Search Results (19)

Statin exposure has been associated with a broad spectrum of muscle toxicity, ranging from asymptomatic creatine kinase (CK) elevation to immune-mediated necrotizing myopathy (IMNM) with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. The mechanisms underlying these adverse effects are not fully understood, and genetic predisposition may play a role. This observational study evaluated the association of HLA-DRB1*11 and SLCO1B1 rs4149056 variants with statin-induced muscle toxicity. A total of 62 statin-exposed patients treated at a single tertiary center were included and classified as follows: IMNM with anti-HMGCR antibodies (n = 11), non-immune myotoxicity (n = 20), and statin-exposed controls without myopathy (n = 31). The mean age was 66 ± 7.5 years, and 62% were women. The frequency of the HLA-DRB1*11 allele was significantly higher in patients with anti-HMGCR IMNM compared to those with non-immune myotoxicity (81.0% vs. 25.0%; OR = 13.5, 95% CI 1.73–15.3; p < 0.01) and controls (81.0% vs. 17.2%; OR = 21.6, 95% CI 2.87–23.7; p < 0.01). No significant difference was found between the non-immune myotoxicity and control groups. Likewise, the SLCO1B1 rs4149056 variant showed no association with either IMNM or non-immune muscle toxicity. These findings confirm a strong association between the HLA-DRB1*11 allele and anti-HMGCR IMNM. This genetic marker may help to better distinguish immune-mediated from non-immune forms of statin-related myopathy. Full article

Background: Pancreas and pancreas–kidney transplantation are well-established therapeutic options for patients with type 1 diabetes mellitus (T1DM) and end-stage kidney disease (ESKD), offering the potential to restore endogenous insulin production and kidney function. It improves metabolic control, quality of life, and long-term survival. While surgical techniques and immunosuppressive strategies have advanced considerably, graft rejection and limited long-term graft survival remain significant clinical challenges. Method: To better understand these risks, the genetic and immunological factors that influence transplant outcomes are examined. Beyond traditional human leukocyte antigen (HLA) matching, non-HLA genetic variants such as gene deletions and single-nucleotide polymorphisms (SNPs) have emerged as contributors to alloimmune activation and graft failure. Result: Polymorphisms in cytokine genes, minor histocompatibility antigens, and immune-regulatory pathways have been implicated in transplant outcomes. However, the integration of such genomic data into clinical practice remains limited due to underexplored gene targets, variability in study results, and the lack of large, diverse, and well-characterized patient cohorts. Initiatives like the International Genetics & Translational Research in Transplantation Network (iGeneTRAiN) are addressing these limitations by aggregating genome-wide data from thousands of transplant donors and recipients across multiple centers. These large-scale collaborative efforts aim to identify clinically actionable genetic markers and support the development of personalized immunosuppressive strategies. Conclusions: Overall, genetic testing and genomics hold great promise in advancing precision medicine in pancreas and pancreas–kidney transplantation. Full article

Background and Objectives: Spondylarthritis is a complex group of inflammatory diseases closely associated with the HLA-B27 antigen. However, the role of non-HLA-B27 alleles in the disease’s pathogenesis has gained significant scholarly attention in recent years. Case presentation: This case study presents a 49-year-old male with a history of progressive inflammatory back pain, characterized by morning stiffness and restricted spinal mobility developed over several years. Initially presenting with non-specific symptoms, the patient eventually experienced persistent axial pain and deteriorating functional limitations, which required further evaluation. Radiographic imaging supported the diagnosis of ankylosing spondylitis (AS) by identifying bilateral sacroiliitis. HLA genotyping revealed a negative result for HLA-B27 but positive results for HLA-B13 and HLA-B37. This finding serves as a foundation for exploring alternative genetic factors contributing to spondylarthritis (SpA). HLA-B13 and HLA-B37 exhibit structural and functional similarities to HLA-B27, particularly in their peptide-binding grooves. This resemblance may lead to overlapping peptide repertoires and increased T cell cross-reactivity. Moreover, these alleles belong to overlapping cross-reactive groups (CREGs) and share the Bw4 epitope. This suggests that they may contribute to disease pathogenesis via similar mechanisms, such as molecular mimicry and the dysregulation of natural killer (NK) cell interactions, as observed in HLA-B27. Conclusions: This case emphasizes the necessity of expanding diagnostic criteria to incorporate non-HLA-B27 markers, particularly for patients who are HLA-B27-negative. Enhancing our understanding of the roles of alternative genetic markers can improve diagnostic accuracy, enable personalized treatment approaches, and enhance outcomes for the diverse SpA patient population. Full article

