WGCNA-ML-MR integration: uncovering immune-related genes in prostate cancer DOI Creative Commons

Jing Lv,

Yuhua Zhou,

Shengkai Jin

et al.

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: April 7, 2025

Prostate cancer is one of the most common tumors in men, with its incidence and mortality rates continuing to rise year by year. Prostate-specific antigen (PSA) commonly used screening indicator, but lack specificity leads overdiagnosis overtreatment. Therefore, identifying new biomarkers related prostate crucial for early diagnosis treatment cancer. This study utilized datasets from Gene Expression Omnibus (GEO) screen differentially expressed genes (DEGs) employed Weighted Co-expression Network Analysis (WGCNA) identify driver highly associated within modules. The intersection was taken, Kyoto Encyclopedia Genes Genomes (KEGG) Ontology (GO) enrichment analyses were performed. Furthermore, a machine learning algorithm core construct diagnostic model, which then validated an external validation dataset. correlation between immune cell infiltration analyzed, Mendelian randomization (MR) analysis conducted closely identified six biomarkers: SLC14A1, ARHGEF38, NEFH, MSMB, KRT23, KRT15. MR demonstrated that MSMB may be important protective factor In q-PCR experiments on tumor tissues adjacent non-cancerous patients, it found that: compared tissues, expression level ARHGEF38 significantly increased, while levels KRT15 decreased. To further validate these findings at protein level, we Western blot analysis, corroborated results, demonstrating consistent patterns all biomarkers. IHC results confirmed markedly reduced. Our reveals are potential cancer, among play role

Language: Английский

Insights Into Causal Effects of Genetically Proxied Lipids and Lipid‐Modifying Drug Targets on Cardiometabolic Diseases DOI Creative Commons
Liwan Fu, Qin Liu, Hong Cheng

et al.

Journal of the American Heart Association, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Background The differential impact of serum lipids and their targets for lipid modification on cardiometabolic disease risk is debated. This study used Mendelian randomization to investigate the causal relationships underlying mechanisms. Methods Genetic variants related profiles were sourced from Global Lipids Genetics Consortium. Summary data 10 diseases compiled both discovery replication sets. Expression quantitative trait loci relevant tissues employed evaluate significant lipid‐modifying drug targets. Comprehensive analyses including colocalization, mediation, bioinformatics conducted validate results potential mediators Results Significant associations identified between lipids, targets, various diseases. Notably, genetic enhancement LPL (lipoprotein lipase) was linked reduced risks myocardial infarction (odds ratio [OR] 1 , 0.65 [95% CI, 0.57–0.75], P =2.60×10 −9 ; OR 2 0.59 0.49–0.72], =1.52×10 −7 ), ischemic heart (OR 0.968 0.962–0.975], =5.50×10 −23 0.64 0.55–0.73], =1.72×10 −10 coronary 0.980 0.975–0.985], =3.63×10 −14 0.54–0.75], =6.62×10 −8 ) across Moreover, strong colocalization expression in blood subcutaneous adipose tissue with (OR, 0.918 0.872–0.967], =1.24×10 −3 PP.H4, 0.99) 0.991 0.983–0.999], =0.041; PP.H4=0.92). Glucose levels pressure as total effect outcomes. Conclusions substantiates role specific diseases, highlighting a potent target. effects are suggested be influenced by changes glucose pressure, providing insights into its mechanism action.

Language: Английский

Citations

2
Diabetes as a risk factor for MASH progression DOI Creative Commons

Sofiya Gancheva,

Michael Roden, Laurent Castéra

et al.

Diabetes Research and Clinical Practice, Journal Year: 2024, Volume and Issue: 217, P. 111846 - 111846

Published: Sept. 6, 2024

Language: Английский

Citations

11
Causal association of plasma circulating metabolites with nephritis: a Mendelian randomization study DOI Creative Commons

Fengling Shao,

Yingling Yao,

Dunchu Weng

et al.

