Genetic assessment of efficacy and safety profiles of coagulation cascade proteins identifies Factors II and XI as actionable anticoagulant targets DOI Creative Commons
Éloi Gagnon, Arnaud Girard, Jérôme Bourgault

et al.

European Heart Journal Open, Journal Year: 2024, Volume and Issue: 4(3)

Published: May 1, 2024

Abstract Aims Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in undergoing prolonged anticoagulation. New safer targets needed. Methods results To prioritize the strongest efficacy [venous thromboembolism (VTE) prevention] safety (low risk) profiles, we performed two-sample Mendelian randomization genetic colocalization. We leveraged three large-scale plasma protein data sets (deCODE as discovery set Fenland Atherosclerosis Risk Communities replication sets] one liver gene expression (Institut Universitaire de Cardiologie et Pneumologie Québec bariatric biobank) evaluate evidence for causal effect 26 coagulation cascade proteins on VTE from new genome-wide association meta-analysis 44 232 cases 847 152 controls, stroke subtypes, outcomes, parental lifespan an overall measure efficacy/safety ratio. A 1 SD genetically predicted reduction F2 levels was associated lower [odds ratio (OR) = 0.44, 95% confidence interval (CI) 0.38–0.51, P 2.6e−28] cardioembolic (OR 0.55, CI 0.39–0.76, 4.2e−04) but not 1.13, 0.93–1.36, 2.2e−01). Genetically F11 0.61, 0.58–0.64, 4.1e−85) 0.77, 0.69–0.86, 4.1e−06) 1.01, 0.95–1.08, 7.5e−01). These associations were concordant across hepatic well colocalization analyses. Conclusion provide strong that may represent safe efficacious therapeutic strokes without substantially increasing risk.

Language: Английский

Venous Thromboembolic Disease Genetics: From variants to function DOI Open Access
Mary Underwood,

Clint R. Bidlack,

Karl C. Desch

et al.

Journal of Thrombosis and Haemostasis, Journal Year: 2024, Volume and Issue: 22(9), P. 2393 - 2403

Published: Sept. 1, 2024

Language: Английский

Citations

1
Causal Relationships Between Retinal Diseases and Psychiatric Disorders Have Implications for Precision Psychiatry DOI
Zicheng Zhang, Siqi Bao,

Dongxue Yan

et al.

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 6, 2024

Language: Английский

Citations

1
Dynamic observation of circRNA and mRNA profiles in a rat model of deep vein thrombosis DOI Open Access

Baolan Sun,

Xi Cheng,

Mu Zhang

et al.

Experimental and Therapeutic Medicine, Journal Year: 2023, Volume and Issue: 26(4)

Published: Aug. 14, 2023

The goal of the present study was to identify different transcriptome expression profiles involved in pathogenesis deep vein thrombosis (DVT), and illustrate diagnostic therapeutic potential circular RNAs (circRNAs) mRNAs DVT progression. A Sprague‑Dawley rat model successfully established through stenosis method samples were sequenced at four time points (1, 6 12 h, 3 days after ligation) observe dynamic changes circRNAs during RNA sequencing used analyze circRNA mRNA profiles, associated functions pathways, blood rats points. In addition, Short Time Series Expression Miner (STEM) analysis performed explore temporal gene expression. Differential 1,680, 4,018, 3,724, 3,036 circRNAs, 400, 1,176, 373, 573 observed 1, 3‑day groups, respectively, compared with sham group (fold change >2.0 or <‑2.0, P<0.05). Functional enrichment indicated that differentially expressed following terms: Immune response, cell activation, stasis facilitated organelle, extracellular membrane‑bounded microparticle, oxygen transporter activity. STEM 366 profile 45 270 consistent thrombus Enrichment on 45. main Gene Ontology annotations chromosome segregation, mitotic sister chromatid cycle process, ligand‑dependent nuclear receptor transcription coactivator Pathway identified platelet‑associated pathway, immune‑associated inflammation‑relation pathway. According enriched ten candidate selected for reverse transcription‑quantitative PCR verification. nine all results. summary, are dynamically development. Dysregulated corresponding pathways may provide mechanistic insights into diagnosis treatment.

Language: Английский

Citations

1
Genetically predicted causal associations between 152 blood-related exposures and pan-cancer in the framework of prediction, prevention and personalized medicine: a study integrating Mendelian randomization and bioinformatics DOI Creative Commons

