epidemiologic factors in pemphigus vulgaris and bullous pemphigoid.

Autoimmune blistering diseases such as bullous pemphigoid (BP) and pemphigus vulgaris (PV) are complex, multifactorial, and polygenic diseases, whose exact pathogenesis is difficult to pinpoint. Research aimed at elucidating the associated epidemiologic risk factors of these two diseases has been hampered by their rare disease status. Further, a lack of centralization and standardization of available data makes the practical application of this information challenging. In order to collate and clarify the available literature we comprehensively reviewed 61 PV articles from 37 different countries and 35 BP articles from 16 different countries addressing a range of disease relevant clinical parameters including age of onset, sex, incidence, prevalence, and HLA allele association. The reported incidence of PV ranged from 0.098 to 5 patients per 100,000 people, while BP ranged from 0.21 to 7.63 patients per 100,000. Prevalence of PV ranged from 0.38 to 30 per 100,000 people and BP ranged from 1.46 to 47.99 per 100,000. The mean age of onset in patients ranged from 36.5 to 71 years for PV and 64 to 82.6 years for BP. Female-to-male ratios ranged from 0.46 to 4.4 in PV and 1.01 to 5.1 in BP. Our analysis provides support for the reported linkage disequilibrium of HLA DRB1*0402 (an allele previously shown to be associated with PV) and DQB1*0302 alleles in Europe, North America, and South America. Our data also highlight that HLA DQB1*0503 (also known to be associated with PV) appears in linkage disequilibrium with DRB1*1404 and DRB1*1401, mainly in Europe, the Middle East, and Asian countries. The HLA DRB1*0804 allele was only associated with PV in patients of Brazilian and Egyptian descent. Only two HLA alleles were reported as associated with BP more than twice in our review, DQB1*0301 and DQA1*0505. Collectively, our findings provide detailed insights into the variation of disease parameters relevant to PV and BP that can be expected to inform future work aimed at unraveling the complex pathogenesis of these conditions across the globe.

Comparison of proteomic landscape of extracellular vesicles in pleural effusions isolated by three strategies.

Extracellular vesicles (EVs) derived from pleural effusion (PE) is emerging as disease biomarkers. However, the methods for isolation of EVs from PE (pEVs) were rarely studied. In our study, three methods for isolating pEVs of lung cancer patients were compared, including ultracentrifugation (UC), a combination of UC and size exclusion chromatography (UC-SEC) and a combination of UC and density gradient ultracentrifugation (UC-DGU). The subpopulation of pEVs was identified by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), Western blotting (WB) and nano-flow cytometry (nFCM). Additionally, the proteomic landscape of pEVs was analyzed by Label-free proteomics. The results showed that, compared with UC and UC-DGU, the UC-SEC method separated pEVs with the highest purity. In the proteomic analysis, on average, 1595 proteins were identified in the pEVs isolated by UC-SEC, much more than pEVs isolated by UC (1222) or UC-DGU (807). Furthermore, approximately 90% of identified proteins in each method were found in the EVs public database ExoCarta. Consistent with this, GO annotation indicated that the core proteins identified in each method were mainly enriched in "extracellular exosome." Many of the top 100 proteins with high expression in each method were suggested as protein markers to validate the presence of EVs in the MISEV2018 guidelines. In addition, combined with lung tissue-specific proteins and vesicular membrane proteins, we screened out and validated several novel protein markers (CD11C, HLA DPA1 and HLA DRB1), which were enriched in pEVs rather than in plasma EVs. In conclusion, our study shows that the method of UC-SEC could significantly improve the purity of EVs and the performance of mass spectrometry-based proteomic profiling in analyzing pEVs. The exosomal proteins CD11C, HLA DPA1 and HLA DRB1 may act as potential markers of pEVs. The proteomic analysis of pEVs provides important information and new ideas for studying diseases complicated with PE.

