Human Genomics最新文献

While genome-wide association studies (GWAS) have linked common genetic variants to COVID-19 susceptibility and severity, rare high-impact variants may also contribute to phenotypic heterogeneity. Inborn errors of type I interferon immunity (IFN-I-IEIs), including X-linked TLR7 deficiency, account for ~ 2% of critical COVID-19 cases. In this study, we investigated rare potentially deleterious variants in IFN-I-IEI and GWAS-prioritized genes in young, severely affected COVID-19 patients from the German National Pandemic Cohort Network (NAPKON). Genome sequencing was performed on 110 hospitalized COVID-19 patients, including 82 males and 28 females, all under 60 years of age and without relevant pre-existing medical conditions. Rare potentially deleterious variants in TLR7 and 25 additional IFN-I-IEI genes, as well as 23 GWAS risk genes for COVID-19 severity, were analyzed based on allele frequency, predicted functional impact, and inheritance pattern models and subsequently classified based on the American College of Medical Genetics and Genomics (ACMG) criteria. Polygenic Risk Scores (PRS) were additionally calculated as an exploratory and case-only analysis to assess the contribution of common variant-derived genetic predisposition for severe COVID-19. Consistent with prior findings from other studies in German cohorts, no candidate variants or large deletions were identified in TLR7. However, 7 variants of uncertain significance in IFN-I-IEI genes as well as 13 candidate variants of potential deleterious effect in GWAS risk genes were present in 19 individuals (17.3%). We observed nominally significant differences in PRS distributions, with younger individuals (< 40 years) having higher PRS (p = 0.045) compared to older individuals, and carriers of rare variants having lower PRS compared to non-carriers (p = 0.037). These patterns are consistent with an age-dependent contribution of polygenic risk to severe COVID-19 and a potentially lower polygenic burden among rare-variant carriers, although confirmation in larger well-controlled cohorts will be required. The candidate variants identified in IFN-I-IEI and GWAS risk genes represent targets for further functional studies to clarify their potential contribution to disease risk. These findings highlight the need for future integrative genomic approaches to better understand the joint contribution of common and rare variants to COVID-19 severity.

The interaction between the genome and the exposome is increasingly recognized as central to human health and disease. While exposome research has generally focused on adverse exposures such as pollutants and toxins, the concept of the beneficial exposome-positive environmental exposures that promote health-remains underexplored. Among the most promising beneficial exposures are plant-derived phytochemicals, a rich class of bioactive compounds with therapeutic potential. Phytoncides, a specific subset of volatile organic compounds released by plants, exemplify this beneficial potential through their antimicrobial, anti-inflammatory, antioxidant, and neuroprotective effects. Historically utilized in traditional medicine across cultures, plant-based remedies containing these compounds are now being examined through modern genomics, exposomics, and systems biology approaches to understand the specific contributions of phytoncides and other bioactive constituents. Emerging data suggest that phytochemicals modulate gene expression, immune function, and metabolic pathways across multiple organ systems, contributing to immune, neurological, endocrine, cardiovascular, respiratory, integumentary, and mental health improvements. However, the evidence base is predominantly preclinical, with limited human validation, considerable heterogeneity in plant-extract composition, and incompletely characterized molecular mechanisms. This review synthesizes current evidence on genome-exposome interactions (GxE) related to plant-derived compounds, highlighting recent mechanistic insights and exploring translational applications-including forest bathing, green space integration in urban design, and bioengineering approaches-while addressing the challenges of clinical translation. As environmental change accelerates, understanding beneficial GxE offers new opportunities for preventative and precision public health interventions and calls for integrating nature-based solutions into modern healthcare paradigms.

Background: Atherosclerosis (AS) is a chronic vascular disease and the principal cause leading to ischemic cardiomyopathy (ICM). It involves complex metabolic dysregulation beyond the resolution of single-omics. Emerging evidence implicates arginine-proline metabolism (APM) in driving inflammation and impairing efferocytosis, yet the cellular basis of plaque instability remains elusive.

Methods: We employed a five-stage analytical framework. First, metabolomic profiling revealed shared pathways between AS and ICM. Second, single-cell RNA sequencing identified APM-enriched macrophage subtypes in both diseases. Pseudotime analysis, Scissor algorithm, and cell-cell communication analyses linked these subtypes to APM signaling, stroke prognosis, and key ligand-receptor interactions. Third, cNMF and unsupervised clustering defined APM-related gene signatures in macrophages, validated by survival analysis. Fourth, spatial transcriptomics confirmed their spatial distribution and colocalization within unstable plaques. Finally, key biomarkers were validated in atherosclerotic lesions using ApoE^-/- mouse.

