Genetically nominated cardiovascular-kidney-metabolic features are not consistently more responsive to weight-loss and cardiometabolic interventions
Abstract
Background: Substantial cardiovascular and kidney risk persists after successful weight loss. Whether features that genetics implicates in cardiovascular-kidney-metabolic (CKM) disease show larger short-term responses to weight-loss and cardiometabolic interventions than other features is unknown.
Methods: Across four molecular layers (proteome, transcriptome, methylome, metabolome), we applied layer-specific cis-Mendelian randomization with colocalization or summary-data shared-signal filtering against eight CKM genome-wide association studies. Within 13 omics-by-intervention analyses (diet, bariatric surgery, empagliflozin, behavioral weight loss), we compared response magnitude between nominated and adequately-instrumented non-nominated features using rank-based Cliff’s δ; methylation was baseline-variance-matched and directional analyses exploratory.
Results: Here we show genetic nomination is not consistently associated with larger observed response magnitude: estimates are small (|δ| < 0.08 in all 13; median |δ| = 0.03), near zero (descriptive pooled δ = +0.001, 95% CI −0.013 to +0.015; I² = 0%), none significant by label-permutation, though smaller proteomic and transcriptomic analyses remain compatible with modest differences. Nominated proteins and metabolites frequently changed (48–71% were responsive), at rates similar to comparison features; the null is not one of universal non-response. Nominated CpG sites have lower baseline inter-individual variance…
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