Multi-omic characterization of the Hispanic/Latino blood lipidome reveals an additional locus and attenuated genetic prediction.

Discovery of functional variants regulating lipid metabolism in an East Asian population.

The findings refine the genetic architecture of lipid traits and nominate candidate genes and regulatory variants for future studies of lipid-related cardiometabolic disease.

Integrative exome sequencing and multi-omics analysis elucidates the regulatory role of rare variants in metabolic syndrome

Multi-omics dissection of MASLD reveals divergent pathways to systemic diseases and targets for prevention.

BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent but heterogeneous condition. How its genetic diversity shapes systemic disease risk remains unclear. We aimed to identify genetically defined MASLD subtypes, assess their effects on extrahepatic diseases, and uncover potential protein-mediated mechanisms. METHODS We performed a genome-wide association study of MRI-derived hepatic fat content (HFC) in 33,592 UK Biobank (UKBB) participants to identify MASLD-related SNPs. Clustering of associations between MASLD-SNPs and triglyceride-related traits identified distinct genetic subtypes. Phenotypic associations were evaluated in 427,030 UKBB European-ancestry participants and validated in two independent populations. Plasma proteomic profiling and Mendelian randomization/mediation analyses were used to identify protein mediators linking subtypes to disease outcomes. RESULTS We identified three MASLD polygenic subtypes reflecting hepatic lipid retention, hepatic lipid synthesis, and systemic lipid metabolism. These subtypes exhibited distinct risk profiles across 22 incident diseases spanning multiorgan systems in the UKBB European-ancestry cohort, with partial replication in the UKBB non-European-ancestry populations and the Taizhou Longitudinal Study in China. All three subtypes consistently increased liver disease risk but showed divergent cardiometabolic effects. Proteomic profiling revealed subtype-specific signatures; for instance, systemic lipid metabolism was linked to elevated PCSK9 and higher cardiovascular risk, whereas hepatic lipid retention showed the opposite. Mediation and Mendelian randomization analyses identified both established (e.g., PCSK9, FURIN, APOE) and potentially novel (e.g., CCN1, ASGR1) protein mediators as putative targets for subtype-specific chronic disease prevention. CONCLUSION Our findings delineate etiologically and clinically distinct MASLD subtypes, reveal protein-mediated pathways to systemic diseases, and inform biologically guided prevention strategies.

Integrative bioinformatics analysis identifies APOE as a candidate link between lipid dysregulation and macrophage activation in inborn errors of metabolism

Background Inborn errors of metabolism (IEM) are a heterogeneous group of genetic disorders characterized by metabolic dysregulation and high mortality. Despite extensive genetic discoveries, the molecular mechanisms underlying severe disease progression remain incompletely understood. Increasing evidence suggests that host metabolic states, particularly lipid dysregulation, can profoundly influence immune cell function and may contribute to impaired responses against intracellular pathogens. Methods We integrated genomic data from four high-confidence databases (GWAS Catalog, CTD, Open Targets, and ClinVar) and identified 1,288 IEM-associated genes. Disease ontology enrichment, multi-parametric functional annotation, and cell-type enrichment analyses were performed using Open-XGR, WebGestalt, and Tabula Sapiens. Bioinformatics findings were interpreted alongside clinical and cytomorphological observations from a pair of one-year-old twins with suspected IEM and macrophage activation syndrome. No patient-specific genetic or molecular validation of APOE was available. Results Functional annotation identified APOE as the highest-scoring gene across seven biological categories, with enrichment in lipid metabolism- and macrophage-related pathways. Cell-type enrichment demonstrated an overrepresentation of IEM-associated genes in macrophage-related reference signatures, including datasets annotated as M2 macrophages. APOE was the only gene consistently represented across macrophage, M2 macrophage, protein–lipid complex, and vasculature-associated macrophage categories. Clinical evaluation of the twin cases showed persistent hyperbilirubinemia, elevated transaminases, cholestasis, and macrophage activation. Bone marrow and cerebrospinal fluid cytology demonstrated lipid-laden monocyte/macrophage morphology. These clinical observations are concordant with lipid-handling abnormalities in macrophages but do not establish an APOE-dependent mechanism or macrophage polarization state. Conclusion This study identifies APOE as a highly prioritized candidate gene associated with lipid metabolism pathways and macrophage-related signatures in IEM. These findings support the hypothesis that APOE-associated lipid dysregulation may contribute to macrophage dysfunction and warrant further experimental validation.

Using human proteomic and lipidomic to exploration drug target of bladder cancer

Integrative genomic and transcriptomic analysis of hypertension in a Taiwanese population.

OBJECTIVES Hypertension is highly prevalent in Asian populations and represents a major cardiovascular risk factor. However, most genome-wide association studies (GWASs) and transcriptome-wide association studies (TWASs) have focused primarily on Caucasian cohorts. This study aimed to identify genetic loci and gene expression signatures associated with hypertension in an Asian population. METHODS We analyzed 10 739 hypertensive patients and 49 668 controls from the Taiwan Biobank, testing 4 512 191 genome-wide single nucleotide polymorphisms (SNPs). Integrated GWAS, TWAS, and expression quantitative trait locus (eQTL) analyses were conducted to characterize genetic risk. Additionally, a polygenic risk score (PRS) was constructed using a split-sample design to evaluate genetic risk stratification. RESULTS We identified 14 loci significantly associated with hypertension, including a novel locus at 5p13.1. eQTL analysis linked this locus to DAB2 expression in whole blood. TWAS detected 55 hypertension-associated genes, with 20 (36%) overlapping GWAS loci. Several novel genes outside GWAS loci, including FBXL15, KCNIP2, and CRIP3, were highly significant and implicated in vascular biology and hypertension mechanisms. PRS analysis effectively differentiated hypertension risk, with individuals in the top 10% showing a > 3.5-fold increased risk compared to the bottom 10%. CONCLUSIONS Our findings provide new insights into the genetic and transcriptomic landscape of hypertension in Asians. The identification of novel loci and genes advances understanding of disease biology and may guide precision medicine approaches for risk prediction and therapeutic development.