PI3K gene variants are associated with elevated IL-6 levels and COVID-19 severe outcomes in a multicenter study.

Investigation of PDCD1 Gene Polymorphisms and Haplotypes in COVID‐19 Severity and Outcome in a Brazilian Population

COVID‐19 severity and survival are influenced by the host immune response to SARS‐CoV‐2. Programmed cell death 1 (PD‐1), a key immune checkpoint, regulates T‐cell activation and antiviral immune balance. Since genetic variability can modulate these responses, we investigated whether the PDCD1 polymorphisms rs11568821 C > T, rs2227982 G > A, rs2227981 G > A and rs10204525 C > T are associated with COVID‐19 severity and mortality in a Brazilian cohort. A total of 366 COVID‐19 patients (165 mild, 72 moderate, and 129 severe cases) were genotyped for the four PDCD1 SNPs, and their haplotype structures were estimated. Significant differences were observed in the allele frequencies of rs11568821, and in genotypes and allele frequencies of the exonic rs2227982, among mild, moderate, and severe cases. Multinomial logistic regression identified associations between rs2227982 (dominant and overdominant models) and moderate COVID‐19, and between the rs2227981 AA genotype (genotypic and recessive models) and severe COVID‐19. The rs10204525 polymorphism (CT genotype under genotypic dominant and overdominant models) also presented an association with severe COVID‐19. However, none of these associations remained independent. Haplotype analysis identified five major haplotypes with significantly different frequencies among the groups (p = 0.02); however, no association was found between the haplotypes and disease severity or outcome. This is the first study to evaluate SNP rs2227982 in COVID‐19 patients, and the first to evaluate the four aforementioned SNPs in a Brazilian population. Overall, our findings suggest that these polymorphisms, although involved in COVID‐19 immunopathogenesis, are not suitable biomarkers for predicting COVID‐19 severity or clinical outcomes.

Synergistic IL-1 pathway genetic variants amplify susceptibility and inflammatory severity in COVID-19

Host genetic variation within the interleukin-1 (IL-1) signaling pathway may contribute to heterogeneity in COVID-19 susceptibility and disease outcomes and represents a potential target for precision risk stratification. We investigated whether polymorphisms in the IL-1 pathway influence SARS-CoV-2 infection risk and inflammatory responses. A hospital-based case–control study was conducted in Maharashtra, India, including 156 RT-PCR–confirmed COVID-19 patients and 154 SARS-CoV-2–negative controls. IL-1RN intron-2 VNTR (rs2234663) and IL-1β+3953C/T (rs1143634) polymorphisms were genotyped using PCR-based methods. Multivariable logistic regression was used to assess associations with COVID-19 susceptibility. Gene–gene interactions, haplotype analyses, genotype–biomarker correlations, and weighted Genetic Risk Score (GRS)-based models were evaluated. Carriers of the IL-1RN allele 2 and IL-1β T allele (driven primarily by the CT genotype) were associated with increased susceptibility to COVID-19. Multivariable analysis confirmed independent associations for IL-1RN allele 2 (OR 2.48, 95% CI 1.56–3.95) and IL-1β T allele (OR 3.12, 95% CI 1.92–5.07), primarily driven by the CT genotype. A significant gene–gene interaction between IL-1RN and IL-1β variants further increased susceptibility, indicating a synergistic genetic effect. Individuals carrying both risk alleles showed significantly higher CRP and ferritin levels, suggesting enhanced systemic inflammation. Incorporation of these variants into a Genetic Risk Score improved predictive performance compared with the clinical model alone (AUC 0.82 vs. 0.71). IL-1 pathway genetic variants are associated with COVID-19 susceptibility and inflammatory biomarker profiles. Integration of host genetic markers with clinical factors may improve risk stratification and support precision immunomodulatory strategies.

IL1R2⁺ Inflammatory Monocytes Contribute to Immune Dysregulation and Predict Mortality in COVID-19.