Background: Behçet’s Disease (BD) is a complex vasculitis affecting multiple organ systems, with Neuro-Behçet’s Disease (NBD) representing a rare yet severe manifestation. Data on NBD are limited, particularly in Middle Eastern populations. Methods: This retrospective observational study, spanning from 2000 to 2021, involved 262 BD patients at a tertiary medical center in Lebanon. NBD was diagnosed based on International Consensus Recommendation diagnostic criteria. Clinical data, including demographics, manifestations, inflammatory blood markers, genetics, and treatments, were collected. The modified Rankin Scale (mRS) was used to assess disease severity. Results: Among the cohort, 27 (10.3%) had NBD, with headaches, weakness, and dizziness as the most common presenting symptoms. The prevalence of NBD was similar across genders, which differs from some regional studies. HLA-B51 positivity was found in 50 out of 60 (83.3%) tested BD patients. Parenchymal NBD cases exhibited greater disease severity than non-parenchymal cases, with female patients experiencing a more severe course compared to males. Elevated inflammatory markers (CRP and ESR) were more common in patients with severe NBD. Corticosteroids and colchicine were the most commonly used therapies overall, while patients with better disease severity were more frequently prescribed methotrexate, mycophenolate, cyclophosphamide, adalimumab, and rituximab. An analysis of disease progression showed that at presentation, 57.1% (n = 12) of NBD patients had mild to moderate disability, which increased to 76.2% (n = 16) at the last follow-up, including 10 patients who showed an improvement in their mRS score. Conclusions: This study provides valuable insights into the prevalence and clinical characteristics of NBD in a Middle Eastern population. These findings enhance our understanding of NBD in the Middle East, highlighting the need for further research to improve diagnosis and management. Full article

Background: Acute myeloid leukemia (AML) complicated by disseminated intravascular coagulation (DIC) poses major diagnostic and therapeutic challenges. While DIC is well documented in acute promyelocytic leukemia, its manifestations in non-APL AML remain underexplored, necessitating precise diagnostic strategies for effective management. Methods: AML patients with overt DIC were analyzed, including morphological, immunophenotypic, cytogenetic, and genetic evaluations. DIC was diagnosed using the ISTH scoring system, and AML subtypes were classified following WHO criteria. Results: Three diagnostic patterns were identified. (1) Acute promyelocytic leukemia: Leukemia characterized by PML::RARa rearrangements, FLT3 co-mutations, and frequent Auer rods and faggot bundles. Immunocytological analysis showed CD34 and HLA-DR negativity. (2) AML with FLT3 and/or NPM1 mutations: A high prevalence of cup-like blasts was found in 70% of cases. FLT3 mutations, often co-occurring with NPM1, dominated, while karyotypes were typically normal. Immunophenotyping revealed strong myeloid marker expression (MPO+, CD13+, and CD33+), with occasional CD34 negativity. (3) AML with monocytic differentiation: Leukemia defined by monoblastic/promonocytic morphology, DNMT3A mutations, and complex karyotypes or 11q23 rearrangements. Immunophenotyping demonstrated a dominance of monocytic markers (CD4+, CD14+, CD15+, and CD64+). Two patients presented unique profiles with no alignment to these patterns. Conclusions: This study highlights distinct hematopathological patterns of AML with overt DIC, providing a framework for early and precise diagnosis. Recognizing these patterns is critical for tailoring diagnostic and therapeutic approaches to improve outcomes in this high-risk population. Full article

