Abstract 5526: Genetic Variation at <i>PCSK5</i> Influences HDL-C Levels
Bibliographic record
Abstract
Low plasma HDL-C is a well-established risk factor for coronary artery disease. The role of endothelial lipase (EL) in HDL metabolism has been recently characterized. The proprotein convertase subtilisin/kexin 5 (PC5/6 or PCSK5) is known to inactivate both EL and lipoprotein lipase (LPL) ex vivo , enzymes critical in modulating plasma levels of HDL-C. In the present study, we investigated the role of human PCSK5 genetic variants on HDL-C; in addition, we characterized lipoprotein fractions in Pcsk5 +/− mice, compared with wild type. Sequencing of the PCSK5 gene was performed in 12 probands with low HDL-C (<5 th percentile) and 7 novel non-coding genetic variants were found. We genotyped these SNPs along with 163 tag SNPs and 12 additional SNPs (n=182 total) selected from the HapMap Project, in 457 individuals with documented coronary artery disease. We identified 10 SNPs associated with HDL-C (p<0.05), with the strongest result being rs11144782 (minor allele frequency: 0.164, p=0.002). In an analysis of HDL-C as a dichotomous trait, 3 of the 10 SNPs were also associated with low HDL-C at either the 5 th or the 10 th percentile (p<0.05). The rare allele of rs111447782 decreased HDL by 0.076 mmol/L in a gene dosage-dependent fashion. We further investigated the effect of this SNP on other lipoprotein levels and identified an association with very low density lipoprotein (p=0.039), triglycerides (p=0.049) and total ApoB (p=0.022) levels. Furthermore, in conditional regression analysis, we identified 3 additional SNPs contributing to HDL-C (p<0.05), all independent of the effect of rs11144782. In addition, we characterized serum from Pcsk5 KO mice. Serum from Pcsk5 +/− mice ( Pcsk5 −/− is embryonic lethal) showed reduction in HDL-C by gel permeation chromatography on HPLC and size redistribution of HDL species by 1D and 2D PAGGE. These results, and the rs11144782 SNP result presented above, are consistent with the concept that PCSK5 modulates HDL, likely upstream of EL and LPL. We conclude that variability at the PCSK5 gene locus influences HDL-C levels and consequently, atherosclerotic cardiovascular disease risk.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.010 | 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".