Abstract 217: Coronary Artery Disease Locus 1p32.2 Harbors a Flow-Sensitive Endothelial Enhancer that Regulates PLPP3
Bibliographic record
Abstract
Genome-wide association studies (GWAS) have identified chromosome 1p32.2 as one of the loci most strongly associated with coronary artery disease (CAD) susceptibility; however, the causal mechanism related to this CAD locus remains poorly understood. A unique feature of atherosclerotic vascular disease such as CAD is that atherosclerosis develops preferentially at arterial sites of curvature, branching, and bifurcation where endothelial cells are activated by disturbed blood flow. Recent investigations by us and others strongly implicate PhosphoLipid PhosPhatase 3 (PLPP3, also known as PhosPhatidic-Acid-Phosphatase-type-2B/ PPAP2B or Lipid Phosphate Phosphohydrolase/LPP3) as the causal gene at this locus. PLPP3 encodes an enzyme that suppresses endothelial inflammation and promotes monolayer integrity by hydrolyzing the bioactive lipid lysophosphatidic acid (LPA). Our studies demonstrated that PLPP3 is significantly reduced in vascular endothelium exposed to disturbed flow in vitro and in vivo, as the result of increased miR-92a and reduced KLF2, when compared to cells subjected to unidirectional blood flow. In addition, CAD risk allele at rs17114036 located in 1p32.2 locus is associated with reduced PLPP3 expression in an endothelium-specific manner, shown by expression quantitative trait locus (eQTL). Employing Transposase-Accessible Chromatin using Sequencing (ATAC-Seq), ChIP-Seq, CRISPR/Cas9-based genome editing, luciferase reporters, and allelic imbalance assays, we report here that CAD SNP rs17114036 is located in an endothelial enhancer that is dynamically activated by athero-protective unidirectional flow and deletion of this enhancer causatively reduces PLPP3 expression in vascular endothelium. In addition, CAD risk allele at rs17114036 is associated with reduced activity of this enhancer and its response to unidirectional flow. These results described a new molecular mechanism by which human genetic variance and mechano-transduction converge on critical vascular functions related to atherosclerosis. Moreover, we have engineered innovative polymeric nano-carriers that preferentially target inflamed endothelium and deliver therapeutic nucleotides that intervene in miR92a-PLPP3 signaling in animal models of atherosclerosis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.017 | 0.004 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".