Introduction: Articular cartilage damage presents a significant clinical challenge, with limited options for effective regeneration. Mesenchymal stromal cells (MSCs) derived from Wharton’s jelly (WJ) are a promising cell source for cartilage repair due to their regenerative and immunomodulatory properties. While undifferentiated MSCs have demonstrated potent immunoregulatory effects, the immunomodulatory potential of chondrocytes derived from WJ-MSCs remains underexplored, particularly under inflammatory conditions. This study investigates the differential cytokine expression profiles of WJ-MSC-derived chondrocytes and undifferentiated MSCs under inflammatory stimulation with phytohemagglutinin (PHA) to understand their immunomodulatory capacities. Materials and Methods: WJ-MSCs were differentiated into chondrocytes using a micromass culture system. Differentiated chondrocytes were then co-cultured with immune cells under PHA-induced inflammatory conditions. Control groups included co-cultured cells without PHA activation and chondrocytes activated with PHA in the absence of immune cell interaction. Cytokine expression profiles were analyzed using the RT² Customized Gene Array to evaluate pro- and anti-inflammatory markers. Morphological changes were assessed microscopically. The immunomodulatory responses of chondrocytes were compared to those of undifferentiated MSCs under the same experimental conditions. Results: Chondrocytes co-cultured with immune cells under PHA activation exhibited downregulation of IDO, HLA-G, PDGF, IL-10, TNF-α, IL-6, and IFN-γ compared to undifferentiated MSCs in similar conditions. In non-PHA co-cultured conditions, chondrocytes showed increased expression of IL-6, IFN-γ, IL-4, VEGF, iNOS, PDGF, PTGS-2 and TGF-β, while TNF-α, IL-10, IDO and HLA-G were decreased. In contrast, chondrocytes activated with PHA without immune cell interaction displayed reduced expression of HLA-G and TNF-α, with no significant changes in IL-6, IFN-γ, IL-4, IL-10, VEGF, PDGF, PTGS-2, TGF-β, IDO, and iNOS compared to PHA-stimulated undifferentiated MSCs. Conclusion: This study demonstrates that chondrocytes derived from WJ-MSCs exhibit limited immunomodulatory potential compared to undifferentiated MSCs, particularly under PHA-induced inflammatory conditions. Undifferentiated MSCs showed superior regulation of key cytokines associated with immune modulation. These findings suggest that maintaining MSCs in an undifferentiated state may be advantageous for therapeutic applications targeting inflammatory conditions, such as osteoarthritis. Future research should explore strategies to enhance the immunomodulatory efficacy of chondrocytes, potentially through genetic modification or adjunctive therapies. Full article

Background/Objectives: The highly polymorphic Major Histocompatibility Complex (MHC) genomic region, located on the short arm of chromosome 6, is implicated genetically in Parkinson’s disease (PD), a progressive neurodegenerative disorder with motor and non-motor symptoms. Previously, we reported significant associations between SINE-VNTR-Alu (SVA) expression quantitative trait loci (eQTLs) and Human Leucocyte Antigen (HLA) class I genotypes in PD. In this study, we aimed to evaluate SVA associations and their regulatory effects on transposable element (TE) transcription in the MHC class I region. Methods: Transcriptome data from the peripheral blood cells of 1530 individuals in the Parkinson’s Progression Markers Initiative (PPMI) cohort were reanalyzed for TE and gene expression using publicly available bioinformatics tools, including Salmon and Matrix-eQTL. Results: Four structurally polymorphic SVAs regulated the transcription of 18 distinct clusters of 235 TE loci, comprising LINEs (33%), SINEs (19%), LTRs (35%), and ancient transposon DNA elements (12%) located near HLA genes. The transcribed TEs were predominantly short, with an average length of 445 nucleotides. The regulatory effects of these SVAs varied significantly in terms of TE types, numbers, and transcriptional activation or repression. The SVA-regulated TE RNAs in blood cells appear to function as enhancer-like elements, differentially influencing the expression of HLA class I genes, non-HLA genes, and noncoding RNAs. Conclusions: These findings highlight the roles of SVAs and their associated TEs in the complex regulatory networks governing coding and noncoding gene expression in the MHC class I region, with potential implications for immune function and disease susceptibility. Full article