The association of HLA-DRB1 alleles and MBL2 gene variant in pediatric acute lymphoblastic leukemia patients

IntroductionEpidemiologic studies on pediatric acute lymphoblastic leukemias (ALL) have been conducted to evaluate the possible risk factors including genetic, infectious and environmental factors with the objective of idenfying the etiology. Mannose-binding lectin 2 (MBL2) plays an important role in first-line immune defense. HLA DRB1 alleles play a role in presentation of peptides to T cells and in activation of the adaptive immune response. ObjectiveIn our study, we aimed to investigate both the MBL2 gene variant and HLA-DRB1 alleles in pediatric ALL patients. MaterialsIn this study, 86 high-risk ALL patients and 100 controls were included. Polymerase Chain Reaction (PCR)-Restriction Fragment Length Polymorphism (PCR-RFLP) and PCR-sequence specific primer (SSP) methods were used for detection of polymorphism of the MBL2 and HLA-DRB1 alleles, respectively. ResultsThe frequency of the MBL2 AB genotype was lower in female ALL patients, compared to male ALL patients (p = 0.034). An association was found between the MBL2 BB genotype and DRB1*07 and among patients with the MBL2 BB genotype; those who also carried the DRB1*07 and *04 alleles were significantly higher than those without the DRB1*07 and *04 alleles. (p = 0.048, p = 0.022, respectively). ConclusionThis is the first study suggesting that the MBL2 BB genotype in association with the DRB1*07 or co-inheritance of the HLA-DRB1*04 and HLA DRB1*07 may have an impact on the etiopathogenesis of the disease.

HLA-DRB1 polymorphism and risk of pediatric-onset and adult-onset multiple sclerosis: a case–control study

The association of predisposition to multiple sclerosis (MS) with HLA-DRB1 gene polymorphisms is the strongest. It is not clear whether the DRB1 alleles associated with the risk of this disease diff er in adult and pediatric populations living in the same environmental conditions.Objective: comparative study of associations of HLA-DRB1 gene polymorphism with the risk of pediatric-onset MS and adult-onset MS in the Altai region.Material and methods. Caucasian with relapsing-remitting MS, born and living in the Altai region of Russia in the southeast of Western Siberia, participated in the case–control study: 200 patients with adult-onset MS, 86 patients with pediatric-onset MS. The control group included 200 volunteers. Genotyping was performed by TaqMan probes. Results. Alleles 03, 13, 15 of the HLA-DRB1 gene are genetic risk factors for both adult-onset MS and pediatric-onset MS in Caucasians in the Altai region. Alleles 01 and 07 of the HLA-DRB1 gene may have a protective eff ect against pediatric-onset MS, alleles 01, 07, 11 and 16 against adult-onset MS.Conclusion. It can be assumed that the diff erence in the age of MS onset is not associated with the diff erent infl uence of risk alleles of the HLA-DRB1 gene in populations under and over 18 years of age.

Geo-epidemiology of autoantibodies in rheumatoid arthritis: comparison between four ethnically diverse populations

BackgroundRheumatoid arthritis (RA) occurs across the globe in different ethnic populations. Most RA patients harbor anti-modified protein antibodies (AMPA); however, it is unclear whether differences exist in autoantibody responses at different geographic locations and between different ethnic groups, which could provide new clues regarding factors underlying autoantibody development. We therefore investigated AMPA prevalence and association with HLA DRB1 alleles and smoking in four ethnically diverse populations on four different continents.MethodsAnti-carbamylated (anti-CarP), anti-malondialdehyde acetaldehyde (anti-MAA), and anti-acetylated protein antibodies (anti-AcVim) IgG were determined in anti-citrullinated protein antibody-positive Dutch (NL, n = 103), Japanese (JP, n = 174), First Nations Peoples in Canada (FN, n = 100), and black South African (SA, n = 67) RA patients. Ethnicity-matched local healthy controls were used to calculate cut-offs. Risk factors associated with AMPA seropositivity in each cohort were identified using logistic regression.ResultsMedian AMPA levels were higher in First Nations Peoples in Canada and especially South African patients, as reflected by percentage seropositivity: NL, JP, FN, and SA: anti-CarP: 47%, 43%, 58%, and 76% (p < 0.001); anti-MAA: 29%, 22%, 29%, and 53% (p < 0.001); and anti-AcVim: 20%, 17%, 38%, and 28% (p < 0.001). Total IgG levels also differed markedly, and when autoantibody levels were normalized to total IgG, differences between cohorts became less pronounced. Although there were some associations with AMPA and HLA risk alleles and smoking, none was consistent across all four cohorts.ConclusionsAMPA against various post-translational modifications could consistently be detected on different continents across ethnically diverse RA populations. Differences in AMPA levels corresponded to differences in total serum IgG levels. This suggests that, despite differences in risk factors, a common pathway may be involved in AMPA development across geographic locations and ethnicities.

