Air pollution exacerbates cardiovascular-kidney-metabolic syndrome and sarcopenia comorbidity via shared genetic-epigenetic mechanisms: A multi-omics and Mendelian Randomization study.

<p><b>BACKGROUND</b></p><p>Ambient air pollution aggravates cardiovascular-kidney-metabolic (CKM) disorders and sarcopenia, yet the shared genetic and epigenetic mechanisms that underlie their frequent co-occurrence remain poorly understood.</p><p><b>METHODS</b></p><p>We integrated genome-wide association study (GWAS) data for CKM components (cardiovascular disease [CVD], chronic kidney disease [CKD], metabolic syndrome), CKM-related cardiovascular events, and sarcopenia diagnostic criteria from European-ancestry cohorts, and conducted meta-analyses harmonizing each phenotype across at least three studies. We employed Mendelian Randomization (MR) to assess potential causal links and genetic correlation analyses (global and local) to quantify shared heritability.

Multi-omics analyses included two sequential phases: Phase 1 identified and validated novel shared CKM-sarcopenia genes through integrated methylation (n = 1980) and expression (n = 31,684) analyses, followed by cross-validation using two complementary transcriptome-wide association studies (TWAS). Phase 2 prioritized druggable targets through proteomic analysis across five independent cohorts (deCODE, n = 35,559; UK Biobank Pharma Proteomics Project (UKB-PPP), n = 54,219; Fenland, n = 10,708; FinnGen Olink, n = 619; FinnGen Somascan, n = 828) and integrated colocalization.</p><p><b>RESULTS</b></p><p>MR suggested genetically predicted associations between sarcopenia and CKM; genetically slower walking pace was associated with higher CVD risk (OR = 0.85, P = 9.56 × 10 -6) and metabolic syndrome risk (OR = 0.43, P = 3.90 × 10 -17), while conversely, genetically predicted lower appendicular lean mass exhibited inverse associations with heart failure with heart failure and atrial fibrillation.

Multi-omics identified key shared genes (ANAPC4, UNC50, TPO), with ANAPC4 methylation sites linked to CVD (cg13918811, P adj = 0.0212) and reduced muscle mass (cg04009456, P adj = 0.0049). Blood-based analyses identified 13 air pollution-associated comorbid genes, primarily responsive to PM 2.5/NO 2, with 11 confirmed by cross-tissue validation.

Proteomics (F-statistics > 10) revealed potential targets linking CKM/sarcopenia (HP, FCGR3B, GALNT2) and CKM-events/sarcopenia (SERPINA1, FER).</p><p><b>CONCLUSION</b></p><p>Ambient air pollution likely promotes CKM-sarcopenia comorbidity chiefly via inflammatory signaling and epigenetic modifications. Our multi-omics integration reveals convergent pathways, candidate driver genes, and differential methylation sites that link these conditions.

We propose these targets for environmental mitigation and molecular intervention, which require validation in diverse populations.</p>