Background: AML with NPM1 mutation is the largest subcategory of AML, representing about 35% of AML cases. It is characterized by CD34 negativity, which suggests a relatively differentiated state of the bulk of leukemic blasts. Notably, a significant subset of NPM1-mutated AML cases also exhibit HLA-DR negativity, classifying them as “double-negative”, and mimicking, therefore, the CD34⁻ HLA-DR⁻ immunophenotype of acute promyelocytic leukemia (APL). Objectives: This study focuses on the “acute promyelocytic leukemia-like” (“APL-like”) subset of NPM1-mutated AML, which can be challenging to distinguish from APL at presentation, prior to confirming RARa translocations. We aim to investigate the hematologic and immunophenotypic parameters that may aid to its distinction from APL. Additionally, we explore differences in genetic profile and prognosis between “APL-like” and “non-APL-like” NPM1-mutated AML cases. Methods: We conducted a retrospective evaluation of 77 NPM1-mutated AML cases and 28 APL cases. Results: Morphological characteristics, hematologic parameters (such as DD/WBC and PT/WBC), and specific immunophenotypic markers (including SSC, CD64, and CD4) can assist in the early distinction of “APL-like” NPM1-mutated AML from APL. Regarding differences in genetic profiles and outcomes between “APL-like” and non-“APL-like” NPM1-mutated AML cases, we observed a significantly higher incidence of IDH1/2 /TET2 mutations, along with a significantly lower incidence of DNMT3A mutations in the “APL-like” subset compared to the non-“APL-like” subset. The frequency of Ras-pathway and FLT3 mutations did not differ between these last two groups, nor did their prognoses. Conclusions: Our findings contribute to a comprehensive characterization of NPM1-mutated AML, enhancing diagnostic accuracy and aiding in the detailed classification of the disease. This information may potentially guide targeted therapies or differentiation-based treatment strategies. Full article

Autoimmune blistering diseases of the pemphigus and pemphigoid groups are immune-mediated disorders due to circulating pathogenetic autoantibodies. Multiple human leukocyte antigen (HLA) genes have been associated with predisposition to these disorders. HLA-Cw6 is involved in antigen presentation processes and has been linked to psoriasis. The aim of our study was to investigate the association between the presence of the HLA-Cw6 allele and susceptibility to pemphigus vulgaris and bullous pemphigoid. A genetic study in vitro with a cross-sectional design was performed enrolling forty patients with pemphigus vulgaris and forty patients with bullous pemphigoid. The detection of HLA-Cw6 was performed through the EUROArray test on DNA obtained from whole blood samples. The polymorphism was detected in 3/40 genotypes in the pemphigus vulgaris group and in 4/40 genotypes of patients with bullous pemphigoid, unveiling a non-statistically significant different frequency in pemphigus (p = 0.6368) and in pemphigoid (p = 0.62) compared to the reference frequency from the literature of 0.086. Further research is needed to better investigate the role of HLA-Cw6 in immune-mediated diseases and to identify novel genetic markers associated with susceptibility to autoimmune blistering diseases and with disease severity and response to immunosuppressive therapies. Full article