SOD2 in platelets: with age comes responsibility

SOD2 in platelets: with age comes responsibility

The relevance of HLA class II genes in JAK2 V617F-positive myeloproliferative neoplasms

In the present study we analyzed the relevance of HLA class II in JAK2 V617F-positive (JAK2 V617F+) myeloproliferative neoplasms (MPNs) focusing on genotype diversity, associations with specific alleles and haplotypes and the level of gene expression. One hundred and thirty-nine JAK2 V617F+ MPN patients and 1083 healthy controls, typed by Next generation sequencing (NGS) were included in the study. Multivariate generalized linear models with age as a covariate were applied for analysis of HLA-II allele and haplotype associations. Publicly available gene expression datasets were used to analyze HLA-II pathway genes expression in CD34+ stem cells (SCs) from MPN patients and healthy controls. We did not observe differences in HLA evolutionary divergence (HED) between JAK2 V617F+ MPNs and healthy controls. Two alleles: HLA-DPB1*03:01, DQB1*04:02 and 4 haplotypes: DPB1*02:01-DQA1*05:05-DQB1*03:01-DRB1*11:01, DPB1*04:02-DQA1*05:05-DQB1*03:01-DRB1*11:03, DPB1*02:01-DQA1*01:04-DQB1*05:03-DRB1*14:04, and DPB1*04:01-DQA1*03:01-DQB1*03:02-DRB1*04:01 had significantly lower frequency in MPN patients compared to controls. Additionally, we observed HLA-II alleles and haplotypes with statistically higher frequencies in JAK2 V617F+ patients. Differential gene expression analysis showed down-regulation of HLA-DRB1, -DRA, -DMA, -DMB, -DOA,-DRB4, CIITA, and CD74 genes in JAK2 V617F+ MPN CD34+ SCs as compared to normal CD34 + SCs. In conclusion, this study provides evidence for the pleiotropic effects of HLA-II genes in JAK2 V617F-driven MPNs.

Patient genetics shape the autoimmune response in the blistering skin disease pemphigus vulgaris.

Pemphigus vulgaris (PV) is known to have one of the strongest HLA associations among autoimmune diseases. DRB1*0402 and DQB1*0503 in particular are significantly overrepresented in PV patients in certain worldwide populations. Yet, there remain significant gaps in our understanding regarding the precise link between PV-associated HLA molecules, the specificity of the autoimmune response, and clinical expression. In this study we assessed correlations between factors including HLA genotype, ethnicity, autoantibody levels, and lesion distribution in a cohort of 293 patients. Participants were recruited from multiple outpatient dermatology clinic settings and patient support meetings in the USA. On intake, patients provided venous blood samples and answered questionnaires regarding their current disease activity. Eighty-one percent of patients typed as either DRB1*0402 or DQB1*0503 with a high prevalence of DRB1*0402 in patients of Ashkenazi Jewish or Caucasian (non-Jewish) descent (86% and 42%, respectively) and DQB1*0503 in patients of Southeast Asian descent (78%). Patients typing as HLA DRB1*0402 had higher levels of anti-desmoglein (Dsg)3 antibodies (204.6 +/- 340.5 IU/ml) than patients without DRB1*0402 (138.5 +/- 236.4 IU/ml) (p=0.03) and had mucosal only lesions more often than cutaneous only or mucocutaneous lesions. Patients typing as DQB1*0503 had higher levels of anti-Dsg1 antibodies (47.3 +/- 59.8 IU/ml) compared to other groups (27.8 +/- 43.7 IU/ml) (p=0.06) and higher rates of mucocutaneous disease than other lesion types. We also report an unexpected HLA association of DRB1*0804 in PV patients of African descent. Sixty-four percent of this population carried the DRB1*0804 allele, and presented with highly elevated levels of anti-Dsg3 (p=0.02). However, neither African heritage nor the presence of DRB1*0804 correlated with a predilection to any specific lesion morphology. Patients that carried neither DRB1*0402, nor DQB1*0503 or DRB1*0804 had the lowest levels of anti-Dsg3 antibodies (60.0 +/- 80.0 IU/ml) and the highest rate of solely cutaneous disease compared to carriers of thesealleles. Our data illuminate the broader impact of genetic factors on disease development by showing that differences in HLA expression among patients and ethnicities play a large role in driving distinct patterns of antibody selection and disease phenotype in PV. These findings provide insights regarding clinical heterogeneity, and are relevant to developing improved, patient tailored management strategies.