Results: Metabolomic profiling revealed APM as a shared dysregulated pathway in AS and ICM. We identified a macrophage subset (SPP1⁺ macrophages and mono-macrophages), termed APM_high macrophages, enriched in the fibrous cap and characterized by elevated collagenase activity, heightened inflammation, and disrupted cholesterol homeostasis. Spatial and cell-cell communication analyses revealed strong interactions with dendritic cells via the MIF-(CD74 + CXCR4) axis, potentially contributing to plaque destabilization. Transcriptomic clustering uncovered a high-APM plaque subtype associated with worse ischemic outcomes. Six diagnostic biomarkers were identified through machine learning and validated across multiple cohorts and in ApoE^-/- mouse.

Conclusion: In summary, our study decodes the metabolic basis of inflammation shared between AS and ICM, suggesting an APM_high macrophage-centered regulatory axis across multiple omics layers. This work advances our understanding of the cardio-metabolic axis and suggests new avenues for targeted therapy.

Background: The Human Exposome Project (HEP) aims to chart lifelong environmental exposures and their biological consequences, furnishing the environmental counterpart to the genomic revolution. Yet the fine‑grained, multimodal data streams that fuel exposomics-biospecimens, geolocation traces, wearable‑sensor feeds, and socio‑environmental metadata-raise privacy, justice, and governance questions that may exceed the reach of conventional bioethics.

Main body: Building on lessons from genomics, biobanking, digital health, and environmental‑justice research, we identify five foundational ethical domains for exposome science: (1) privacy and data sovereignty, (2) informed consent and sustained participant engagement, (3) environmental justice, (4) governance and oversight, and (5) actionability and the responsible return of results,as well as (6)the adherence to research program goals. Similar to the "values in design" construct widely used in the socio-technical field and the "ethics by design" in the artificial intelligence (AI) field, we translate these domains into operational pillars for ethics‑by‑design research practice: dynamic or tiered consent architectures; participatory governance mechanisms such as community advisory boards; embedded ethics research programs; algorithmic‑fairness protocols for artificial‑intelligence analytics; and dedicated review bodies equipped to evaluate longitudinal, sensor‑based, multi‑omics studies. Concrete recommendations include federated data stewardship to minimize re‑identification risk, Evidence‑to‑Decision frameworks that couple exposomic evidence with societal values, and transparent pathways for communicating context‑dependent findings to individuals, communities, and policymakers.

Conclusions: Ethical preparedness and action are a prerequisite for the scientific impact and social license of exposome research. Institutionalizing the proposed roadmap-via an international Exposome Ethics Consortium, expanded training for Institutional Review Boards, harmonized regulatory guidance, and sustained community co‑governance-will help protect privacy, promote equity, and foster public trust. Embedding systematic ethical reflection as core infrastructure will enable the Human Exposome Project to realize its promise of precision public health without replicating patterns of opaque surveillance, marginalization, or data commodification. The Human Exposome Project (HEP) represents an ambitious endeavor to characterize lifelong environmental exposures in relation to health. Yet, this vision brings profound ethical challenges: from managing massive, sensitive datasets to ensuring justice for disproportionately exposed communities. This article synthesizes foundational work on exposome ethics, outlines core ethical challenges, and proposes a proactive ethical governance model that ensures scientific integrity and social legitimacy.

Changes in gene function or expression caused by epigenetic modifications may play a role in painful diabetic neuropathy. Two independent cohorts of patients deeply phenotyped for painful diabetic neuropathy underwent whole genome DNA methylation data analysis. Burden of rare site events at the global, chromosomal and gene level; epigenetic homogeneity for regions enriched in epivariants (epilesions) and functional analysis of the genes with stochastic phenomena was undertaken. This revealed significant involvement of the SLIT/ROBO signaling axis-engaged in peripheral nerve regeneration after injury, among several molecular pathways, making it an attractive therapeutic target in patients with diabetic painful neuropathy.

Background: Hemophilia B (HB), an X-linked recessive disorder, results from variants in the coagulation factor IX gene (F9). The F9 c.520 + 13 A > G variant is a recurrent intronic variant in HB patients, accounting for 15.05% of all documented F9 intronic variants. Despite prior predictions of its impact, the molecular mechanism associated with moderate to mild HB remains undissected.

Materials and methods: In silico predictions and splicing-competent cDNA constructs were used to assess the impact of F9 c.520 + 13 A > G on mRNA splicing. Factor IX (FIX) variant (p.V174delinsGHNLM) expression in HEK293T cells was evaluated using activated partial thromboplastin time, enzyme-linked immunosorbent assay, Western blot analysis, and immunofluorescence analyses. Structural modeling and molecular dynamics simulations were performed to evaluate the structural impact of the variant. Engineered U1 small nuclear RNA (U1snRNA) was challenged with F9 full-length splicing-competent constructs to evaluate splicing correction.