The rise in food intolerances and celiac disease, along with advanced diagnostic techniques, has prompted health professionals to seek effective and economical testing methods. This study evaluates combining genetic tests with routine carbohydrate-absorption breath tests to classify patients with chronic gastrointestinal disorders into therapeutic groups, enhancing dietary management and improving gut health and quality of life. Forty-nine patients with suspected carbohydrate intolerance underwent genetic testing for lactase non-persistence, hereditary fructose intolerance, and celiac disease risk. Simultaneously, breath tests assessed lactose and fructose absorption. The lactase non-persistence genotype appeared in 36.7% of cases, with one hereditary fructose-intolerance case in a heterozygous condition. Celiac disease risk markers (HLA-DQ2/8 haplotypes) were found in 49.0% of the population. Secondary lactose and/or fructose malabsorption was present in 67.3% of patients, with 66.1% of lactase non-persistence individuals showing secondary lactose malabsorption. Fructose malabsorption was prevalent in 45.8% of patients at risk for celiac disease. Two main treatment groups were defined based on genetic results, indicating primary and irreversible gastrointestinal disorder causes, followed by a sub-classification using breath test results. Genetic testing is a valuable tool for designing dietary management plans, avoiding unnecessary diet restrictions, and reducing recovery times. Full article

Background: Rheumatoid arthritis (RA) is a complex autoimmune disease that negatively affects synovial joints, leading to the deterioration of movement and mobility of patients. This chronic disease is considered to have a strong genetic inheritance, with genome-wide association studies (GWAS) highlighting many genetic loci associated with the disease. Moreover, numerous confounding and non-genetic factors also contribute to the risk of the disease. Aims: This study investigates the association of selected genetic polymorphisms with rheumatoid arthritis risk and develops a polygenic risk score (PRS) based on selected genes. Methods: A case-control study recruited fully consenting participants from the East Midlands region of the UK. DNA samples were genotyped for a range of polymorphisms and genetic associations were calculated under several inheritance models. PRS was calculated at crude (unweighted) and weighted levels, and its associations with clinical parameters were determined. Results: There were significant associations with the risk of RA at six genetic markers and their associated risk alleles (TNRF2*G, TRAF1*A, PTPN22*T, HLA-DRB1*G, TNFα*A, and IL4-590*T). The TTG haplotype at the VDR locus increased the risk of RA with an OR of 3.05 (CI 1.33–6.98, p = 0.009). The GA haplotype of HLADRB1-TNFα-308 was a significant contributor to the risk of RA in this population (OR = 2.77, CI 1.23–6.28, p = 0.01), although linkage disequilibrium was low. The polygenic risk score was significantly higher in cases over controls in both unweighted (mean difference = 1.48, t₂₈₅ = 5.387, p < 0.001) and weighted (mean difference = 2.75, t₂₈₅ = 6.437, p < 0.001) results. Conclusion: Several genetic loci contribute to the increased risk of RA in the British White sample. The PRS is significantly higher in those with RA and can be used for clinical applications and personalised prevention of disease. Full article

Background: The advent of the hepatitis B vaccine has achieved tremendous success in eradicating and reducing the burden of hepatitis B infection, which is the main culprit for hepatocellular carcinoma—one of the most fatal malignancies globally. Response to the vaccine is achieved in about 90–95% of healthy individuals and up to only 50% in immunocompromised patients. This review aimed to provide an overview of hepatitis B vaccine non-response, the mechanisms involved, B cell amnesia, and strategies to overcome it. Methods: Databases, including Google Scholar, PubMed, Scopus, Cochrane, and ClinicalTrials.org, were used to search and retrieve articles using keywords on hepatitis B vaccine non-response and B cell amnesia. The PRISMA guideline was followed in identifying studies, screening, selection, and reporting of findings. Results: A total of 133 studies on hepatitis B vaccine non-response, mechanisms, and prevention/management strategies were included in the review after screening and final selection. Factors responsible for hepatitis B vaccine non-response were found to include genetic, immunological factors, and B cell amnesia in healthy individuals. The genetic factors were sex, HLA haplotypes, and genetic polymorphisms in immune response markers (cytokines). Non-response was common in conditions of immunodeficiency, such as renal failure, haemodialysis, celiac disease, inflammatory bowel disease, hepatitis C co-infection, and latent hepatitis B infection. Others included diabetes mellitus and HIV infection. The mechanisms involved were impaired immune response by suppression of response (T helper cells) or induced suppression of response (through regulatory B and T cells). Discussion: A comprehensive and careful understanding of the patient factors and the nature of the vaccine contributes to developing effective preventive measures. These include revaccination or booster dose, vaccine administration through the intradermal route, and the use of adjuvants in the vaccine. Full article

