Urolithiasis, Journal Year: 2024, Volume and Issue: 52(1)
Published: Nov. 25, 2024
Language: Английский
Cardiovascular Therapeutics, Journal Year: 2025, Volume and Issue: 2025(1)
Published: Jan. 1, 2025
Background: Cardiovascular diseases (CVDs) encompass a group of that affect the heart and/or blood vessels, making them leading cause global mortality. In our study, we performed proteome‐wide Mendelian randomization (MR) and colocalization analyses to identify novel therapeutic protein targets for CVDs evaluate potential drug‐related side effects. Methods: We conducted comprehensive MR study assess causal relationship between plasma proteins risk CVDs. Summary‐level data 4907 circulating levels were extracted from large‐scale quantitative trait loci (pQTL) involving 35,559 individuals. Additionally, genome‐wide association (GWAS) UK Biobank Finnish database. Colocalization analysis was utilized variants shared Finally, phenome‐wide (PheWAS) using R10 version This aimed at examining effects in treatment A total 2408 phenotypes included analysis, categorized into 44 groups. Results: The research findings indicate following associations: (1) coronary artery disease (CAD), A4GNT, COL6A3, KLC1, CALB2, KPNA2, MSMP, ADH1B showed positive ( p ‐fdr < 0.05). LAYN GCKR exhibited negative (2) chronic failure (CHF), PLG demonstrated 0.05), while AZGP1 displayed (3) ischemic stroke (IS), ALDH2 PELO (4) Type 2 diabetes (T2DM), MCL1, SVEP1, PIP4K2A, RFK, HEXIM2, ALDH2, RAB1A, APOE, ANGPTL4, JAG1, FGFR1, MLN PTPN9, SNUPN, VAT1, COMT, CCL27, BMP7, MSMP conclusively identified AZGP1, RAB1A share single variant with (PPH3 + PPH4 > 0.8). Further phenotype‐wide studies have shown some these nine Conclusions: identifies significant associations CVDs, providing more understanding targets. These contribute knowledge underlying mechanisms offer insights avenues treatment.
Language: Английский
Citations
1
Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 306 - 306
Published: Jan. 27, 2025
Objective: The purpose of this study was to assess the causal effects circulating plasma proteins on ankylosing spondylitis (AS) and explore potential therapeutic targets. Methods: used protein quantitative trait loci (pQTLs) for thousands from nine genome-wide association studies (GWAS) as instrumental variables. relationship between genetically predicted AS assessed through Mendelian randomization (MR) analysis. Further analyses, including colocalization analysis, Steiger filtering protein-altering variant assessment, protein–protein interaction (PPI), pathway enrichment were conducted validate robustness direction results, well investigate functions drug Results: Nine unique found have strong associations with AS. analysis confirmed that all identified by MR a direct link Colocalization four proteins—Interleukin-6 receptor alpha (IL-6Rα), Interleukin-23 (IL-23R), Thrombospondin-2 (THBS2), Interleukin-1 type 2 (IL-1R2)—that share same variants PPI revealed roles these in inflammatory responses immune regulation. Moreover, valuable targets or considered druggable. Conclusions: This has multiple associated AS, revealing important pathogenesis providing
Language: Английский
Citations
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BMC Neurology, Journal Year: 2025, Volume and Issue: 25(1)
Published: March 3, 2025
Language: Английский
Citations
0
Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16
Published: March 18, 2025
In the practice of clinical rheumatology, identifying individuals at higher risk to develop a chronic inflammatory disease based on their genetic profiles remains major wish.In case axial spondyloarthritis (axSpA), (1) strong association with HLA-B27 may well fulfil this expectation but vast prevalence allele in general population makes unsuitable for early diagnosis. With better tools available, clinicians tailor more effective therapeutic interventions, molecular pathways involved.EQTLs are genomic loci that modulate expression genes. Notably, these factors prevalently non-coding variants can act across cell types and states.