Plasma circulating microRNAs associated with blood-based immune markers: a population-based study DOI Creative Commons
Samantha Leonard, Irma Karabegović, M. Arfan Ikram

et al.

Clinical & Experimental Immunology, Journal Year: 2023, Volume and Issue: 215(3), P. 251 - 260

Published: Nov. 9, 2023

Abstract MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression and different immune-related pathways. There is a great interest in identifying miRNAs involved immune cell development function to elucidate the biological mechanisms underlying system, its regulation, disease. In this study, we aimed investigate association of circulating with blood compositions blood-based markers. Circulating levels 2083 were measured by RNA-sequencing plasma samples 1999 participants from population-based Rotterdam Study collected between 2002 2005. Full count measurements performed for absolute granulocyte, platelet, lymphocyte, monocyte, white, red counts. Multivariate analyses test We evaluated overlap predicted target genes candidate associated markers determining response First, principal component regression analysis showed significantly cell, lymphocyte Second, cross-sectional identified 210 (P < 2.82 × 10−5) neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte (PLR), systemic immune-inflammation index. Further genetic look-ups seven (miR-1233-3p, miR-149-3p, miR-150-5p, miR-342-3p, miR-34b-3p, miR-4644, miR-7106-5p) also previously linked NLR PLR Collectively, our study suggests several innate adaptive systems, providing insight into pathogenesis diseases paving way future clinical applications.

Language: Английский

Short Chain Fatty Acid Metabolism in Relation to Gut Microbiota and Genetic Variability DOI Open Access
Guilherme Ramos Meyers, Hanen Samouda, Torsten Bohn

et al.

Nutrients, Journal Year: 2022, Volume and Issue: 14(24), P. 5361 - 5361

Published: Dec. 16, 2022

It is widely accepted that the gut microbiota plays a significant role in modulating inflammatory and immune responses of their host. In recent years, host-microbiota interface has gained relevance understanding development many non-communicable chronic conditions, including cardiovascular disease, cancer, autoimmunity neurodegeneration. Importantly, dietary fibre (DF) associated compounds digested by resulting metabolites, especially short-chain fatty acids (SCFA), were significantly with health beneficial effects, such as via proposed anti-inflammatory mechanisms. However, SCFA metabolic pathways are not fully understood. Major steps include production microbiota, uptake colonic epithelium, first-pass effects at liver, followed biodistribution metabolism host's cellular level. As patterns do affect all individuals equally, host genetic makeup may play fate these addition to other factors might influence age, birth through caesarean, medication intake, alcohol tobacco consumption, pathogen exposure physical activity. this article, we review DF, from intake intracellular fibre-derived products, identify possible sources inter-individual variability related variation. Such be indicative phenotypic flexibility response diet, predictive long-term adaptations factors, maladaptation tissue damage, which develop into disease specific predispositions, thus allowing for better prediction potential following personalized intervention DF.

Language: Английский

Citations

72
Human germline heterozygous gain-of-functionSTAT6variants cause severe allergic disease DOI Creative Commons
Mehul Sharma, Daniel Leung, Mana Momenilandi

et al.

The Journal of Experimental Medicine, Journal Year: 2023, Volume and Issue: 220(5)

Published: March 8, 2023

STAT6 (signal transducer and activator of transcription 6) is a factor that plays central role in the pathophysiology allergic inflammation. We have identified 16 patients from 10 families spanning three continents with profound phenotype early-life onset immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All carried monoallelic rare variants functional studies established their gain-of-function (GOF) sustained phosphorylation, increased target gene expression, TH2 skewing. Precision treatment anti–IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations immunological biomarkers. This study identifies heterozygous GOF as novel disorder. anticipate our discovery multiple kindreds germline will facilitate recognition more affected individuals full definition this new primary

Language: Английский

Citations

64
Pilot work of the 10K Chinese People Genomic Diversity Project along the Silk Road suggests a complex east-west admixture landscape and biological adaptations DOI
Guanglin He,

Hongbing Yao,

Shuhan Duan

et al.

Science China Life Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Language: Английский

Citations

4
Variant to function mapping at single-cell resolution through network propagation DOI Creative Commons
Fulong Yu, Liam D. Cato, Chen Weng

et al.

Nature Biotechnology, Journal Year: 2022, Volume and Issue: 40(11), P. 1644 - 1653

Published: June 6, 2022

Abstract Genome-wide association studies in combination with single-cell genomic atlases can provide insights into the mechanisms of disease-causal genetic variation. However, identification disease-relevant or trait-relevant cell types, states and trajectories is often hampered by sparsity noise, particularly analysis epigenomic data. To overcome these challenges, we present SCAVENGE, a computational algorithm that uses network propagation to map causal variants their relevant cellular context at resolution. We demonstrate how SCAVENGE help identify key biological underlying human variation, applying method blood traits distinct stages hematopoiesis, monocyte subsets increase risk for severe Coronavirus Disease 2019 (COVID-19) intermediate lymphocyte developmental predispose acute leukemia. Our approach not only provides framework enabling variant-to-function resolution but also suggests more general strategy maximizing inferences be made using

Language: Английский

Citations

55
Multitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis DOI Creative Commons
Younghun Han, Jinyoung Byun, Catherine Zhu

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 24, 2023

Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical epidemiological traits estimate the genetic contribution each trait correlations between identify new lead risk-associated loci. We identified seven loci have not been previously reported one independent variant in locus. Functional annotation fine-mapping nominated several potential susceptibility genes such as MANBA IRF5. Network-based silico drug efficacy screening provided candidate agents for further study pharmacological effect PSC.

