The etiology of ankylosing spondylitis (AS) is complex and not yet fully understood. Interleukin-6 (IL-6), vitamin D and the vitamin D receptor (VDR) play an important role in modulating immune response, and Torque teno virus is considered a marker of immune status. This case-control study aimed to investigate the predisposition to AS. A total of 85 patients with AS and 100 clinically healthy individuals were included. VDR polymorphisms (rs2228570, rs1544410, rs7975232, rs731236) were genotyped using the PCR-RFLP technique, while for the IL-6 -174 G>C (rs1800795) polymorphism the tetra-primer ARMS-PCR technique was used. The presence of TTV was detected using the hemi-nested PCR technique. Our findings indicate a statistically significant association between TTV and AS (p = 0.035). C allele of both rs1800795 polymorphism in main groups (p = 0.027) and rs731236 polymorphism in women subgroups (p = 0.036) may be linked to an increased susceptibility to AS. However, none of these associations reach statistical significance after Bonferroni correction. Furthermore, within female subgroups, a significant association was found between the T allele of rs1544410 polymorphism and AS (p = 0.000038, corrected p = 0.00076). A significant association was also observed between the TT genotype of rs2228570 polymorphism, TTV and AS (p = 0.029). Haplotype analysis revealed that certain VDR haplotypes may confer either a protective effect against AS or an increased risk of developing the condition. Notably, rs1544410 polymorphism or a linked polymorphism may influence AS susceptibility. In conclusion, our data suggest that TTV and VDR polymorphisms may be associated with an increased risk of developing AS, indicating that these markers could potentially be used in the future for earlier diagnosis and more targeted treatment of the disease.
Antibodies directed to mismatched donor human leucocyte antigen (HLA-DSA) play a well-established role in antibody mediated rejection (AMR) and graft failure in kidney transplantation, with their presence being correlated with poorer transplant outcomes. The diagnosis of AMR is based on three criteria: Histologic evidence of acute tissue injury, evidence of current/recent antibody interaction with the donor endothelium and serologic evidence of circulating donor-specific antibody (DSA), HLA and non-HLA. Whilst there is significant evidence around the role of HLA-DSA, there is limited evidence of the role of the latter and the elucidation of these targets is still in its infancy, but it is clear that these may play a significant role in the immune response to a transplanted organ. This literature review aims to summarise what is currently known about the role of non-HLA antibody in renal transplantation.
Peri-implantitis is a pathological condition occurring in tissues around dental implants. This study aims to analyse the effect of TGF-β1 rs1800470 polymorphism on peri-implantitis. A total of 160 patients with implants without peri-implantitis and 160 patients with peri-implantitis were recruited from the clinic for this study. The genotype of TGF-β1 rs1800470 and TGF-β1 expression were detected by TaqMan-qPCR and RT-qPCR, respectively. Distributions of genotypes and allele frequencies were analysed by the chi-square test. A Hardy-Weinberg equilibrium (HWE) test was performed to detect whether the gene distribution was established. The diagnostic value of TGF-β1 for peri-implantitis was analysed by the ROC curve. TGF-β1 expression was significantly lower in peri-implantitis patients, which has diagnostic significance for peri-implantitis. TGF-β1 rs1800470 genotypic distribution conformed to the Hardy-Weinberg equilibrium test. CT and TT genotypes were significantly correlated with the development of peri-implantitis (p = 0.004, OR = 2.107, 95% CI = 1.259-3.527). CT and TT genotypes were validated as causative genotypes for peri-implantitis. Polymorphisms at the TGF-β1 rs1800470 locus have an impact on the development of peri-implantitis, and CT and TT genotypes increase the risk of developing peri-implantitis.
Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the axial skeleton and sacroiliac joints, with both genetic and environmental factors playing a role in its pathogenesis. Toll-like receptor 4 (TLR4) has been implicated in immune response and inflammation, but its genetic variations have not been extensively studied in AS. This study investigates the association between the TLR4 rs41426344 polymorphism and AS susceptibility and disease activity in a Turkish population. A total of 200 participants (100 AS patients and 100 healthy controls) were recruited. Genotyping of the TLR4 rs41426344 (G/C) polymorphism was performed using real-time PCR melting curve analysis. Disease activity was assessed using Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) scores. Statistical analyses were conducted to determine the association between genotypes and disease risk. The CC genotype was significantly associated with AS susceptibility, with an odds ratio (OR) of 10.000 (95% CI: 4.091-24.431, p < 0.0000001), indicating a strong genetic risk factor. Additionally, CC genotype carriers exhibited higher BASFI, BASDAI and ASDAS-CRP scores, suggesting greater disease severity and inflammation levels. A statistically significant difference (p < 0.05) was observed in ASDAS-CRP scores between CC and GC genotypes This is the first study to investigate the TLR4 rs41426344 polymorphism in AS, and our findings indicate a strong association with both disease susceptibility and severity in the Turkish cohort. These findings reinforce the role of innate immunity in AS pathogenesis and suggest that TLR4 polymorphisms may serve as potential genetic markers for AS risk assessment and disease activity monitoring.
