Abstract 12056: Angiopoietin-Like Protein 3 Blood Levels and Cardiometabolic Traits and Diseases: A Mendelian Randomization Study
Bibliographic record
Abstract
Introduction: Angiopoietin-like 3 (ANGPTL3) is a key regulator of blood lipid levels. ANGPTL3 inhibitors are currently under investigation for their impact on metabolic and cardiovascular health. Our objective was to investigate the causal effect of genetically-predicted blood ANGPTL3 levels on cardiometabolic traits and diseases using Mendelian randomization (MR). Methods: We performed a series of two-sample MR studies using cis-acting variants on ANGPTL3 blood levels measured using aptamers in 35,559 participants of the deCODE study. We used inverse-variance weighted-MR to assess the effect of genetically-predicted blood ANGPTL3 levels on lipid and apolipoprotein B levels (from the UK Biobank, n = 441,016 participants), non-alcoholic fatty liver disease (from a genome-wide association meta-analysis [GWAS] of 8434 cases and 770,614 controls of European ancestry), type 2 diabetes (from the DIAGRAM consortium, 74,124 cases and 824,006 controls), acute pancreatitis (from a GWAS of 7832 cases and 793,427 controls of European ancestry) and coronary artery disease (from the CARDIoGRAMplusC4D and UK Biobank GWAS meta-analysis [34,541 cases and 261,984 controls of European ancestry]). Results: We selected 27 independent variants near or in the ANGPTL3 region associated with ANGPTL3 blood levels (R2<0.1, p<5x10 -08 ). Genetically-predicted ANGPTL3 levels were strongly and significantly associated with triglyceride and apolipoprotein B levels (beta [SE] = 0.156 [0.032], p-value = 1.05x10 -06 , and beta [SE] = 0.058 [0.013], p-value = 8.16x10 -06 , respectively) but were not associated with non-alcoholic fatty liver disease, type 2 diabetes or coronary artery disease (all p-values > 0.05). Genetically-predicted ANGPTL3 levels were however significantly associated with acute pancreatitis (beta [SE] = 0.071 [0.025], and p-value = 0.004). Conclusions: Our two-sample MR study revealed that blood ANGPTL3 levels may be causally-related to lipid-lipoprotein levels, but not with cardiometabolic diseases. Blood ANGPTL3 levels were however associated with acute pancreatitis, thereby suggesting that ANGPTL3 inhibition might warrant further investigation in the prevention of acute pancreatitis.
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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 | 0.017 | 0.030 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.003 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.000 |
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".