Frontiers in Nutrition, Journal Year: 2024, Volume and Issue: 11

Published: May 3, 2024

Nephritis is a pivotal catalyst in chronic kidney disease (CKD) progression. Although epidemiological studies have explored the impact of plasma circulating metabolites and drugs on nephritis, few harnessed genetic methodologies to establish causal relationships. Through Mendelian randomization (MR) two substantial cohorts, spanning large sample sizes, we evaluated over 100 263 discern their effects nephritis risk. The primary analytical tool was inverse variance weighted (IVW) analysis. Our bioinformatic scrutiny GSE115857 (IgA nephropathy, 86 samples) GSE72326 (lupus 238 unveiled anomalies lipid metabolism immunological characteristics nephritis. Thorough sensitivity analyses (MR-Egger, MR-PRESSO, leave-one-out analysis) were undertaken verify instrumental variables' (IVs) assumptions. Unique lipoprotein-related molecules established links with diverse subtypes. Notably, docosahexaenoic acid (DHA) emerged as protective factor for acute tubulointerstitial (ATIN) (OR1 = 0.84, [95% CI 0.78-0.90], p1 0.013; OR2 0.89, 0.82-0.97], p2 0.007). Conversely, multivitamin supplementation minus minerals notably increased risk ATIN (OR 31.25, 9.23-105.85], p 0.004). Reduced α-linolenic (ALA) levels due lipid-lowering linked both 4.88, 3.52-6.77], < 0.001) (TIN) 7.52, 2.78-20.30], 0.042). While non-renal drug indivina showed promise TIN treatment, use digoxin, hydroxocobalamin, liothyronine elevated (CTIN). Transcriptome analysis affirmed that anomalous immune infiltration are characteristic IgA nephropathy lupus robustness these reinforced by tests, indicating no signs pleiotropy. Dyslipidemia significantly contributes development. Strategies aimed at reducing low-density lipoprotein or ALA may enhance efficacy existing regimens treatment. Renal functional status should also be judiciously considered regard nonrenal medications.

Language: Английский

Citations

9
Body Fat Distribution and Ectopic Fat Accumulation as Mediator of Diabetogenic Action of Lipid-Modifying Drugs DOI
Yuanlong Hu, Xinhai Cui,

Mengkai Lu

et al.

Mayo Clinic Proceedings, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

1
Lipids, lipid-modifying drug target genes and migraine: a Mendelian randomization study DOI Creative Commons
Yaodan Bi, Yingchao Zhu, Shuai Tang

et al.

The Journal of Headache and Pain, Journal Year: 2023, Volume and Issue: 24(1)

Published: Aug. 18, 2023

Migraine, a prevalent headache disorder with unclear mechanisms and limited treatments, may be influenced by dyslipidemia genetic factors. Statins emerging lipid-modifying agents show potential but lack evidence for migraine management. Mendelian Randomization analysis offers insights into causal relationships therapeutic targets. This study aims to explore genetically predicted lipid traits, drug targets, their association risk.We conducted randomization (MR) analyses utilizing variants associated traits in genes encoding the protein targets of various classes lipid-lowering drugs. The specific investigated included HMGCR, PCSK9, NPC1L1, ABCG5/ABCG8, LDLR, LPL, ANGPTL3, APOB, CETP, APOC3. To determine effects on risk, we meta-analyzed MR estimates regional using data from two large sample sets. were weighted based associations such as low-density lipoprotein cholesterol (LDL-C), high-density (HDL-C), Apolipoprotein A1, B. obtain weights, utilized genetics consortia. For that exhibited suggestive significance, further employed expression quantitative trait locus (eQTL) data. Additionally, performed colocalization assess confounding.The use proxies HMGCR inhibition demonstrated significant decreased risk FinnGen dataset (OR = 0.64, 95% CI: 0.46-0.88, p 0.0006) nearly Choquet 0.78, 0.60-1.01, 0.06). When pooling estimates, overall effect size showed reduced 0.73, 0.60-0.89, 0.0016). Similarly, mimicry LPL enhancement was lower 0.82, 0.69-0.96, 0.01) 0.91, 0.83-0.99, 0.03). Pooling consistent 0.89, 0.83-0.96, 0.002). Sensitivity yielded no statistically bias arising pleiotropy or confounding.In study, it observed among 10 investigated, risk. These findings indicate have serve candidate treatment prevention migraines.