(2) The most common method analyzing such impact is directly assay levels RNA produced from gene interest connection specific variant, done single transcript level via quantitative real-time PCR (qRT-PCR), or transcriptome-wide manner sequencing (RNA-seq) methodologies (3). Therefore, eQTLs validated functional effects differential genes, linked ways similar GWAS variants. There crucial steps must be followed process eQTL data, including quality control, mean aggregation, covariate correlation procedures, multiple testing corrections (4).It critical sort approach map context link direct contribution regulatory pathogenesis (5).EQTLs classified into two main types: cis-eQTLs, which affect genes located nearby same chromosome, trans-eQTLs, influencing situated far away genome different chromosomes. It's not trivial identify indicative variations really contributing mechanisms.For mapping provide insights, changes assayed conditions relevant (6). specificity it's pivotal concept because transcriptome its mechanisms dynamic very frequently contextdependent (7). Further, seminal studies have demonstrated only detected certain upon stimulation, introducing response (8), connect disease-relevant treatments variation. Response power show how variation might contribute activated conditions, as stimulus shown osteoarthritis (with cartilage matrix breakdown product, fibronectin fragment), allowing investigation stages disease. (9,10). It has been also associations limited overlap (11).The activity likely active following immune activation, it occurs axSpA.Several works proven significantly associated processes (12,13). axSpA, previously identified ankylosing spondylitis, involved bone remodelling (14,15). Back 2016, Ellinghaus colleague published cross-disease study where they simultaneously investigated landscape pleiotropy five clinically related psoriasis, Crohn's disease, primary sclerosing cholangitis, ulcerative colitis. authors were able new coding Fc Gamma Receptor IIa (FCGR2A), Endoplasmic reticulum aminopeptidase 2 (ERAP2), tyrosine-protein kinase (TYK2) fucosyltransferase (FUT2) shared by diseases (16). Very importantly, IL23R gene, encodes receptor interleukin 23 (IL23R) potential influence susceptibility although no convincing arising SNPS rs11209032 observed transcription either (and cognate IL12RB2) (17). On matter, libraries generation described Fairfax et al. monocytes helpful, highly therefore (8). More recently, Roberts colleagues found an intergenic SNP IL23R-IL12RB2 region had effect despite apparent regulation mRNA expression, proportion IFN-γ+ CD4+ T-cells was increased homozygote subjects carrying genotype 'A/A' (18). other acting locus identification axSpA help researchers shedding light pathophysiology highlighting targets.From perspective, Brown reported eQTLs, comprehensive analysis performed cells obtained peripheral blood patients (19). A total nine loci, Runt-related factor 3 (RUNX3), Interleukin 7 (IL7R, encoding IL-7Ra subunit), ETS proto-oncogene 1 (ETS1, ETS2) B3GNT2 (previously AS ( 14)), showed chromatin interaction, open profile, peaks histone marks (such H3K4me3 H3K27ac) enhancer (eRNA) peaks, them overlapped types. allele-specific differences ATAC-seq signal (Assay Transposase-Accessible Chromatin using regions) (20) GWAS-associated SNP, rs4672505, abundance B3GNT2, poly-Nacetyllactosamine synthase enzyme important modulating T activation cancer (21). reduction caused reduced openness locus. suggest higher-order structures, looping event between distal B3GNT2. (19) 2018, group Professor Gaffney QTLs accessibility human macrophages exposed stimuli IFNγ, Salmonella IFNγ + Salmonella. Understanding binding factors, altering enhancers behaviours during central untangling architecture disease-associated (22) so, strategies mediate axSpA).Single (sc) technology revolutionary field biology genomics, measuring molecules per cell, detecting transcriptomic unprecedented scale resolution (23,24). Thanks development sc-eQTL models cell-state-specific now possible define single-cell varies way along trajectories. This already powerful integrating existing knowledge about alleles predicted targets defined cellular context. Sc profiling will affecting magnitude responses together rate timing.