Neutrophils are short-lived innate immune cells, which develop in the bone marrow and replenish daily the circulatory and marginal pools in various organs in the steady state. Recent technological advances have reshaped the traditional paradigms for neutrophil biology and have identified intriguing (epi)genetic phenomena associated with their differentiation, maturation and function. Herein we summarise these developments and discuss: the new model for instructed programming of neutrophil development and continuous cell development via the lineage trajectory path; new aspects of epigenetic regulation of neutrophil development and in particular changes in chromatin structure, 3D architecture as well as heterochromatin condensation during nuclear segmentation; the remarkable breadth of neutrophil heterogeneity and the atypical function of neutrophils acting as antigen-presenting cells. Understanding these concepts can advance the design of new models of in vitro neutrophil generation and drug discovery in immune-mediated disease and cancer where neutrophils play important roles in the pathogenesis.
BACKGROUND:Variations in individuals' susceptibility to coronavirus disease 2019 may be linked to the presence of genetic polymorphisms. The interferon-induced transmembrane 3 (IFITM3) has a powerful protective function by blocking viral entry into the host cell. Similarly, Interferon Lambda 3 (IFNL3) binds to its receptors and induces a variety of interferon-stimulated genes (ISGs) that inhibit viral replication. Our study aimed to investigate the potential association of IFITM3 gene polymorphism (rs12252) as well as serum IFNL3 level with COVID-19 infection, severity, and mortality. METHOD:This case-control study was held during the period from July 2021 to October 2022 in Mansoura University hospitals in Egypt. We included 100 healthy controls and 154 COVID-19 patients. TaqMan real-time polymerase chain reaction was used for allelic discrimination in the genotyping of rs12252 of the IFITM3 gene. Serum IFNL-3 was assayed using the ELISA technique. RESULTS:The genotype and allele frequency distributions of the rs12252 showed that the frequency of the G allele and AG/GG genotypes was significantly higher in patients than in controls, with no significant association with either disease severity or outcome. Serum IFNL3 level is significantly higher among patients, with no statistically significant difference between mild and severe cases and no significant association with the outcome of COVID-19. CONCLUSION:We found that the AG genotype and G allele of IFITM3 rs12252 are associated with COVID-19 infection in the Egyptian population but not with severity or outcome. Additionally, serum IFNL3 level is significantly associated with COVID-19 susceptibility but not with severity. It is associated with tachypnea and end-organ failure in severe cases. So, they are independent predictors only for developing COVID-19 infection, but not for developing severe infection.
Chronic hepatitis B (CHB) is a major risk factor for liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Genes involved in the JAK/STAT signalling pathway play a critical role in the pathogenesis of HBV-related liver diseases, especially HCC. Although SOCS1 and SOCS3 have been extensively studied, the role of SOCS6 in HBV infection and disease progression remains unclear. This study aimed to investigate the association between SOCS6 gene polymorphisms and promoter methylation with HBV-related liver diseases. This study examined SOCS6 gene polymorphisms in a cohort of 335 patients with HBV-related liver diseases (120 with CHB, 100 with LC and 115 with HCC) and 120 healthy controls (HCs). In addition, SOCS6 promoter methylation was analysed in tumour and adjacent tissues from 41 HCC patients. We found that the rs2062345GA genotype and the dominant genetic model were associated with an increased risk of HBV infection and HCC. The rs7228049GA genotype increased the risk of LC and HCC. Conversely, the rs7228049AA genotype and the recessive model were associated with a reduced risk of CHB, LC and HCC. The SNPs rs2062345, rs7228049 and rs11151580 were related to several clinical parameters such as AST, albumin and prothrombin levels, platelet counts in LC and HCC patients. Promoter hypermethylation of SOCS6 was more prevalent in tumour tissues, especially in larger tumours with poorer histological differentiation (p < 0.01 and p < 0.05, respectively). SOCS6 gene variants and promoter methylation are associated with susceptibility and progression of HBV-related liver diseases. These findings suggest their potential utility as useful prognostic biomarkers for HCC.