Juvenile Idiopathic Arthritis and Its HLA Association: A Study from Bangladesh

Background: HLA alleles may have association with overall JIA including specific sub-types. Determation of HLA DRB1, DPB1, DQA1, DQB1 and B27, may be helpful to diagnose JIA cases where diagnostic dilemma is present. The aim of the study was to find out the association of HLA alleles with JIA and its subtypes. Methods: This cross sectional study was conducted in the department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, from April 2020 to March 2021. A total of 50 cases and 25 controls attending pediatric rheumatology clinic and pediatric OPD were enrolled in the study. Data were collected by a pre-designed questionnaire containing socio-demographic, clinical and laboratory parameters. HLA DR-B1, DQ-A1, DQ-B1 and B27 typing were done for the cases and controls from blood samples by polymerase chain reaction sequence specific primer (PCR-SSP) method. Data were analyzed by SPSS version 26. Frequency, percentage, chi square test and Fisher exact tests were done for statistical analysis. Results: HLA DR-B1_10 had significant positive association whereas HLA DR-B1_03 and B1_16 had negative association with overall JIA cases. Poly-articular JIA, oligo-articular JIA and ERA had association with HLA DRB1_01, B1_08 and B1_12 respectively. HLA DQA1-01 and A1_02 had positive association. However, DQ-A1_06 was negatively associated with JIA cases. Oligo JIA was positively associated with HLA DQ-A1_01, whereas poly JIA and ERA had association with A1_02. Though, HLA DQ_B1 had no association with overall JIA cases, analysis showed association of poly JIA with DQ-B1_04. Frequency of HLA DQ-B1_02 and 03 were higher among ERA cases, though not significant, but they had strong association with HLA B27. Conclusion: HLA associations were present with overall JIA and each sub-groups had different patterns of HLA associations including some protective roles.

In Silico Analysis: HLA-DRB1 Gene’s Variants and Their Clinical Impact

The HLA-DRB1 gene encodes a protein that is essential for the immune system. This gene is important in organ transplant rejection and acceptance, as well as multiple sclerosis, systemic lupus erythematosus, Addison’s disease, rheumatoid arthritis, caries susceptibility, and Aspirin-exacerbated respiratory disease. The following Homo sapiens variants were investigated: single-nucleotide variants (SNVs), multi-nucleotide variants (MNVs), and small insertions–deletions (Indels) in the HLA-DRB1 gene via coding and untranslated regions. The current study sought to identify functional variants that could affect gene expression and protein product function/structure. ALL target variants available until April 14, 2022, were obtained from the Single Nucleotide Polymorphism database (dbSNP). Out of all the variants in the coding region, 91 nsSNVs were considered highly deleterious by seven prediction tools and instability index; 25 of them are evolutionary conserved and located in domain regions. Furthermore, 31 indels were predicted as harmful, potentially affecting a few amino acids or even the entire protein. Last, within the coding sequence (CDS), 23 stop-gain variants (SNVs/indels) were predicted as high impact. High impact refers to the assumption that the variant will have a significant (disruptive) effect on the protein, likely leading to protein truncation or loss of function. For untranslated regions, functional 55 single-nucleotide polymorphisms (SNPs), and 16 indels located within microRNA binding sites, furthermore, 10 functionally verified SNPs were predicted at transcription factor-binding sites. The findings demonstrate that employing in silico methods in biomedical research is extremely successful and has a major influence on the capacity to identify the source of genetic variation in diverse disorders. In conclusion, these previously functional identified variants could lead to gene alteration, which may directly or indirectly contribute to the occurrence of many diseases. The study’s results could be an important guide in the research of potential diagnostic and therapeutic interventions that require experimental mutational validation and large-scale clinical trials.

Shared epitope classification methods according to Gregersen and de Vries allow adequate characterization of patients with rheumatoid arthritis in a Colombian population