X. Tang,

Xinyu tian,

Jingjing Wu

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 3, 2024

Abstract Objective Blood serves as a powerful tool for monitoring the intricate landscape of cancer development. Previous studies have emerged, suggesting that hematologic indicators hold promise in predicting onset malignancy. This present investigation aims to delve into underlying causal connections between blood-related and pan-cancer, further elucidating potential impact diseases medication utilization reflected these on cancer, within realm predictive, preventive personalised medicine(PPPM). Methods To embark this scientific endeavor, we procured summary-level data from genome-wide association (GWAS) encompassing cis-eQTLs drug target genes, esteemed IEU OpenGWAS. Additionally, obtained GWAS encapsulating pan-cancer (consisting an impressive cohort 659,582 cases 12,186,911 controls), along with annotated by their correlation indicators, sources such OpenGWAS, UK Biobank, FinnGen, Biobank Japan. In order unravel direct associations well implications manifested initiated robust analysis employing two-sample Mendelian randomization(MR) method. Furthermore, utilizing bioinformatics methodologies, went explore effects genes pan-cancer. Results Preliminary findings our MR provided compelling evidence significant link exposures Drawing upon intriguing interplay observed blood pressure tumors, it was postulated hypertension (HTN) may offer notable advantages prevention colorectal adenocarcinoma (COAD), breast carcinoma (BRCA), esophageal (ESCA). Similarly, considering captivating relationship glucose, insulin levels, hypothesized closely diabetes mellitus (DM) could prove beneficial stomach (STAD) COAD. consonance connection discovered red cell counts, distribution width, supported notion anemia impart advantageous lung (LUAD). Remarkably, drawing deep vein thrombosis (DVT) surveillance DVT might valuable noted disparity risk various cancers, including lung, breast, colorectal, ovarian, prostate, pancreatic, consequent drugs aforementioned diseases. Among identified targets, carefully sifted through diligently analyzed three pivotal namely HMGCR, INSR, NR3C1, fostering prospect formulating novel, tumor-targeted therapeutics. However, yielded insufficient confirm any mediating glycated hemoglobin (HbA1c), hemoglobin-gastric, D-dimer, renin HTN, anemia, DVT, DM, Conclusions The study unveils web they manifest, utilization, all which significantly development cancer. Notably, pioneering biomarkers prediction is underscored, showcasing remarkable avenue advancing PPPM strategies field oncology. seminal beacon novel insight, engendering construction refined tailored approaches combat formidable challenge

Language: Английский

Citations

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Multiomic Screening Unravels the Immunometabolic Signatures and Drug Targets of Age-Related Macular Degeneration DOI Open Access

Xuehao Cui,

Qiuchen Zhao,

Bidesh Mahata

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 10, 2024

Abstract Age-related macular degeneration (AMD) is a significant cause of visual impairment in the aging population, with pathophysiology driven by complex interplay genetics, environmental influences and immunometabolic factors. These mechanisms, particular, those distinguishing between dry wet forms AMD, remain incompletely understood. Utilizing an integrated multiomic approach, incorporating Mendelian Randomization (MR) single-cell RNA sequencing (scRNA-seq), we have effectively delineated distinct pathways implicated development AMD. Our comprehensive analysis indicates that androgen-IL10RA-CD16+ monocyte axis could protect against We also identified several immune metabolic signatures unique to each AMD subtype, TNFα Notch signaling being central disease progression. Furthermore, our analysis, leveraging expression Quantitative Trait Loci (eQTLs) from Genotype-Tissue Expression (GTEx) project coupled MR, highlighted genes such as MTOR , PLA2G7 MAPKAPK3 ANGPTL1 ARNT prospective therapeutic targets. The potential these candidate was validated observations existing drug trial databases. robust genetic transcriptomic approach has promising directions for novel interventions, emphasizing significance tackling this important impairment.

Language: Английский

Citations

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Exploring the potential immune cells related to the heredity of acute pancreatitis based on Mendelian randomization study DOI Creative Commons

Shaojian Mo,

R J Ling,

Xuchen Zhao

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: May 24, 2024

Abstract Objective Through Mendelian randomization (MR) analysis method, exploring the potential innate immune cells associated with acute pancreatitis. Methods This study is based on publicly available genetic data, and selects SNP related to from cell data set after filtering a series of steps, matches as covariates for MR AP set.Five regression model methods, including Egger, weighted median (WME), inverse variance weighting (IVW), simple model, were used analyze causal relationship between these AP, verify diversity results. ity, heterogeneity robustness. Results found that 36 types phenotypes have relationships further correction revealed 4 CD14+ CD16- OR=0.93 (95%CI=0.899-0.970, P=0.00045), CD28 OR=0.87 (95%CI=0.801-0.937,P=0.00036),CD14+ (95%CI=0.897-0.971,P=0.00068),Mo MDSC OR=1.07 (95%CI=1.030-1.113, P=0.00049).The was assessed by IVW MR-Egger tests (P>0.05), indicating there no in study. After intercept test P>0.05, it indicated did not multiple effects results robust. The leave-one-out method removed SNPs one find had large impact association estimates, Conclusions Our increased levels CD14+CD16-, CD28, may be protective factors level Mo risk factor AP. These four are genetically

Language: Английский

Citations

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Targeted proteomics involved in cardiovascular health and heart rate variability in children with overweight/obesity DOI Creative Commons
Abel Plaza‐Florido, Marcos Olvera‐Rojas, Juan M. A. Alcántara

et al.

