EBioMedicine最新文献

Background: There are important inter-relationships between miRNAs and metabolites: alterations in miRNA expression can be induced by various metabolic stimuli, and miRNAs play a regulatory role in numerous cellular processes, impacting metabolism. While both specific miRNAs and metabolites have been identified for their role in childhood asthma, there has been no global assessment of the combined effect of miRNAs and the metabolome in childhood asthma.

Methods: We performed miRNAome-metabolome-wide association studies ('miR-metabo-WAS') in two childhood cohorts of asthma to evaluate the contemporaneous and persistent miRNA-metabolite associations: 1) Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (N = 1121); 2) the Childhood Asthma Management Program (CAMP) (N_Baseline = 312 and N_{End of trial} = 454). We conducted a meta-analysis of the two cohorts to identify common contemporaneous associations between CAMP and GACRS (false-discovery rate (FDR) = 0.05). We assessed persistent miRNA-metabolome associations using baseline miRNAs and metabolomic profiling in CAMP at the end of the trial. The relation between miRNAs, metabolites and clinical phenotypes, including airway hyper-responsiveness (AHR), peripheral blood eosinophilia, and airflow obstruction, were then assessed via. Mediation analysis with 1000 bootstraps at an FDR significance level of 0.05.

Findings: The meta-analysis yielded a total of 369 significant contemporaneous associations, involving 133 miRNAs and 60 metabolites. We identified 13 central hub metabolites (taurine, 12,13-diHOME, sebacate, 9-cis-retinoic acid, azelate, asparagine, C5:1 carnitine, cortisol, 3-methyladipate, inosine, NMMA, glycine, and Pyroglutamic acid) and four hub miRNAs (hsa-miR-186-5p, hsa-miR-143-3p, hsa-miR-192-5p, and hsa-miR-223-3p). Nine of these associations, between eight miRNAs and eight metabolites, were persistent in CAMP from baseline to the end of trial. Finally, five central hub metabolites (9-cis-retinoic acid, taurine, sebacate, azelate, and 12,13-diHOME) were identified as primary mediators in over 100 significant indirect miRNA-metabolite associations, with a collective influence on peripheral blood eosinophilia, AHR, and airflow obstruction.

Interpretation: The robust association between miRNAs and metabolites, along with the substantial indirect impact of miRNAs via 5 hub metabolites on multiple clinical asthma metrics, suggests important integrated effects of miRNAs and metabolites on asthma. These findings imply that the indirect regulation of metabolism and cellular functions by miRNA influences Th2 inflammation, AHR, and airflow obstruction in childhood asthma.

Funding: Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).

Background: A better understanding of body-brain links may provide insights on targets for preventing cognitive decline. The aim was to explore associations of body composition with neuroimaging biomarkers and cognitive function among dementia-free 70-year-olds.

Methods: Dual-energy X-ray absorptiometry body composition measures in relation to neuroimaging measures of cortical thickness, hippocampal volume, small vessel disease, predicted brain age, and cognitive performance were explored in a cross-sectional study of 674 dementia-free 70-year-olds from the Swedish Gothenburg H70 Birth Cohort study. Linear or ordinal regression analyses were performed.

Findings: Higher quantity of muscle mass was associated with lower predicted brain age (β: -0.31 [95% CI: -0.45, -0.16], p: 0.00013). Those with normal level muscle mass (>7.0 men, >5.5 women kg/height m²) had overall thicker cortex (β: 0.043 [95% CI: 0.023, 0.064], p: 0.00016), thicker cortex in Alzheimer's disease signature regions (β: 0.051 [95% CI: 0.025, 0.076], p: 0.00040), and larger hippocampal volume (β: 111.52 [95% CI: 25.28, 197.75], p: 0.030) compared to those with sarcopenic level muscle mass. Higher accumulation of visceral fat was associated with overall thinner cortex (β: -0.017 [95% CI: -0.028, -0.005], p: 0.024). Faster gait speed and higher handgrip strength were associated with indicators of better brain health.

Interpretation: Improving muscle mass fitness and lower visceral fat may be beneficial for brain health. Intervention studies are needed to confirm that targeting body composition can promote healthy brain ageing and reduce the risk of cognitive impairment among older adults.

Funding: The Swedish Research Council, Hjärnfonden, and Alzheimerfonden.

Background: Determining spatial relationships between diseases and the exposome is limited by available methodologies. aPEER (algorithm for Projection of Exposome and Epidemiological Relationships) uses machine learning (ML) and network analysis to find spatial relationships between diseases and the exposome in the United States.

