Abstract 610: Functional Relationship of The <i>CARS2</i> Locus to Coronary Artery Disease
Bibliographic record
Abstract
In a recent meta-analysis of GWAS for cardiovascular disease (CAD) with imputation from 1000 Genomes (Nat Genet 2015), we identified 202 significant CAD associated variants (FDR q< 0.05) in 129 loci. Seven independent association signals were identified in a gene cluster at chromosome 13q34 including rs61969072. This SNP is located in an intergenic region proximal to the ING1 , CARKD and CARS2 genes. Expression data (eQTL) obtained from the GTEx Project demonstrate a strong association of rs61969072 with CARS2 mRNA abundance in artery with decreased CARS2 expression in carriers of the risk G allele, hinting that CARS2 may be a causal CAD gene. CARS2 encodes a putative mitochondrial cysteinyl t-RNA synthetase. Bioinformatics data (BioGPS) indicate high gene expression of CARS2 in monocytes, a precursor of macrophages. Having then demonstrated that CARS2 mRNA expression is decreased in M1 macrophages compared to M0 and M2 macrophages, we examined the role of CARS2 in the anti-inflammatory pathway in macrophages using THP-1 cells, a macrophage model system. Gene expression profiling of 84 key players of the inflammatory response was performed on siRNA mediated knockdown of CARS2 samples. Comparisons between knockdown and control samples (n=4) identified 12 upregulated and 4 down regulated genes with ≥ 1.25 or ≤0.75 fold difference in expression (p<0.05). Gene Set Enrichment Analysis (GSEA), using inflammatory response PCR array data, identified the interleukin-10 signaling pathway as an enriched category (FDR q<0.05). IL-10 has an atheroprotective effect against plaque rupture and thrombus formation by influencing the local inflammatory process in the lesion. IL-10 activates the STAT3 cascade, where phosphorylated STAT3 homodimers translocate to the nucleus to activate specific target effector genes which repress the proinflammatory genes at the transcriptional level. IL-10 induced STAT3 phosphorylation was measured by Western blotting in THP-1 cells. In response to IL-10, CARS2 knockdown samples showed dampened STAT3 phosphorylation compared to control suggesting that CARS2 serves an anti-inflammatory function within the IL-10 signaling pathway.
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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 | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.005 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.011 | 0.001 |
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".