Toll-like receptors (TLRs) induce the production of pro-inflammatory cytokines and regulate the immune response to Plasmodium vivax infection. Genetic variants of TLRs are associated with susceptibility and severity of malaria in different populations. This study aimed to evaluate the association between polymorphisms in TLR1, TLR4, TLR7, TLR8, TLR9 and TIRAP and the clinical manifestations of malaria caused by P. vivax in a population from the Amazon region of Pará, Brazil. A total of 148 individuals with symptomatic uncomplicated malaria were genotyped for rs4833095, rs1927911, rs179008, rs3764880, rs352140 and rs8177374 variants, and their associations with parasitaemia levels, gametocytaemia and clinical index were analysed using generalised linear models. TLR9 rs352140TT homozygotes had higher parasitaemia levels than C allele carriers (p = 0.034). TLR4 rs1927911GG homozygotes had a higher clinical index than A allele carriers (p = 0.018). Our results describe, for the first time, the association of the rs1927911 variant found in intron 1 of TLR4 with P. vivax malaria symptoms in Brazilian Amazonian population.

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.

Over the years, accumulating evidence has been associating interleukin-13 gene (IL-13) variants with a wide array of chronic inflammatory diseases. Also, recent findings have associated the potential role of a single nucleotide polymorphism (SNP) of IL-13, rs20541, to promote either anti- or pro-inflammatory responses in chronic inflammatory diseases. Although rs20541 has been widely associated with various immune-related and inflammatory conditions, its precise functional relevance in the pathogenesis of human diseases has yet to be fully clarified. Nonetheless, its consistent associations and known effects on IL-13 signalling underscore its potential biological importance. Hence, this meta-analysis aimed to investigate the associations between IL-13 SNP rs20541 with distinct groups of chronic inflammatory diseases. Eligible studies were selected from seven databases including PubMed, EBSCO Host (all databases), Medline, CINAHL Plus, Scopus, SNPedia and GWAS. In total, 45 case-control studies with 16,045 cases and 23,312 controls were categorised into four major groups: atopic, cardiopulmonary and autoimmune diseases as well as cancer and tumour. While no consistent associations emerged for asthma or overall atopic and cardiopulmonary groups, protective associations for psoriasis and glioma were observed across multiple genetic contrasts. The A allele of rs20541 was significantly associated with higher risk of chronic obstructive pulmonary diseases (COPDs) [1.17 (1.03-1.32)] but reduced risk of cardiovascular diseases (CVDs) [0.87 (0.75-1.00)], psoriasis [allele model: 0.71 (0.65-0.77); dominant model: 0.69 (0.62-0.76)], overall cancer [allele model: 0.82 (0.66-0.98); dominant model: 0.82 (0.67-0.98) and glioma [allele model: 0.82 (0.68-0.95); dominant model: 0.72 (0.57-0.87)]. In subgroup analysis and meta-regression, sources of between-study heterogeneity were associated with ethnicity, age, gender and sample size in respective disease groups (p < 0.05, p > 0.05). Overall, this meta-analysis demonstrates that IL-13 rs20541 is a key immunogenetic variant exerting context-dependent effects, either via direct lgE-dependent or indirect regulatory effects across chronic inflammatory diseases. These mechanistic differences help explain why rs20541 confers susceptibility in some diseases while providing protection in others, reflecting the pleiotropic and tissue-specific functions of IL-13. Future research should integrate transcriptional studies and eQTL analyses of rs20541 to clarify its downstream impact on inflammation-specific genes, ultimately informing cytokine-targeted therapies to more precisely manage and prevent chronic inflammatory disease.

Acute lymphoblastic leukaemia (ALL) is characterized by the clonal proliferation of immature lymphoid precursors in the bone marrow or peripheral blood. This study investigates whether genetic polymorphisms in IL-17RC are associated with an increased risk of ALL in the Saudi population.

IgA nephropathy (IgAN) is one of the most prevalent glomerulonephropathies and commonly leads to kidney failure. The recurrence of IgAN following transplantation remains a significant concern. Currently, detecting IgAN recurrence requires a kidney biopsy, highlighting the need for non-invasive biomarkers such as donor-derived cell-free DNA (dd-cfDNA) to aid in early detection. This prospective pilot study aims to evaluate dd-cfDNA as a non-invasive biomarker for detecting IgAN recurrence post-kidney transplantation. Specifically, the study seeks to compare %dd-cfDNA levels in transplanted patients with and without IgAN recurrence and correlate these levels with other kidney function parameters. A total of 32 patients with histologically confirmed IgAN were enrolled, including those with documented IgAN recurrence post-transplantation and those without recurrence. Plasma samples were collected and processed using the AlloSeq cfDNA kit to quantify relative %dd-cfDNA levels. Kidney function parameters, including estimated glomerular filtration rate (eGFR) and proteinuria, were also assessed. The study found no significant difference in %dd-cfDNA levels between transplanted patients with IgAN recurrence and those without recurrence (median 0.37% [IQR 0.28%-3.53%] vs. median 0.42% [IQR 0.15%-0.84%], p = 0.67). Also, %dd-cfDNA (AUC = 0.57 [95% CI 0.28-0.85], p = 0.64) failed to effectively discriminate IgAN recurrence compared to traditional kidney function parameters such as proteinuria (AUC = 0.96 [95% CI 0.87-1.00], p = 0.002) and eGFR (AUC = 0.74 [95% CI 0.47-1.00], p = 0.09). Relative (%) dd-cfDNA alone may not be a robust biomarker for detecting IgAN recurrence post-transplantation. While proteinuria proved a more effective indicator in this study, kidney biopsy remains the gold standard for definitive diagnosis. These findings highlight the challenges of using %dd-cfDNA as a standalone diagnostic tool for monitoring IgAN recurrence post-transplantation. Future research should explore larger patient cohorts and longitudinal assessments to refine the utility of dd-cfDNA and investigate potential combination strategies with other biomarkers.

