Genetically nominated cardiovascular-kidney-metabolic features are not consistently more responsive to weight-loss and cardiometabolic interventions

Abstract

BackgroundSubstantial 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. MethodsAcross 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 Cliffs {delta}; methylation was baseline-variance-matched and directional analyses exploratory. ResultsHere we show genetic nomination is not consistently associated with larger observed response magnitude: estimates are small (|{delta}| < 0.08 in all 13; median |{delta}| = 0.03), near zero (descriptive pooled {delta} = +0.001, 95% CI -0.013 to +0.015; I{superscript 2} = 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 (Mann-Whitney P = 1.7 x 10- to 4 x 10-3 at the primary nomination tiers), and apparent methylation persistence attenuates after variance-matching. ConclusionsUnder the definitions and datasets studied, genetic target support does not consistently predict pharmacodynamic responsiveness and should not be read as a treatment-response or reversibility biomarker; baseline dynamic range should be assessed and controlled when comparing molecular change across selected features. Nominated features are not shown unchanged or to explain residual risk; same-subject longitudinal studies are needed to test prognostic or therapeutic value. Plain Language SummaryPeople who lose weight often see their heart, kidney and metabolic health improve, yet some risk remains. We asked whether the molecular features that genetics links to these diseases are also the ones that improve most with treatment. We gathered four kinds of molecular measurement from studies of dieting, weight-loss surgery and medicines, and compared them with other measured molecules. They still changed with treatment -- but no more than the rest, with no consistent link to their genetic importance. An apparent lasting "memory" of obesity largely reflected how the molecules were measured rather than a persistent biological change. On this evidence, genetically implicated features do not consistently respond more, and better-designed studies are needed.