IntroductionThe most important genetic association in rheumatoid arthritis (RA) is presented with some alleles from the HLA-DRB1 gene that encode the shared epitope (SE). ObjectivesTo apply the SE classification methods of Gregersen, de Vries, Raychaudhuri, Mattey, and Tezenas du Montcel in a group of Colombian patients with RA and determine the most common HLA-DRB1 alleles in the population. MethodsRA diagnosis, genetic study of the HLA-DRB1 region using Luminex technology in 50 RA and 50 healthy subjects. For the classification analysis, Fisher's exact test and chi-squared test were applied. Tables were created to count the RA-related alleles. We used odds ratio to determine the risk between the presence of the shared epitope (SE) and anti-cyclic citrullinated peptides (Anti-CCP). ResultsGregersen and de Vries methods were suitable for the characterization of RA in this population (p = .006). The most prevalent HLA-DRB1 alleles in the RA group were 14:02, 04:04, 08:02, 04:05, and 10:01. High frequencies of the 07:01, 03:01, 13:02, 01:02, and 12:01 HLA-DRB1 alleles were found in the healthy population. HLA-DRB1 alleles with similar distribution in both populations were 04:07, 15:01, 11:01, 16:02, and 01:01. A high frequency of SE + was observed in Anti-CCP + individuals (63.15%); however, this was not statistically significant [OR 2.4 (.63–9.01); p = .19]. ConclusionThe SE classification methods of Gregersen and de Vries were adequate in characterizing RA in a Colombian population group. An equivalence of 100% was verified between the susceptibility alleles defined by de Vries and the alleles assigned as SE according to Gregersen.

Association of HLA DRB1 Alleles with Asthma in Pakistani Population of Punjab Region

Association of HLA DRB1 Alleles with Asthma in Pakistani Population of Punjab Region

Typing of HLA-A, -B and DRB1 antigens in clinical practice in patients of the Rostov population for early diagnosis of rheumatoid arthritis

Objective: a retrospective analysis of the results obtained by typing HLA-A, -B antigens and HLA DRB1 allele groups in patients with rheumatoid arthritis (RA) in the Rostov population.Materials and methods: typing of patients with rheumatic inflammatory diseases who were on inpatient treatment in the rheumatology department of the SBI “OKB No. 2” was carried out in the LITT SBI RO "BTS" in 2019-2020. 41 patients (9 men, 32 women, median age — 42 years) were diagnosed with RA. All patients were typed by HLA-DRB1 alleles by real-time polymerase chain reaction with DNA-TECH reagents (Russia). To isolate DNA, a set of Sample-Rapid-Genetics was used by NPO DNA Technology LLC. 39 patients were typed аccording to HLA-A, -B. Typing was carried out by a standard lymphocytotoxic test with DILEN reagents (Czech Republic). Lymphocytes were isolated in a density gradient of “Lympholot”, DILEN company. The control group consisted of healthy residents of the Rostov population (donors of the hematopoietic stem cell registry).Results: a retrospective analysis showed that HLA DRB1*04 occurs in 46.3% of the Rostov population with RA, in 61.1% of the seropositive RA group (control — 20%). There was a decrease in the frequency of HLA DRB1*13 (9.7%) compared to the control (24.4%).Conclusions: the high level of reliability (p&lt;0.001) of the increase in the frequency of HLA DRB1*04 alleles confirms their associative relationship with RA in the Rostov population. A decrease in the frequency of HLA DRB1*13 indicates the protective function of these alleles in RA. Typing results are important for early diagnosis of RA.

Olfatory HLA-associated mechanism of formation of married couples in the development of congenital heart diseases in children

Taking into account the significance of the HLA complex in the inflammatory and immune responses, we can assume that the potential for limiting or developing pathology in the next generation will be determined at the stage of selection of certain alleles in the spousal genotype.The aim. To study the role of HLA assortativity in couples with healthy children and couples with children with congenital heart diseases (CHD) through the prism of immunogenetic mechanisms of mutual olfactory choice.Materials and methods. We studied the distribution of HLA-DRB1 alleles in married couples with healthy children and with children having CHD. To identify the associations of HLA-DRB1 alleles with odor preferences, we also studied the group included young males and females. HLA-DRB1 gene typing was carried out in all participants.Results. The combination of HLA-DRB1 alleles in couples with healthy children was similar to the combination of these alleles in the mutual olfactory sympathy between unfamiliar young males and females. Allele combinations in the spouses from the experimental group differ from the group of random selection. The frequency of matches for HLA-DRB1 alleles in married couples with children having CHD without was significantly higher than in the control group.Conclusion. The first stage of selection, associated with olfactory selection, is aimed to the whole population, and it is significantly manifested in the control group (married couples with healthy children). At the same time, in the experimental group (couples with children having CHD), some deviations from the main selection were discovered. Generally, specific HLA-DRB1 allele combinations obtained on the basis of olfactory assessments, indicate the involvement of HLA molecules in pheromone reception.

Prediction of response to anti-TNF treatment using laboratory biomarkers in patients with rheumatoid arthritis: a systematic review

ObjectivesIn this systematic review, we aim to identify laboratory biomarkers that predict response to tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA).MethodsEMBASE, PubMed and Cochrane Library (CENTRAL)...