( 7) recent linking complex (i.e neurological disorders): 196 eight nervous system thousands having cell-type-specific (25).Transcriptomic just first layer machinery controls functions signalling cell. Other readouts, accessibility, surface proteins, (TCR)/B (BCR) repertoires, measured complement sc resolution. Simone recently Tregs clusters synovial fluid axSpA. Of note, one CD8+ subset expressed cytotoxic markers, Th17-like RORC+ Treg specifically characterized immunomodulatory molecule lymphocyte activating (LAG-3) (26). value patient and/or tissue derived tissue/fluid perform scRNA-seq-based undeniable We think differently: instead treating observations, trajectories treat each own observation gene. Few years ago, Perez work profiled than million circulating multiplexed sc-RNA-seq. Integrating data genotyping typeand context-specific cis-eQTLs systemic lupus erythematosus (SLE) plausible effect. Joint genome-wide results enabled immune-mediated diseases, fine-mapping discovery novel SLE (27). Furthermore, Yazar through population-based segregating function 14 integration autoimmune (including RA, AxSpA) cohorts causal 160 (28). sctranscriptomics offers opportunity expand depth transcriptional regulation, several methodological limitations still remain. Sctechnology exempt batch effects, influenced technical factors. Nevertheless, computational correction methods aim remove thus preventing confounding downstream (29). there rare particular (i.e. neutrophils high RNases) challenging measure, accentuating need improving annotation efficiency, state definitions analysis. standard pipelines lack accurately quantify HLA polymorphic individuals): suggests instances specialized quantification (30).Studying opportunities personalized medicine axSpA.Understanding facilitate therapeutics aimed targeting pathways. As indicated, combined genomics PI (priority index, genetics-led interprets GWASs prioritize disorders) (31). successfully confirmed known pathogenesis, Th17/IL-23 TNF, drug targets, PTGER4, phosphatidylinositol 3-kinase (PI3K)/AKT, NOTCH, ErbB GPCR. variant diseaseassociated benefits. Existing inhibitors study, PI3K currently used treatment lymphoma, could repurposed, optimized combination therapies those synergistically line, Goldmann samples treatment-naïve rheumatoid arthritis (RA). 898 synovium, 1251 blood, Among these, HLA-DPB2 discovered, rs3128921 driving expression. Both correlated severity lympho-myeloid pathotype, indicating immediate aggressive stratification (32).The multimodal approaches we briefly discussed here, consisting assessing interactions, inform interpretation networks targets.EQTLs represent promising frontier research By elucidating connections variation, mechanisms, hold enhance our understanding SpA improve outcomes approaches.Future should focus omics approaches, proteomics metabolomics, create regulation. Recently, Zhao proteome-wide mendelian randomization assess relationships plasma proteins susceptibility, repurpose licensed drugs (33). utility metabolomic integrated indisputed, understand metabolite (34). so-called metabQTLs, discovered levels, add another complexity full picture extreme gain metabolic insights (35). Metabolomics proteiomics analyses widely applied biomarkers discovery: both considered occurring SpA.As anticipated, advancements sc-RNA-seq dissect level, revealing cell-typespecific patterns stratified subgroups (36).However, step, consequences real point. Validating biological assays, CRISPR/Cas9 editing interference clarify (37) providing robust basis (38). evaluation role haplotype (a set determinants inherited together) (39) fundamental evidence support So, perturbing (gene overexpression silencing) CRISPR (CRISPR KO, interferece) (40). chromosome conformation capture techniques (Hi-C, Micro-C Micro Capture C) resolve (41) signals functionally correlate SNPs target explain differenatial (42). Assessing include protein-DNA formation, mediated complexes DNA regions, euchromatin (open chromatin). (40,43) Artificial intelligence (AI) machine learning research, technologies analyze large datasets efficiently, uncovering interactions missed traditional analytical (44). AI predictive integrate genetics, epigenomics, phenotypic anticipate outcomes, optimization therapies.
