Lipoprotein(a) levels, genotype and incident aortic stenosis: a prospective Mendelian randomization study and replication in a case-control cohort
Bibliographic record
Abstract
Purpose: Aortic valvular stenosis (AVS) is a complex disorder and previous, non-replicated studies have suggested that AVS patients are characterized by high lipoprotein(a) [Lp(a)] levels. The objective of our study was to test the hypothesis that high Lp(a) levels are associated with an increased risk of developing AVS. We also tested the hypothesis that a common genetic variant that is strongly associated with Lp(a) levels is also associated with AVS risk, an approach that may support causality. Methods: Serum Lp(a) levels were measured in 17,553 participants of the EPIC-Norfolk cohort. Among these study participants, 118 developed AVS during a mean follow-up of 11.7 years. Participants were identified as having incident AVS if they were either hospitalized or died with AVS reported as an underlying cause. The rs10455872 genetic variant in LPA was genotyped in 14,735 study participants who simultaneously had Lp(a) levels measurements. In a replication study of 379 patients with echocardiography-confirmed AVS (aortic jet velocity ≥2.5 m/s) and 404 controls (aortic jet velocity ≤1.7 m/s), we genotyped 446 genetic variants in the SLC22A3-LPAL2-LPA-PLG region with a minor allele frequency >0.05. Results: Compared to participants in the bottom Lp(a) tertile, those in the top Lp(a) tertile had a higher risk of AVS (HR=1.57 [95% CI, 1.02-2.42]) after adjusting for age, sex and smoking. There was an allele-dose dependent association between rs10455872 and Lp(a) levels with AA, AG, and GG carriers having Lp(a) levels of 9.7 (IQR, 5.6-17.5), 45.1 (34.9-57.7) and 69.8 (49.9-88.1) mg/dL, respectively (p<0.001). Compared to AA homozygotes, carriers of one or two G alleles were at increased risk of AVS (HR=1.78 [1.11-2.87] and HR=4.83 [1.77-13.20]), respectively for AG and GG carriers). In the replication study, the genetic variant rs3106164 in the SLC22A3 gene showed the strongest association with AVS presence (p=3.8E-04). Conclusions: Results of the present study suggest that patients with high Lp(a) levels are at increased risk for AVS. The LPA rs10455872 variant which is associated with higher Lp(a) levels is also associated with increased risk of AVS, suggesting that this association may in fact be causal. Whether pharmacological interventions to reduce Lp(a) levels will concomitantly reduce the risk of AVS needs would require testing in randomized controlled trials.
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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 | 0.005 | 0.008 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".