Results: The F9 c.520 + 13 A > G variant caused nearly complete aberrant splicing, producing the F9 c.520_521insGTCATAATCTGA insertion and the in-frame FIX p.V174delinsGHNLM variant. A small amount (approximately 10%) of wild-type FIX was also detected. We characterize the p.V174delinsGHNLM variant, which exhibited impaired secretion and increased intracellular accumulation. Interestingly, an engineered U1snRNA partially rescued aberrant splicing, restoring functional FIX levels to approximately 40%.

Conclusion: This study elucidates the molecular mechanism of the F9 c.520 + 13 A > G variant, which activates a cryptic 5' splice site in intron 5, leading to an in-frame FIX (p.V174delinsGHNLM) with secretion defects and loss of protein function. And Engineered U1snRNA partially rescued the splicing defect.

Background: Oral squamous cell carcinoma (OSCC) is one of the most common oral malignancies, which can occur in any part of the mouth and is highly malignant. DNA Methylation is an epigenetic modification of the genome, which is involved in key cellular processes and has a crucial impact on the occurrence, development, invasion and metastasis of tumors. In this study, we conducted a comprehensive analysis of DNA methylation characteristics in OSCC with the aim of identifying potential diagnostic epigenetic biomarkers and exploring possible mechanisms of methylation's influence on OSCC.

Methods: In this study, genome-wide DNA methylation analysis was performed using Infinium Methylation EPIC arrays, including tumor tissue and adjacent non-tumor tissue from 12 OSCC patients. Differential methylation probes and regions (DMP/DMR) were identified for gene function analysis. Characteristic DMPs and genes were screened according to the specific situation, and OSCC-targeted methylation data from 25 patients in the validation cohort were used to further validate the differential methylation levels of our selected genes. Finally, the expression levels of methylated genes in OSCC were verified by combining RNA-Seq data with quantitative real-time polymerase chain reaction (qRT-PCR).

Results: There were 277,805 DMPs in OSCC tumor tissue. Hypermethylated DMP accounted for 37.4% of all DMPs and hypomethylated DMPs was 62.6%. Functional pathway analysis showed that it was mainly related to passive transmembrane transporter activity, cancer proteoglycan and PI3K-Akt signaling pathway. The methylation level of ZNF880 was emphatically verified in the verification cohort, and the results showed that there was high methylation in ZNF880 in the verification cohort. Subsequently, through RNA-Seq data and qRT-PCR, it was confirmed that the expression of ZNF880 in OSCC tissues was significantly lower than that in normal tissues. This verified the correlation between the high methylation of ZNF880 and gene expression.

Conclusions: This study comprehensively reveals changes in genome-wide DNA methylation patterns in OSCC, indicating that abnormal hypermethylation of the ZNF880 gene plays a catalytic role in the pathogenesis of OSCC.

Background: Patients with congenital heart disease are identified in 1% of live births. Improved surgical intervention means many patients now survive to adulthood, the corollary of which is increased mortality in the over-65-year-old congenital heart disease (CHD) population. In the clinic, genetic sequencing increasingly identifies novel genetic variants in genes related to CHD. Traditional assays for interpreting novel genetic variants are often limited by gene-specificity, whereas animal models are cumbersome and may not accurately reflect human disease. This study investigates CRISPR gene editing in induced pluripotent stem cells and cardiomyocyte-directed differentiation as a human disease model to investigate novel genetic variants identified in association with CHD.

Methods and results: We identified a GATA4 p.Arg284His genetic variant in a paediatric patient. This genetic variant was introduced into induced pluripotent stem cells (iPSCs) using CRISPR gene editing with homology-directed-repair. GATA4 genetic variant and isogenic control iPSCs were selected and differentiated into cardiomyocytes. Expression of the GATA4 p.Arg284His variant resulted in altered calcium transients, indicative of CHD and consistent with the patient's clinical phenotype. Transcriptomics revealed cellular pathway changes in cardiac development, calcium handling, and energy metabolism that contribute to disease aetiology, mechanism and identification of potential treatments.

Conclusion: Directed differentiation of iPSCs harbouring the GATA4 p.Arg284His genetic variant recapitulated the CHD phenotype, indicated disease mechanisms, and pointed to potential sites for targeting with therapy. The study highlights the utility of transcriptomics for the functional interpretation of cardiac genetic variants and is an exemplar for precision medicine approaches for the investigation of CHD.