Methods: Using aPEER we examined the relationship between 12 chronic diseases and 186 pollutants. PCA, K-means clustering, and map projection produced clusters of counties derived from pollutants, and the Jaccard correlation between these clusters with chronic disease geography (defined as groups of counties with high chronic disease prevalence rates) was calculated. Disease-pollution correlation matrices were used together with network analysis to identify the strongest disease-pollution relationships. Results were compared to LISA, Moran's I, univariate, elastic net, and random forest regression.

Findings: aPEER produced 68,820 human interpretable maps with distinct pollution-derived regions, and acetaldehyde/benzo(a)pyrene was found to be strongly associated with hypertension (J = 0.5316, p = 3.89 × 10^-208), stroke (J = 0.4517, p = 1.15 × 10^-127), and diabetes mellitus (J = 0.4425, p = 2.34 × 10^-127); formaldehyde/glycol ethers with COPD (J = 0.4545, p = 8.27 × 10^-131); and acetaldehyde/formaldehyde with stroke mortality (J = 0.4445, p = 4.28 × 10^-125). Methanol, acetaldehyde, and formaldehyde formed distinct regions in the southeast United States (which correlated with both the Stroke and Diabetes Belts) which were strongly associated with multiple chronic diseases. Pollutants predicted chronic disease geography with similar or superior areas under the curve compared to SDOH and preventive healthcare models (determined with random forest and elastic net methods). Conventional geospatial analysis methods did not identify these geospatial relationships, highlighting aPEER's utility.

Interpretation: aPEER identified a pollution-defined geographical region associated with chronic disease, highlighting the role of aPEER in epidemiological and geospatial analysis, and exposomics in understanding chronic disease geography.

Funding: This work was primarily funded by the BPHC, NHLBI (R03 HL157890) and the CDC, and this work was funded in part by grants from the NIH (U01 HG007691, R01 HL155107, and HL166137), the American Heart Association (AHA24MERIT1185447), and the EU (HorizonHealth 2021 101057619) to JL.

Background: Synuclein pathology in neurodegenerative diseases, such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), begins years before motor or cognitive symptoms arise. Alpha-Synuclein seed amplification assays (α-syn SAA) may detect aggregated synuclein before symptoms occur.

Methods: Data from the Parkinson Associated Risk Syndrome Study (PARS) have shown that individuals with hyposmia, without motor or cognitive symptoms, are enriched for dopamine transporter imaging (DAT) deficit and are at high risk to develop clinical parkinsonism or related synucleinopathies. α-syn aggregates in CSF were measured in 100 PARS participants using α-syn SAA.

Findings: CSF α-syn SAA was positive in 48% (34/71) of hyposmic compared to 4% (1/25) of normosmic PARS participants (relative risk, 11.97; 95% CI, 1.73-82.95). Among α-syn SAA positive hyposmics 65% remained without a DAT deficit for up to four years follow-up. α-syn SAA positive hyposmics were at higher risk of having DAT deficit (12 of 34) compared to α-syn SAA negative hyposmics (4 of 37; relative risk, 3.26; 95% CI, 1.16-9.16), and 7 of 12 α-syn SAA positive hyposmics with DAT deficit developed symptoms consistent with synucleinopathy.

Interpretation: Approximately fifty percent of PARS participants with hyposmia, easily detected using simple, widely available tests, have synuclein pathology detected by α-syn SAA. Approximately, one third (12 of 34) α-syn SAA positive hyposmic individuals also demonstrate DAT deficit. This study suggests a framework to investigate screening paradigms for synuclein pathology that could lead to design of therapeutic prevention studies in individuals without symptoms.

Funding: The study was funded by the U.S. Department of Defense, the Helen Graham Foundation and the Michael J. Fox Foundation for Parkinson's Research.

Background: The ovarian cancer (OC) preclinical detectable phase (PCDP), defined as the interval during which cancer is detectable prior to clinical diagnosis, remains poorly characterised. We report exploratory analyses from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

Methods: In UKCTOCS between Apr-2001 and Sep-2005, 101,314 postmenopausal women were randomised to no screening (NS) and 50,625 to annual multimodal screening (MMS) (until Dec-2011) using serum CA-125 interpreted by the Risk of Ovarian Cancer Algorithm (ROCA). All provided a baseline blood sample. Women with invasive epithelial OC diagnosed between randomisation and trial censorship (Dec-2014) in the MMS and NS arms with two or more CA-125 measurements, including one within two years of diagnosis were included. OC-free women (2:1 to cases) from the MMS arm provided information on baseline CA-125 distribution. CA-125 measurements were obtained from MMS results, secondary analysis of baseline samples, and medical records. PCDP duration and in-vivo tumour doubling time were estimated using the change-point model underlying ROCA. Early-stage (Stage I and II) PCDP was estimated from a Bayesian model for the probability of early stage given a CA-125 measurement.