The highly polymorphic HLA genes inform susceptibility and resistance to infectious and autoimmune diseases and cancers and are key for successful solid-organ and stem-cell transplantation therapies. Over 41,000 HLA alleles are known and are unevenly distributed across the human population. Here, we describe HLAtools, Searching Shared HLA Amino-Acid Residue Prevalence (SSHAARP) and the Global Frequency Browser (GFB), new informatic tools developed to facilitate working with HLA data and visualizing the global distribution of HLA variants in human populations. HLAtools is an R package that consumes static resources for HLA alleles and sequences and makes these data locally computable alongside data-query, data-customization and data-analysis functions. The package further includes new reference datasets that dissect and catalogue HLA regions and HLA gene structures and provide insight into the organization of HLA pseudogenes and gene fragments. SSHAARP is an R package that describes the frequency distributions of individual HLA haplotypes, alleles and amino-acid motifs as global heatmaps. Allele frequency maps for more than 800 HLA alleles can be browsed using the GFB web and mobile applications. HLAtools and SSHAARP are available from the Comprehensive R Archive Network, and the GFB apps are available on GitHub.

This study was performed to determine anti-C1q serum level, genetic polymorphism in cytotoxic T lymphocyte-associated antigen 4 gene (CTLA-4 gene) (rs 231775), and HLA class II genes in susceptibility and early prediction of systemic lupus erythematosus (SLE) and lupus nephritis (LN) in Upper Egyptian patients. A total of 60 unrelated cases of SLE (30 cases with LN) and 60 healthy controls were studied for HLA-DQB1, HLA-DQA1, and HLA-DRB1 (DR4 subtypes) alleles. Anti-C1q level was estimated by ELISA. CTLA-4 gene genotypes were detected by PCR-RFLP. The means of age of SLE patients without nephritis and LN patients were 24 ± 5.09 and 32 ± 7.26, respectively. Most of the patients were females (93.3%). Anti-C1q serum level was significantly higher in LN patients (24.11 ± 4.26) versus SLE patients without nephritis (18.17 ± 1.35) (p value < 0.001). The AA genotype of the CTLA-4 gene was significantly higher in patients with LN versus SLE patients without nephritis (53.5% vs. 26.5%; p value = 0.035). (DR7)-DQA1*02-DQB1*0303 haplotype was higher in SLE patients versus the control group and showed the highest odds ratio (7.37) with a significant p value (0.031). Odds ratios of DRB1*0405-DQA1*03-DQB1*0302 and DRB1*0405-DQA1*03-DQB1*02 were 6.263 and 4.214, respectively. DRB1*0405-DQA1*03-DQB1*02 haplotype was detected in 11.7% of LN patients versus 1.7% of SLE patients without nephritis (OR = 8.82, p value = 0.02). DRB1*0405-DQA1*03-DQB1*02 haplotype, in addition to CTLA-4 gene (AA genotype), and high anti-C1q serum level can predict the progression of SLE Upper Egyptian patients to LN.

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.

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.

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.

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.

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.

Familial cold autoinflammatory syndrome 2 is a rare autoinflammatory disorder caused by mutations in the NLRP12 gene, characterized by recurrent fever, arthralgia and rash triggered by cold exposure. This case report presents a 9-year-old boy with intellectual disability, microcephaly and skin lesions, where genetic testing revealed heterozygous pathogenic variants in both KIF11 (NM_004523.4:c.2304_2305del) and NLRP12 (NM_144687.4:c.770del) genes. While the KIF11 variant has been previously documented, the NLRP12 variant is novel and classified as likely pathogenic. This study also includes a systematic review analysing 28 studies and 100 patients with NLRP12 mutations, revealing a phenotypic spectrum ranging from classic symptoms like fever and rash to rarer features such as hypogonadism, hypothyroidism and neurological abnormalities. A significant concentration of variants was noted in Exon 3 of NLRP12, but no clear genotype-phenotype correlation was established. These findings underscore the utility of next-generation sequencing in diagnosing rare genetic conditions, particularly in patients presenting with seemingly minor symptoms. The coexistence of mutations in KIF11 and NLRP12 highlights potential interactions between distinct genetic pathways, emphasizing the need for further research. Including NLRP12 in diagnostic panels and updating databases like the Human Phenotype Ontology are crucial for improving diagnosis, understanding phenotypic diversity and optimizing patient management.

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.