Integrative Systems Genomics and Pharmacology Define Shared Immune-Vascular Programs and Prioritize an Experimentally Testable Candidate Linking Sleep Loss to Human Atherosclerosis.

Background: Sleep loss is epidemiologically linked to atherosclerotic cardiovascular disease, yet shared-transcriptome studies typically intersect differentially expressed gene lists and treat the overlap as a shared response, assuming rather than testing directional agreement. Methods: Controlled human sleep restriction (GSE39445; 438 whole-blood samples from 26 participants) and paired carotid plaque versus patient-matched intact artery (GSE43292; 32 patients) were compared across biological compartments at three resolutions: individual genes, annotated gene sets, and redundancy-collapsed programs. The resulting architecture was transferred unmodified to acute total sleep deprivation, plaque progression, and aneurysm enlargement, and was evaluated by participant-grouped cross-validation, network topology, exact-cis Mendelian randomization with colocalization, and single-cell localization. Results: Convergence was resolution dependent. The cohorts shared more differentially expressed genes than expected under independence (274 of 16,869; p = 3.54 × 10-4), yet only 48.9% changed concordantly (p = 0.66). Concordance reached 78.0% among jointly significant gene sets and 70.0% (35 of 50) after redundancy collapse (bootstrap 95% CI, 0.560-0.820), coupling neutrophil-granule and myeloid-effector enrichment with depletion of RNA-processing, chromatin, and ciliary programs. Under a contrast-independent maximum interquartile range probe-selection rule, the gene-level overlap was smaller and no longer nominally significant (190 genes; p = 0.082), whereas the prespecified 50-program architecture, rescored without re-clustering, retained the same 35 concordant programs. The architecture generalized to acute sleep deprivation (91.4%) and plaque progression (97.1%) but inverted during aneurysm enlargement (20.0%). Prespecified separability was borderline (AUC 0.558; 95% CI, 0.486-0.630; permutation p = 0.052). Of twelve topology-prioritized spliceosomal candidates, SF3A3 alone combined FDR-significant exact-cis Mendelian randomization (OR 0.851; 95% CI, 0.772-0.939) with regional colocalization (PP.H4 = 0.831). Conclusions: Sleep loss and atherosclerosis converge as coordinated transcriptional programs rather than as shared individual genes, although the magnitude and statistical enrichment of gene-level overlap were sensitive to representative probe selection; this represents cross-compartment transcriptional convergence rather than replication and does not confer individual-level separability. SF3A3 is an experimentally testable candidate, not a validated therapeutic target.