BACKGROUND Coronavirus disease 2019 (COVID-19) is characterized by dysregulated immune responses and excessive inflammation, contributing to severe disease and mortality. Interleukin-1 receptor type 2 (IL1R2), a decoy receptor for interleukin-1 (IL-1), regulates inflammatory responses; however, its cellular distribution and clinical significance in COVID-19 remain unclear. METHODS Publicly available single-cell RNA sequencing (scRNA-seq) dataset (GSE149689) of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients were analyzed. An independent monocyte transcriptomic dataset (GSE198256) was analyzed to evaluate IL1R2 dynamics during COVID-19 and recovery. Differential expression, functional enrichment, regulon activity, and CellChat analyses were performed to characterize IL1R2⁺ monocytes. Serum IL1R2 levels were measured in COVID-19 patients and healthy controls (HCs), and their associations with disease severity and mortality were evaluated. RESULTS Single-cell analysis revealed that IL1R2 was predominantly expressed in monocytes from COVID-19 patients. IL1R2 expression was increased during active COVID-19 and decreased after recovery. IL1R2⁺ monocytes exhibited enhanced inflammatory transcriptional programs, increased activity of inflammation-associated regulons, and activation of TNFα/NF-κB, interferon, and IL6-JAK-STAT3 pathways. Cell-cell communication analysis identified IL1R2⁺ monocytes as active mediators of CCL, CXCL, IL1, and TNF signaling networks. Serum IL1R2 levels were elevated in COVID-19 patients, further increased in non-survivors, and correlated with inflammatory markers, tissue injury indicators, and coagulation abnormalities. IL1R2 showed predictive performance for mortality comparable to procalcitonin and D-dimer. CONCLUSIONS IL1R2 identifies a highly inflammatory monocyte state associated with COVID-19 immune dysregulation. Elevated IL1R2 levels reflect disease activity and poor outcomes, supporting its potential role as a complementary prognostic biomarker and therapeutic target.

Association Study of IFIH1/MDA5 Gene Variants with COVID-19 in Moroccan Patients

Gene-environment interaction between VDR variants and vitamin D deficiency identifies a high-risk inflammatory phenotype associated with COVID-19 severity

Host determinants of inflammatory escalation remain incompletely defined in COVID-19. Vitamin D receptor (VDR) signaling regulates immune activation and cytokine responses, yet the contribution of VDR genetic variation to severe disease is unclear. We investigated two common VDR polymorphisms (rs7975232 and rs1544410) in a prospective, clinically stratified Indian cohort ( n  = 323), integrating genotype–phenotype associations, inflammatory biomarkers, interaction modeling, and polygenic risk stratification. Both variants were independently associated with severe disease under additive genetic models (per-risk allele adjusted OR 1.69 for rs7975232 and 1.82 for rs1544410) and demonstrated allele-dose relationships across severity categories. Risk alleles correlated with elevated IL-6, C-reactive protein, and ferritin levels, indicating amplified inflammatory signaling. A statistically significant gene–gene interaction between rs7975232 and rs1544410 (OR 2.48, p  = 0.006) was observed; however, this finding should be considered exploratory pending independent replication. Vitamin D deficiency (< 20 ng/mL) further amplified genotype-associated risk, supporting a biologically relevant gene-environment interaction. Integration of genetic information into multivariable clinical models improved model discrimination within this cohort (AUC 0.83 vs. 0.72), although external validation is required. In silico functional annotation was performed using RegulomeDB, HaploReg, and GTEx (Supplementary Table S7). Together, these findings identify a genetically associated inflammatory risk profile characterized by VDR risk alleles, vitamin D deficiency, and heightened inflammatory responses, providing a framework for precision risk stratification targeting the vitamin D-VDR axis.

Immunological Consequences of rs5742621 Variant and IGF-1 in Modulating MIF, IL-27, and CXCL12 Expression in Individuals with Prostate Cancer

The GA genotype of rs5742621 was significantly associated with elevated IGF-1 levels and increased PCa risk, promoting cell proliferation, inhibiting apoptosis, and accelerating tumor growth.