Findings: Of 541 women (2371 CA-125 measurements) with high-grade serous cancer (HGSC), 93% (504/541) secreted CA-125 into the circulation. Median CA-125 PCDP duration for clinically-diagnosed HGSC was 15.2 (IQR 13.1-16.9, 95% IPR 9.6-21.8) months, of which 11.9 (IQR 10.5-13.1, 95% IPR 7.5-16.5) months was in early stage. The median HGSC in-vivo tumour doubling time for cancers secreting CA-125 was 2.9 (IQR 2.3-3.7, 95% IPR 1.5-7.6) months.

Interpretation: We report a comprehensive characterisation of the OC CA-125 PCDP. The 12-month window for early-stage detection and short tumour doubling time of HGSC provide a benchmark for researchers evaluating novel screening approaches including need to reduce diagnostic workup interval. Equally the findings provide urgent impetus for clinicians to reduce intervals from presentation to treatment onset.

Funding: NCI Early Detection Research Network, Concord (MA) Detect Ovarian Cancer Early Fund, MRC Clinical Trials Unit at UCL Core Funding.

Background: The widespread and evolution of RNA viruses, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), highlights the importance of fast identification of virus subtypes, particularly in non-laboratory settings. Rapid and inexpensive at-home testing of viral nucleic acids with single-base resolution remains a challenge.

Methods: Topologically constrained DNA ring is engineered as substrates for the trans-cleavage of Cas13a to yield an accelerated post isothermal amplification. The capacity of CRISPR/Cas13a for discriminating single nucleotide variant (SNV) in viral genome is leveraged by designing synthetic mismatches and hairpin structure in CRISPR RNA (crRNA), enabling robust discrimination of different SARS-CoV-2 variants. Via optimisation of CasTDR_3pot to be one-pot assay, CasTDR_1pot can detect Omicron and its subvariants, with only a few copies in clinical samples in less than 30 min without pre-amplification.

Findings: The detection system boasts high sensitivity (0.1 aM), single-base specificity, and the advantage of a rapid "sample-to-answer" process, which takes only 30 min. In the detection of SARS-CoV-2 clinical samples and their variant strains, CasTDR_1pot has achieved 100% accuracy. Furthermore, the design of a portable signal-reading device facilitates user-friendly result interpretation. For the detection needs of different RNA viruses, the system can be adapted simply by designing the corresponding crRNA.

Interpretation: Our study provides a rapid and accurate molecular diagnostic tool for point-of-care testing, epidemiological screening, and the detection of diseases associated with other RNA biomarkers with excellent single nucleotide differentiation, high sensitivity, and simplicity.

Funding: National Key Research and Development Program of China (No. 2023YFB3208302), National Natural Science Foundation of China (No. 22377110, 22034004, 82402749, 82073787, 22122409), National Key Research and Development Program of China (No. 2021YFA1200104), Henan Province Fund for Cultivating Advantageous Disciplines (No. 222301420019).

Background: Lipid species are emerging as biomarkers for cardiometabolic risk in both adults and children. The genetic regulation of lipid species and their impact on cardiometabolic risk during early life remain unexplored.

Methods: Using mass spectrometry-based lipidomics, we measured 227 plasma lipid species in 1149 children and adolescents (44.8% boys) with a median age of 11.2 years. We performed genome-wide association analyses to identify genetic variants influencing lipid species. Colocalisation and Mendelian randomisation (MR) analyses were performed to infer causality between lipid species and cardiometabolic outcomes.

Findings: We identified 37 genome-wide significant loci for 52 lipid species, nine of which are previously unreported. Colocalisation analyses revealed that seven lipid loci shared genetic variants associated with adult cardiometabolic outcomes. One-sample MR analysis identified positive causal associations between ceramides and liver enzymes, sphingomyelins and hemoglobin A1c (HbA1c), and phosphatidylethanolamines and high-sensitivity C-reactive protein in children and adolescents. Two-sample MR using adult-based summary statistics showed consistent direction of associations and indicated additional causal links, specifically between ceramides and elevated HbA1c levels, and phosphatidylinositols with elevated liver enzymes.

Interpretation: These findings highlight the potential long-term implications of plasma lipid genetic determinants on cardiometabolic risk.

Funding: Novo Nordisk Foundation, The Innovation Fund Denmark, The Danish Heart Foundation, EU Horizon, and LundbeckFonden.