Language: Английский
Citations
0
Biological Procedures Online, Journal Year: 2025, Volume and Issue: 27(1)
Published: March 18, 2025
Gastric cancer (GC) is one of the most prevalent malignancies in world. Most patients are diagnosed at advanced stages disease, primarily attributable to insidious nature early symptoms and infrequent occurrence routine screening. Further biomarkers still needed for more comprehensive analysis, targeted prognostication, effective treatment strategies. Plasma proteins promising potential drug targets GC. This study aims identify therapeutic GC by conducting a proteome-wide Mendelian randomization (MR) colocalization analyses. were obtained from UK Biobank Pharma Proteomics Project (UKB-PPP), including Genome-Wide Association Study(GWAS)data 1463 plasma proteins. Genetic associations with derived European Bioinformatics Institute (EBI) database, 1029 475,087 controls (dataset: ebi-a-gcst90018849). MR analysis was conducted assess association between risk developing cancer. Additionally, employed investigate whether identified gastric exhibited shared incidental variants. Finally, using extensive Finnish database R9 version, harmful effects target on explored through whole phenomenon (PheWAS). The results showed that 15 may be associated cancer, protein expected become There positive genetic levels 11 increased risk, while 4 an inverse (P < 0.05). Colocalization revealed PPCDC loci among examined, indicating serve as direct intervention phenotype wide studies 0.05) could certain side effects. Our research examined causal relationship shedding light targets. These findings have significant implications development diagnostic markers therapies GC, potentially improving patient outcomes survival rates. Future should validate these diverse populations explore clinical applications
Language: Английский
Citations
0
Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15
Published: Aug. 9, 2024
Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the spine and sacroiliac joints. Recent genetic studies suggest certain plasma proteins may play causal role in AS development. This study aims to identify characterize these using Mendelian randomization (MR) colocalization analyses.
Language: Английский
Citations
2
International Immunopharmacology, Journal Year: 2024, Volume and Issue: 142, P. 113027 - 113027
Published: Aug. 30, 2024
Language: Английский
Citations
1
Analytical and Bioanalytical Chemistry, Journal Year: 2024, Volume and Issue: unknown
Published: Sept. 10, 2024
Abstract The proteome serves as the primary basis for identifying targets treatment. This study conducted proteomic range two-sample Mendelian randomization (MR) analysis to pinpoint potential protein markers and treatment ankylosing spondylitis (AS). A total of 4907 data points on circulating expression were collected from a large-scale quantitative trait locus investigation involving 35,559 individuals. Using Finnish AS outcome, dataset comprised 166,144 individuals European ancestry (1462 cases 164,682 controls), causal relationships determined through bidirectional two samples. Proteins further validated identified single-cell analysis, certain cells showing enriched levels detected, possible optimized. Increased HERC5 predicted by genes was related increased risk, whereas remaining five proteins, AIF1, CREB3L4, MLN, MRPL55, SPAG11B, negatively correlated with risk. For each increase in gene-predicted levels, ORs 2.11 (95% CI 1.44–3.09) HERC5, 0.14 0.05–0.41) 0.48 0.34–0.68) 0.54 0.42–0.68) 0.23 0.13–0.38) 0.26 0.17–0.39) SPAG11B. hypothesis reverse relationship between these six proteins is not supported. Three protein-coding expressed both healthy control groups, while SPAG11B detected. are correlate MRPL55 therapeutic AS. advanced field employing novel combination MR identify approach enabled comprehensive understanding AS, which has been extensively explored previous studies. Graphical
Language: Английский
Citations
0
International Journal of Rheumatic Diseases, Journal Year: 2024, Volume and Issue: 27(11)
Published: Nov. 1, 2024
Previous research has revealed connections between ankylosing spondylitis (AS) and comorbid conditions. However, observational studies frequently encounter difficulties in establishing definitive causal links potential risk factors AS. In contrast, Mendelian randomization (MR) offers a more robust approach to exploring causality by leveraging the random allocation of alleles at birth, thereby minimizing confounding factors.
Language: Английский
Citations
0
Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)
Published: Nov. 24, 2024
Language: Английский
Citations
0