Language: Английский

Citations

18
Fast and flexible joint fine-mapping of multiple traits via the Sum of Single Effects model DOI Creative Commons
Yuxin Zou, Peter Carbonetto,

Dongyue Xie

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 14, 2023

Abstract We introduce mvSuSiE, a multi-trait fine-mapping method for identifying putative causal variants from genetic association data (individual-level or summary data). mvSuSiE learns patterns of shared effects data, and exploits these to improve power identify SNPs. Comparisons on simulated show that is competitive in speed, precision with existing methods, uniformly improves single-trait (SuSiE) each trait separately. applied jointly fine-map 16 blood cell traits using the UK Biobank. By analyzing modeling heterogeneous effect sharing patterns, we discovered much larger number SNPs (>3,000) compared fine-mapping, narrower credible sets. also more comprehensively characterized ways which affect one traits; 68% showed significant than type.

Language: Английский

Citations

17
The Physiological and Pathological Role of Acyl-CoA Oxidation DOI Open Access
Sylwia Szrok-Jurga, Aleksandra Czumaj, Jacek Turyn

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14857 - 14857

Published: Oct. 3, 2023

Fatty acid metabolism, including β-oxidation (βOX), plays an important role in human physiology and pathology. βOX is essential process the energy metabolism of most cells. Moreover, also source acetyl-CoA, substrate for (a) ketone bodies synthesis, (b) cholesterol (c) phase II detoxication, (d) protein acetylation, synthesis many other compounds, N-acetylglutamate—an regulator urea synthesis. This review describes current knowledge on importance mitochondrial peroxisomal various organs, liver, heart, kidney, lung, gastrointestinal tract, peripheral white blood cells, In addition, diseases associated with a disturbance fatty oxidation (FAO) alimentary organs or cells are presented. Special attention was paid to abnormalities FAO cancer caused by mutations gene-encoding enzymes involved FAO. Finally, issues related α- ω- discussed.

Language: Английский

Citations

16
Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing DOI Creative Commons
Lourdes Ortiz‐Fernández, Elio G. Carmona, Martin Kerick

et al.

Annals of the Rheumatic Diseases, Journal Year: 2023, Volume and Issue: 82(6), P. 837 - 847

Published: Feb. 16, 2023

Objectives The number of susceptibility loci currently associated with vasculitis is lower than in other immune-mediated diseases due part to small cohort sizes, a consequence the low prevalence vasculitides. This study aimed identify new genetic risk for main systemic vasculitides through comprehensive analysis their overlap. Methods Genome-wide data from 8467 patients any forms and 29 795 healthy controls were meta-analysed using ASSET. Pleiotropic variants functionally annotated linked target genes. Prioritised genes queried DrugBank potentially repositionable drugs treatment vasculitis. Results Sixteen independently two or more vasculitides, 15 them representing shared loci. Two these pleiotropic signals, located close CTLA4 CPLX1 , emerged as novel Most polymorphisms appeared affect by regulating gene expression. In this regard, some common potential causal prioritised based on functional annotation, including RNF145 IL12B IL5 IRF1 IFNGR1 PTK2B TRIM35 EGR2 ETS2 each which has key roles inflammation. addition, drug repositioning showed that several drugs, abatacept ustekinumab, could be repurposed management analysed Conclusions We identified impact pinpointed genes, represent promising targets

Language: Английский

Citations

15
The genetic risk of acute lymphoblastic leukemia and its implications for children of Latin American origin DOI Creative Commons
Adam J. de Smith, Silvia Jiménez‐Morales, Juan Manuel Mejı́a-Aranguré

et al.

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 13

Published: Jan. 9, 2024

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and disproportionately affects children of Hispanic/Latino ethnicity United States, who have highest incidence disease compared with other racial/ethnic groups. Incidence childhood ALL similarly high several Latin American countries, notably Mexico, concern rising some populations that may further widen this disparity. Prior studies implicated germline genetic variants increased risk among children. In review, we describe known disparities as well patient outcomes affect across Americas, focus on role variation Indigenous ancestry etiology these disparities. Finally, discuss future avenues research to our understanding causes origin, which will be required for precision prevention efforts.

Language: Английский

Citations

5
Ribosomal DNA copy number variation associates with hematological profiles and renal function in the UK Biobank DOI Creative Commons
Francisco Rodríguez-Algarra, David M. Evans, Vardhman K. Rakyan

et al.

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(6), P. 100562 - 100562

Published: May 14, 2024

The phenotypic impact of genetic variation repetitive features in the human genome is currently understudied. One such feature multi-copy 47S ribosomal DNA (rDNA) that codes for rRNA components ribosome. Here, we present an analysis rDNA copy number (CN) UK Biobank (UKB). From first release UKB whole-genome sequencing (WGS) data, a discovery White British individuals reveals CN associates with altered counts specific blood cell subtypes, as neutrophils, and estimated glomerular filtration rate, marker kidney function. Similar trends are observed other ancestries. A range analyses argue against reverse causality or common confounder effects, all core results replicate second WGS release. Our work demonstrates influence on trait variance humans.

Language: Английский

Citations

5