Daily Endocrinology Research Analysis
Cross-ancestry metabolomics GWAS reveals hundreds of variant–metabolite links and causal ties to coronary artery disease and heart failure. Paired chromatin and transcriptome profiling uncovers depot-specific regulatory architecture in human adipose tissue. Real-world comparative effectiveness shows adding a GLP-1 receptor agonist to basal insulin is associated with markedly fewer complications and lower mortality than insulin intensification.
Summary
Cross-ancestry metabolomics GWAS reveals hundreds of variant–metabolite links and causal ties to coronary artery disease and heart failure. Paired chromatin and transcriptome profiling uncovers depot-specific regulatory architecture in human adipose tissue. Real-world comparative effectiveness shows adding a GLP-1 receptor agonist to basal insulin is associated with markedly fewer complications and lower mortality than insulin intensification.
Research Themes
- Cross-ancestry metabolomics genetics and causal inference
- Depot-specific epigenomic regulation in adipose tissue
- Comparative effectiveness of GLP-1RA add-on versus insulin intensification
Selected Articles
1. Cross-ancestry analyses of Chinese and European populations reveal insights into the genetic architecture and disease implication of metabolites.
Large cross-ancestry metabolite GWAS identified 15 associations in Han Chinese (8 replicated) and 228 more via meta-analysis with UK Biobank Europeans, improving fine-mapping. Mendelian randomization linked higher HDL-triglyceride levels to increased coronary artery disease risk and higher glycine to reduced heart failure risk across ancestries.
Impact: Provides cross-ancestry genetic architecture of circulating metabolites with causal links to major cardiovascular diseases, enabling hypothesis-driven target discovery and risk stratification.
Clinical Implications: Findings support using metabolite-informed genetics for cardiovascular risk prediction and prioritizing pathways (e.g., HDL-triglycerides, glycine) for therapeutic development and precision prevention.
Key Findings
- GWAS of 171 metabolites in 10,792 Han Chinese identified 15 variant–metabolite associations; 8 replicated in an independent Chinese cohort (n=4,480).
- Cross-ancestry meta-analysis with 213,397 Europeans found 228 additional associations and improved fine-mapping resolution.
- Mendelian randomization implicated HDL-triglycerides in higher coronary artery disease risk and glycine in lower heart failure risk across ancestries.
Methodological Strengths
- Large cross-ancestry sample with discovery, replication, and meta-analysis components
- Use of Mendelian randomization to infer causality between metabolites and diseases
Limitations
- Metabolites measured by a single NMR platform may limit biochemical coverage and quantitation granularity
- Ancestry representation focused on Han Chinese and Europeans; limited generalizability to other populations
- MR assumptions (e.g., no horizontal pleiotropy) may not hold for all instruments
Future Directions: Extend to additional ancestries, integrate multi-omics and longitudinal phenotypes, and functionally validate prioritized loci and pathways to enable translation into biomarkers and therapeutics.
2. Chromatin landscape in paired human visceral and subcutaneous adipose tissue and its impact on clinical variables in obesity.
Integrative ATAC-seq and RNA-seq in paired SAT and OVAT revealed twice as many depot-specific accessible regions in visceral fat, with SAT enriched for enhancer activity and OVAT for promoter and repressive/bivalent chromatin states. CTCF (SAT) and BACH1 (OVAT) motifs marked depot-specific regulation, and gene sets correlated with adiposity distribution and insulin–glucose–lipid metrics.
Impact: Reveals depot-specific epigenomic programs linking adipose regulation to clinical metabolic traits, providing a mechanistic basis for visceral fat’s higher cardiometabolic risk.
Clinical Implications: Identifies candidate regulatory factors and chromatin states that could be targeted to modulate visceral adipose dysfunction, informing precision strategies for obesity-related complications.
Key Findings
- Visceral adipose tissue (OVAT) harbored approximately twice as many depot-specific differentially accessible regions as subcutaneous adipose tissue (SAT).
- SAT-specific regions were enhancer-enriched for ECM and metabolic genes, whereas OVAT-specific regions were promoter-enriched and associated with cardiomyopathy-linked genes.
- OVAT showed enrichment of bivalent TSS and repressive chromatin states and was marked by BACH1 motifs; SAT DARs were enriched for CTCF motifs.
- Gene sets from depot-specific regions correlated with clinical measures of fat distribution and insulin, glucose, and lipid metabolism.
Methodological Strengths
- Intra-individual paired sampling minimizes inter-person variability
- Multi-omics integration (ATAC-seq and RNA-seq) with motif analysis and clinical trait correlations
Limitations
- Sample size and donor diversity not specified in the abstract; external generalizability may be limited
- Descriptive epigenomic correlations lack causal perturbation experiments
- Tissue heterogeneity (cell-type composition) may confound depot-specific signals
Future Directions: Single-cell multi-omics and perturbation studies to identify causal regulators, and validation across larger, diverse cohorts to inform therapeutic targeting of visceral adiposity.
3. Effectiveness of adding glucagon-like peptide-1 receptor agonist on diabetes complications and mortality among basal insulin-treated people with type 2 diabetes: A real-world Korean study.
In 38,634 basal insulin–treated adults with type 2 diabetes, adding a GLP-1RA—versus adding short-acting insulin or switching to premixed—was associated with substantially lower risks of cardiovascular and severe microvascular complications, diabetes-related hospitalization, and all-cause mortality.
Impact: Delivers large-scale real-world comparative effectiveness data supporting GLP-1RA add-on over insulin intensification for hard outcomes, aligning with cardiometabolic benefits seen in trials.
Clinical Implications: For basal insulin–treated T2D patients needing intensification, preferentially adding a GLP-1RA may improve outcomes beyond glycemic control and reduce hospitalizations and mortality.
Key Findings
- Among 38,634 adults, GLP-1RA add-on vs short-acting insulin add-on reduced cardiovascular complications (HR 0.56), severe microvascular complications (HR 0.30), hospitalizations (HR 0.62), and all-cause mortality (HR 0.27).
- Compared with switching to premixed insulin, GLP-1RA add-on lowered cardiovascular complications (HR 0.65), severe microvascular complications (HR 0.36), hospitalizations (HR 0.62), and mortality (HR 0.32).
- Real-world evidence supports GLP-1RA add-on as a superior intensification strategy to insulin-based approaches for multiple clinical endpoints.
Methodological Strengths
- Very large, national claims-based cohort enabling comparative effectiveness analyses across multiple outcomes
- Consistent benefits across cardiovascular, microvascular, hospitalization, and mortality endpoints
Limitations
- Observational design with potential residual confounding and confounding by indication
- Medication adherence, dosing, and lifestyle factors not fully captured in claims data
- Generalizability outside Korean healthcare context requires caution
Future Directions: Propensity-matched and instrumental-variable analyses, subgroup evaluation (e.g., CKD, CVD), and external validation in other health systems to strengthen causal inference.