American Journal of Human Biology, Journal Year: 2024, Volume and Issue: 36(9)

Published: June 12, 2024

Abstract Background Children with overweight/obesity often exhibit alterations in their plasma protein profiles and reduced heart rate variability (HRV). Plasma proteomics is at the forefront of identifying biomarkers for various clinical conditions. We aimed to examine association between plasma‐targeted involved cardiovascular health resting vagal‐related HRV parameters children overweight/obesity. Methods Forty‐four (10.2 ± 1.1 years old; 52% boys) participated study. Olink's technology was used quantify 92 proteins health. measured using a monitor (Polar RS800CX). Four were derived time‐ frequency‐domain. Results Eight (KIM1, IgG Fc receptor II‐b, IDUA, BOC, IL1RL2, TNFRSF11A, VSIG2, TF) associated least one out four ( β values ranging from −0.188 0.288; all p < .05), while KIM1, BOC ≥ three parameters. Multiple hypothesis testing corrections did not reach statistical significance (false discovery [FDR >0.05]). Conclusion Plasma‐targeted suggested novel Future studies larger cohorts longitudinal designs should confirm our findings potential implications.

Language: Английский

Citations

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Causal role of blood metabolites in HER-positive and HER-negative breast cancer: a Mendelian randomization (MR) study DOI Creative Commons
Jian Yue, Huiying Fang, Sheng Chen

et al.

Aging, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 2, 2024

Background: Previous studies provide evidence that in vivo metabolites are associated with breast cancer (BC). However, the causal relationship between blood and BC remains unclear. Method: Comprehensive two-sample Mendelian randomization analysis was conducted to determine association 1400 publicly available genetic data on metabolic factors human epidermal growth factor receptor positive (HER+) or HER- this study. Result: Epiandrosterone sulfate levels (OR = 1.07, 95% CI 1.02 ~ 1.10, p 0.0013), 5alpha-androstan-3beta,17beta-diol monosulfate (2) 1.03 1.12, 0.0012), glycohyocholate 0.85, 0.77 0.93, 0.0007) etiocholanolone glucuronide 1.05 1.20, 0.0013) were causally correlated HER+ BC. 5 BC: Vanillic acid glycine 1.14, 1.06 1.22, 0.0003), Thyroxine 1.26, 1.11 1.44, 0.0004), 1-palmitoyl-2-linoleoyl-GPI (16:0/18:2) 0.86, 0.79 0.94, 0.0010), N-acetylphenylalanine 1.19, Glucose-to-mannose ratio 1.15, 1.24, 0.0008). Two common related identified: Gamma-glutamyl glutamate X-12849 levels. Conclusions: Our study has respectively demonstrated connection by means, thereby offering opportunities for therapeutic targets.

Language: Английский

Citations

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Exploring genetic associations in systemic lupus erythematosus through Mendelian randomization: implications for novel biomarkers and therapeutic targets DOI
Qi Liu, Yuyang Liu,

Hui Feng

et al.

Clinical Rheumatology, Journal Year: 2024, Volume and Issue: 44(1), P. 193 - 205

Published: Aug. 10, 2024

Language: Английский

Citations

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The role of 1400 plasma metabolites in gastric cancer: A bidirectional Mendelian randomization study and metabolic pathway analysis DOI Creative Commons
Yihao He, Peiyuan Cai, Anla Hu

et al.

Medicine, Journal Year: 2024, Volume and Issue: 103(48), P. e40612 - e40612

Published: Nov. 29, 2024

While observational studies have illustrated correlations between plasma metabolites and gastric cancer (GC), the causal association 2 is still unclear. Our study aims to delineate bidirectional relationship GC find potential metabolic pathways. We undertook a 2-sample Mendelian randomization (MR) analysis investigate relationship, specificity, direction of 1400 GC. The GWAS data for was obtained from cohort 8299 European individuals. And GC’s FinnGen Consortium with 2384 individuals, catalog 1029 ancestry cases validation. Causal estimates were primarily calculated by inverse-variance weighted (IVW) method. To ensure robustness, we performed comprehensive sensitivity analyses assess heterogeneity address concerns regarding horizontal pleiotropy. validated forward another database implemented meta-analysis. Furthermore, conducted enrichment pathway these using MetaboAnalyst5.0/6.0 Kyoto Encyclopedia Genes Genomes. All statistical carried out R software. Metabolites like 2s, 3R-dihydroxybutyrate, 4-acetamidobutanoate, ferulic acid 4-sulfate methyl indole-3-acetate proven positively linked development Asparagine, glucose maltose ratio, glycohyocholate, Gulonate levels, linoleoyl ethanolamide Spermidine (N(1) + N(8))-acetylspermidine ratio be negatively associated Moreover, linoleic , histidine, glutamine, bilirubin Succinate proline found potentially our identified 18 significant pathways, including Arginine metabolism ( P < .009) Valine, leucine, isoleucine biosynthesis .031). findings offer evidence supporting casual relations multiple These may great future application biomarkers in screening clinical prevention strategies.

Language: Английский

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