In recent years, research has intensified in exploring the genetic basis of psoriasis (PsO) and psoriatic arthritis (PsA). Genome-wide association studies (GWASs), including tools like ImmunoChip, have significantly deepened our understanding of disease mechanisms by pinpointing risk-associated genetic loci. These efforts have elucidated biological pathways involved in PsO pathogenesis, particularly those related to the innate immune system, antigen presentation, and adaptive immune responses. Specific genetic loci, such as TRAF3IP2, REL, and FBXL19, have been identified as having a significant impact on disease development. Interestingly, different genetic variants at the same locus can predispose individuals to either PsO or PsA (e.g., IL23R and deletion of LCE3B and LCE3C), with some variants being uniquely linked to PsA (like HLA B27 on chromosome 6). This article aims to summarize known and new data on the genetics of PsO and PsA, their associated genes, and the involvement of the HLA system and cytokines. Full article

IgA nephropathy (IgAN) is an autoimmune disorder which is believed to be non-monogenic. We performed an exome-wide association study of 70 children with IgAN and 637 healthy donors. The HLA allele frequencies were compared between the patients and healthy donors from the bone marrow registry of the Pirogov University. We tested 78,020 gene markers for association and performed functional enrichment analysis and transcription factor binding preference detection. We identified 333 genetic variants, employing three inheritance models. The most significant association with the disorder was observed for rs143409664 (PRAG1) in the case of the additive and dominant models (P_BONF = 1.808 × 10⁻¹⁵ and P_BONF = 1.654 × 10⁻¹⁵, respectively), and for rs13028230 (UBR3) in the case of the recessive model (P_BONF = 1.545 × 10⁻⁹). Enrichment analysis indicated the strongly overrepresented “immune system” and “kidney development” terms. The HLA-DQA1*01:01:01G allele (p = 0.0076; OR, 2.021 [95% CI, 1.322–3.048]) was significantly the most frequent among IgAN patients. Here, we characterized, for the first time, the genetic background of Russian IgAN patients, identifying the risk alleles typical of the population. The most important signals were detected in previously undescribed loci. Full article

Rheumatoid arthritis (RA) is a systemic disease characterized by non-infectious inflammation of the joints and surrounding tissues, which can cause severe health problems, affect the patient’s daily life, and even cause death. RA can be clinically diagnosed by the occurrence of blood serological markers, rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP). However, about 20% of RA patients exhibit negative results for both markers, which makes RA diagnosis difficult and, therefore, may delay the effective treatment. Previous studies found some evidence that human leukocyte antigen (HLA)-related genes might be the susceptibility genes for RA and their polymorphisms might contribute to varieties of susceptibility and disease severity. This study aimed for the genetic polymorphisms of the RA patient genome and their effects on the RA patient’s serological makers, RF and anti-CCP. A total of 4580 patients’ electronic medical records from 1992 to 2020 were retrieved from the China Medical University Hospital database. The most representative single-nucleotide polymorphisms (SNPs) were identified through a genome-wide association study (GWAS) followed by enzyme-linked immunosorbent assay (ELISA) validation using the blood from 30 additional RA patients. The results showed significant changes at the position of chromosome 6 with rs9270481 being the most significant locus, which indicated the location of the HLA-DRB1 gene. Further, patients with the CC genotype at this locus were more likely to exhibit negative results for RF and anti-CCP than those with the TT genotype. The C allele was also more likely to be associated with negative results for RF and anti-CCP. The results demonstrated that a genetic polymorphism at rs9270481 affected the expression of RF and anti-CCP in RA patients, which might indicate the necessity to develop a personalized treatment plan for each individual patient based on the genetic profile. Full article