COVID-19, caused by the SARS-CoV-2 virus, manifests with varying degrees of severity, affecting individuals worldwide. The spectrum of symptoms ranges from mild to severe, with respiratory failure being a leading cause of death. Immunological factors, particularly excessive cytokine production such as IL-18 and IL-1β, significantly contribute to disease severity. In this context, the NLRP3 inflammasome, a key component of the innate immune system, has influenced COVID-19 outcomes. This study investigated the association between single-nucleotide variants (SNVs) in the NLRP3 inflammasome and COVID-19 severity. A case-control study was conducted involving 800 adult participants infected with SARS-CoV-2, stratified into mild/moderate and severe/critical cases. Genetic associations were assessed through qPCR-based genotyping. While no association was found between SNVs in IL1B and CASP1 with COVID-19 severity, the multivariate analysis revealed that the gain-of-function SNV in the NLRP3 gene (rs35829419) was associated with a protective effect against COVID-19-related mortality. These findings suggest that genetic variations in the NLRP3 inflammasome may modulate the host response to SARS-CoV-2, highlighting potential biomarkers for disease prognosis.
The MYH9 gene encodes the heavy chain of non-muscle myosin IIA (NMIIA), which converts chemical energy into mechanical energy and provides power for the contraction of the actin cytoskeleton. This is necessary for many important physiological processes such as cell morphology maintenance, migration, adhesion, division and individual development. Patients with autosomal dominant genetic diseases caused by MYH9 mutation show macrothrombocytopenia and complications such as renal failure, deafness and cataracts. However, in recent years, more and more studies have found that the activity of NMIIA is also related to various other diseases, including cancer, neurological diseases and infectious disorders. This article introduces the characteristics of myosin superfamily members and systematically reviews the structure, regulation and physiological functions of MYH9 and NMIIA, as well as MYH9-related disorders (MYH9-RD) caused by MYH9 mutations, focusing on the role of NMIIA in the pathogenesis of various cancers, and summarizes the therapeutic mechanisms of its targeted drugs. Besides, the effects of NMIIA in neurological diseases and infectious diseases are discussed to provide a comprehensive theoretical basis and insights for MYH9 and NMIIA as a therapeutic target for multiple diseases.
This meta-analysis aims to evaluate the association between interleukin-10 (IL-10) -819 C/T (rs1800871), -592 C/A (rs1800872) and -1082 A/G (rs1800896) polymorphisms and leprosy susceptibility by analyzing multiple genetic models in the Asian and Caucasian populations. A systematic literature search was conducted in PubMed, Web of Science, Google Scholar and Embase (January 2001 to February 2025) following PRISMA guidelines. Case-control studies reporting genotype distributions for IL-10 polymorphisms in leprosy cases and controls were included. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under allelic, recessive, dominant and over-dominant models. Heterogeneity was assessed using Cochran's Q test and the I2 statistic. Publication bias was evaluated using Egger's test and funnel plots. A total of 13 studies were included, comprising 5509 leprosy cases and 8135 controls. The -1082 A/G variant exhibited a significant protective effect across allelic (A vs. G OR = 0.73, 95% CI 0.59-0.91, p = 0.005), dominant (AA+AG vs. GG OR = 0.45, 95% CI 0.25-0.80, p = 0.006) and the over-dominant models (AG vs. AA+ GG OR = 0.45, 95% CI 0.25-0.80, p = 0.006). Under the dominant model, the -819 C/T (CC+CT vs. TT OR = 0.76, 95% CI 0.61-0.96, p = 0.02) and -592 C/A (CC+CA vs. AA OR = 0.71, 95% CI 0.52-0.97, p = 0.03) polymorphisms also showed significant protective effects, suggesting a potential role of heterozygosity in reducing leprosy susceptibility. Subgroup analysis indicated stronger protective effects in Asians. Power analysis confirmed that the included studies had sufficient sample sizes to detect significant associations (α error probability < 0.05). This meta-analysis supports the protective role of IL-10 polymorphisms, particularly the -1082 A (rs1800896) allele, in reducing leprosy susceptibility. These findings underscore the role of genetic variation in disease susceptibility and suggest that IL-10 polymorphisms could serve as biomarkers for leprosy susceptibility.
Preeclampsia (PE) is a major pregnancy complication with considerable maternal and fetal morbidities. The recent evidence indicates that immunological factors have critical roles in PE pathogenesis. This study assessed the association between genetic variations in IL-35 components, specifically IL-12A (rs568408) and EBI3 (rs4740) polymorphisms, and PE susceptibility in an Iranian population. A case-control study with 470 participants was carried out, and polymorphism detection was achieved by the PCR-RFLP technique. Genetic analysis revealed distinct associations between IL-35 components polymorphisms and PE risk. For IL-12A rs568408, the AA mutant genotype significantly increased PE susceptibility (OR = 3.350, p = 0.007), with stronger associations in severe PE cases (OR = 5.048, p < 0.001). Similarly, the mutant allele showed risky effects in total group and severe subgroup (OR = 1.743, p = 0.001; OR = 2.307, p < 0.001). The EBI3 rs4740 polymorphism analysis showed that AA genotype carriers had a protective effect (OR = 0.495, p = 0.036), particularly noticeable in severe cases (OR = 0.409, p = 0.037). In addition, the mutant allele demonstrated protective effects in the total PE, severe and particularly in early-onset manifestations (OR = 0.651, OR = 0.559, OR = 0.478, respectively). Combined genotype analysis showed that IL-12A AA/EBI3 GA carriers had the highest risk of severe, early-onset PE (OR = 5.280, p = 0.046, OR = 5.945, p = 0.038). This study provides a better understanding of the causes of PE and points out possible genetic markers to be used in its risk assessment.
