MR vaccine (Mebella)

Genetic evidence linking gout to increased risk of epilepsy: A two-sample Mendelian randomization study.

Chen Zhen Z, Wang Ying Y, Yao Shan S

While observational studies have explored the association between gout, uric acid (UA) levels, and the risk of epilepsy, their findings remain inconsistent. To clarify the potential causal relationship, we performed a Mendelian randomization (MR) analysis. We conducted a bidirectional MR analysis using genome-wide association study (GWAS) summary data. Epilepsy data were sourced from the International League Against Epilepsy (ILAE), gout data from the FinnGen consortium and a GWAS of clinically defined gout and its subtypes, and UA data from the BioBank Japan (BBJ) and a genome-wide meta-analysis of serum UA levels in Japanese individuals. The inverse-variance weighted (IVW) method served as the primary causal inference approach. To ensure robustness, we complemented this with 3 additional methods: MR-Egger, weighted median, and MR using Robust Adjusted Profile Score (MR-RAPS) - the latter specifically employed to account for potential weak instrument bias due to the limited number of single-nucleotide polymorphisms (SNPs) included in this analysis. Our analysis identified a causal association between genetically predicted gout and an increased risk of epilepsy (odds ratio (OR) = 1.014, 95% confidence interval (95% CI): 1.011-1.017, p < 0.001), generalized epilepsy (OR = 1.009, 95% CI: 1.000-1.018, p = 0.042), and focal epilepsy (OR = 1.044, 95% CI: 1.002-1.088, p = 0.041) in Europeans. In contrast, UA levels showed no significant association with epilepsy or its subtypes in this population. Similarly, neither gout nor UA levels were linked to epilepsy in East Asians. Sensitivity analyses generally supported the robustness of the primary findings. This MR study provides genetic evidence supporting a potential causal role of gout in increasing the risk of epilepsy, including generalized and focal epilepsy, in European populations. In contrast, genetically predicted UA levels showed no significant association with epilepsy. These findings support a potential role of gout in epilepsy risk and warrant further investigation into the underlying mechanisms.

Multi-omics analysis reveals MICB promotes cerebral atherosclerosis through FTMT suppression in NK and plasma cells.

Dai Yonggang Y, Liu Ye Y, Yan Yunjun Y, Ji Haoran H et al.

Ferroptosis, an iron-dependent form of regulated cell death, is implicated in vascular injury, but how immune-related proteins modulate ferroptosis and cerebral atherosclerosis (CeA) remains unclear. We performed multi-step Mendelian randomization (MR) integrating plasma proteomics, single-cell eQTL, and FinnGen CeA GWAS data. Mediation MR quantified the role of the ferroptosis regulator FTMT. Cell-type-specific MR was conducted across 14 immune subtypes. Functional enrichment and RT-qPCR of clinical blood samples validated findings. Four immune proteins (KIR2DL3, HLA-E, LTA, MICB) were identified as causal risk factors for CeA, acting primarily by downregulating FTMT (all β1 < 0, P < 0.001). Mediation analysis revealed FTMT explained up to 53% of the immune protein effect. Single-cell MR demonstrated striking cell-type specificity for MICB: higher MICB in NK cells and IgJ+ B cells was strongly associated with CeA risk (e.g., β = 0.90, P = 4.3 × 10-6), while higher MICB in dendritic cells was protective (β = - 0.57, P = 2.1 × 10-30). In clinical samples, RT-qPCR confirmed reduced FTMT expression, and plasma ELISA showed elevated circulating LTA, soluble MICB, and soluble HLA-E in CeA patients. Network analysis highlighted NK cell cytotoxicity as a central pathway. In summary, our study demonstrates that four immune-related proteins, including MICB, promote cerebral atherosclerosis by downregulating the ferroptosis-protective factor FTMT. Importantly, single-cell MR reveals that MICB acts as a risk factor for CeA specifically in NK cells and plasma cells, providing new mechanistic insight into cell-type-dependent immune regulation of vascular disease.

First mRNA Cancer Vaccine Succeeds in Phase III Trial.

Adding the mRNA-based individualized neoantigen vaccine intismeran autogene to the PD-1 inhibitor pembrolizumab following surgery for melanoma reduced the risk of disease recurrence or death by 42%, according to the results of the phase III INTerpath-0001 trial. The data were presented at the ESMO Congress 2026, held October 23-27, in Madrid, Spain.

Integrative Genetic, Transcriptomic, and Single-Cell Analyses Prioritize Druggable Candidate Genes in Knee Osteoarthritis.

Zheng Yiping Y, Xuan Yingying Y, Li Yi Y, Deng Changxu C et al.

Knee osteoarthritis (KOA) is a common degenerative joint disease with a complex pathogenesis and a lack of effective molecular targets. This study aimed to prioritize druggable genes associated with KOA and investigate their expression patterns and cellular localization by integrating genetic, transcriptomic, and single-cell analyses. We first screened for potential druggable genes genetically associated with KOA using MR analysis. Subsequently, batch-corrected synovial transcriptomic data were analyzed using weighted gene co-expression network analysis (WGCNA), and the genes of the most relevant module were integrated with the MR candidates. A total of 127 machine-learning pipelines were evaluated using repeated nested cross-validation, followed by external validation and SHapley Additive exPlanations (SHAP) interpretation. The expression levels of key genes were further validated by experiments. Single-cell RNA sequencing, immune-cell deconvolution, and peripheral immune-cell-specific eQTL-MR were used to investigate the cellular contexts potentially associated with the candidate genes. Finally, potential drug-gene interactions were retrieved from DGIdb, and selected target-compound pairs were evaluated using molecular docking and molecular dynamics simulations. A total of 315 druggable genes showed nominal MR associations with KOA. After integrating KOA-associated WGCNA module, we identified 15 candidate genes. Next, the random forest was selected as the optimal machine-learning model, achieving a mean outer-cross-validation AUC of 0.929 (95% CI, 0.913-0.945). SHAP and differential-expression analyses prioritized four genes. JUN, ADAMTS1, and CRISPLD2 were downregulated in KOA synovium, whereas CX3CR1 was upregulated, and these expression patterns were supported by experimental validation. Single-cell analysis revealed that JUN, ADAMTS1, and CRISPLD2 were predominantly expressed in fibroblast-related populations and CX3CR1 was mainly expressed in myeloid cells, with their expression varying across fibroblast and macrophage states. Peripheral immune-cell-specific eQTL-MR identified nominal associations for JUN in plasma cells, ADAMTS1 in NK_R cells, and CX3CR1 in NK cells. However, none remained significant after correction for multiple testing. Molecular docking and molecular dynamics simulations showed that the ADAMTS1-pravastatin and CX3CR1-Rugocrixan complexes maintained stable protein-ligand contacts during their respective simulations. Integrative multi-omics analyses identified JUN, ADAMTS1, CRISPLD2, and CX3CR1 as prioritized candidate genes associated with KOA. These genes were associated with distinct states of synovial fibroblasts and myeloid cells. These findings provide a foundation for further mechanistic validation and experimental evaluation of candidate drug-target interactions.