Language: Английский

Citations

21
Drug development advances in human genetics‐based targets DOI Creative Commons
X. Zhang,

Wenjun Yu,

Yan Li

et al.

MedComm, Journal Year: 2024, Volume and Issue: 5(2)

Published: Feb. 1, 2024

Drug development is a long and costly process, with high degree of uncertainty from the identification drug target to its market launch. Targeted drugs supported by human genetic evidence are expected enter phase II/III clinical trials or be approved for marketing more quickly, speeding up process. Currently, data technologies such as genome-wide association studies (GWAS), whole-exome sequencing (WES), whole-genome (WGS) have identified validated many potential molecular targets associated diseases. This review describes structure, biology, genetics-based beneficial loss-of-function (LOF) mutation (target mutations that reduce disease incidence) over past decade. The feasibility eight LOF (PCSK9, ANGPTL3, ASGR1, HSD17B13, KHK, CIDEB, GPR75, INHBE) discovery mainly emphasized, their research prospects challenges discussed. In conclusion, we expect this will inspire researchers use genetics genomics support novel therapeutic direction development, which contribute new repurposing.

Language: Английский

Citations

8
Exploring the interplay of gut microbiota, inflammation, and LDL-cholesterol: a multiomics Mendelian randomization analysis of their causal relationship in acute pancreatitis and non-alcoholic fatty liver disease DOI Creative Commons
Congzhi Yan,

Jingxia Bao,

Jinji Jin

et al.

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 19, 2024

Acute pancreatitis and non-alcoholic fatty liver disease are both serious diseases in the digestive system. The pathogenesis of is extremely complex closely it related to gut microbiota, inflammation, blood fat. There a close relationship between microbiota lipids.

Language: Английский

Citations

7
SharePro: an accurate and efficient genetic colocalization method accounting for multiple causal signals DOI Creative Commons
Wenmin Zhang, Tianyuan Lu, Robert Sladek

et al.

Bioinformatics, Journal Year: 2024, Volume and Issue: 40(5)

Published: April 29, 2024

Colocalization analysis is commonly used to assess whether two or more traits share the same genetic signals identified in genome-wide association studies (GWAS), and important for prioritizing targets functional follow-up of GWAS results. Existing colocalization methods can have suboptimal performance when there are multiple causal variants one genomic locus.

Language: Английский

Citations

7
The landscape of the methodology in drug repurposing using human genomic data: a systematic review DOI Creative Commons
Lijuan Wang, Ying Lü, Doudou Li

et al.

Briefings in Bioinformatics, Journal Year: 2024, Volume and Issue: 25(2)

Published: Jan. 22, 2024

Abstract The process of drug development is expensive and time-consuming. In contrast, repurposing can be introduced to clinical practice more quickly at a reduced cost. Over the last decade, there has been significant expansion large biobanks that link genomic data electronic health record data, public availability various databases containing biological information rapid novel methodologies algorithms in integrating different sources data. This review aims provide thorough summary strategies utilize seek drug-repositioning opportunities. We searched MEDLINE EMBASE identify eligible studies up until 1 May 2023, with total 102 finally included after two-step parallel screening. summarized commonly used for repurposing, including Mendelian randomization, multi-omic-based network-based illustrated each strategy examples, as well implemented. By leveraging existing knowledge infrastructure expedite discovery reduce costs, potentially identifies new therapeutic uses approved drugs efficient targeted manner. However, technical challenges when types biased or incomplete understanding interactions are important hindrances cannot disregarded pursuit identifying applications. offers an overview methodologies, providing valuable insights guiding future directions advancing studies.

Language: Английский

Citations

6
Bruceine A alleviates alcoholic liver disease by inhibiting AIM2 inflammasome activation via activating FXR DOI
Li Lin,

Shuai Xu,

Wenyu Wang

et al.

Phytomedicine, Journal Year: 2024, Volume and Issue: 130, P. 155693 - 155693

Published: May 7, 2024

Language: Английский

Citations

6