BACKGROUND/OBJECTIVES:The human major histocompatibility complex (MHC) is characterized by extreme polymorphism, with HLA-C contributing to pathogen defence, disease susceptibility, and transplantation outcomes. Beyond allelic diversity, and variation, the evolutionary restructuring of haplotypes influences functional diversity across the region. This study analysed HLA-C haplotypes in the context of transposable element (TE) architecture and single-nucleotide polymorphism (SNP) patterns to identify conserved modules and ancestral recombination boundaries. METHODS:Paired genomic alignments of fully phased homozygous lymphoblastoid cell lines carrying 36 haplotypes of HLA-C*01-C*07, C*12, and C*16 allelic groups were performed using Mauve to define locally co-linear blocks. SNP density plots were generated to visualize transitions between SNP-rich and SNP-poor regions. Six diverse HLA-C*07 haplotypes (linked to HLA-B*07, *08, *18, *49, *57 and *58) were examined as a primary case study. Particular focus was placed on crossover zones where SNP transitions coincided with TE boundaries, indicating putative ancestral recombination breakpoints. RESULTS:Comparative analyses revealed extensive structural variation among C*07 haplotypes and across the broader C*01-C*16 series. The C*07:02 homologs exhibited significantly higher SNP density (mean = 1.87 ± 0.44 SNPs/kb, n = 10) than C*07:01 and C*07:18 homologs (mean = 0.29 ± 0.21 SNPs/kb, n = 20; p < 0.001). Abrupt SNP transitions frequently aligned with SINE, LINE, and LTR elements (e.g., Alu, L1, L2, HERV), marking recurrent TE-associated junctions. These breakpoints defined shared homozygous HLA-C segments spanning ∼4 kb to ∼4 Mb, consistent with mosaic haplotype evolution through recombination of conserved modules. CONCLUSIONS:HLA-C haplotypes exhibit modular mosaic structures shaped by recurrent recombination at TE-associated crossover zones. Thus, MHC haplotypes may share the same HLA-C allele, yet differ in the surrounding HLA-B and class I genomic organization, preserving or disrupting co-adapted functional units. Incorporating haplotypic mosaicism, rather than focusing solely on allelic polymorphism, may improve models of immune variation, disease risk, and translation matching.
BACKGROUND:Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease resulting from the complex interplay between genetic, environmental, and immunological factors. Genetic polymorphisms in cytokine and transcription factor genes have been proposed as key contributors to disease susceptibility and clinical heterogeneity. OBJECTIVE:To evaluate the association between selected single nucleotide polymorphisms (SNPs) in TNF-α, IL-1, IL-8, and IRF5 genes and the risk of SLE, as well as their correlation with specific organ system involvement. METHODS:We conducted a case-control study including 156 SLE patients and 104 healthy controls from the Algerian population. Seven SNPs were genotyped using TaqMan assays: IL-1 (-31 C/T and -511 C/T), TNF-α (-308 G/A and -238 G/A), IL-8 (-251 A/T), and IRF5 (-13176 A/C and -3835 G/T). Genotype and allele frequencies were compared between groups and correlated with clinical phenotypes. RESULTS:The immunogenetic study revealed a significant association between G allele of the -3835 G/T polymorphism of the IRF5 gene and the risk of genetic susceptibility to the lupus (p = 0.012). Stratification according to clinical manifestations has showed that the G allele of the -31 C/T polymorphism of the IL-1 gene is associated with joint damage (p = 0.024) and the A allele of -511 C/T polymorphism predisposes to hematological damage (p = 0.041) in lupus patients. Also, the A allele of the TNFα -238 G/A polymorphism was associated with neuropsychiatric impairment (p = 0.036) and the A allele of -251A/T SNP of the IL-8 gene to the joint damage (p = 0.04). CONCLUSION:Our findings support a role for IRF5 and cytokine gene polymorphisms in the genetic predisposition to SLE and its clinical manifestations. These polymorphisms may serve as potential biomarkers for disease risk stratification and personalized patient management, particularly in underrepresented populations such as North Africans.
