Polygenic Risk Score for Low-Density Lipoprotein Cholesterol Is Associated With Risk of Ischemic Heart Disease and Enriches for Individuals With Familial Hypercholesterolemia
Why this work is in the frame
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Bibliographic record
Abstract
BACKGROUND: The clinical implications of a polygenic risk score (PRS) for LDL-C (low-density lipoprotein cholesterol) are not well understood, both within the general population and individuals with familial hypercholesterolemia (FH). METHODS: We developed the LDL-C PRS using Least Absolute Shrinkage and Selection Operator regression in 377 286 White British participants from UK Biobank and tested its association with LDL-C according to FH variant carrier status in another 41 748 whole-exome sequenced individuals. Next, we tested for an enrichment of FH variant carriers among individuals with severe hypercholesterolemia and low LDL-C PRS. Last, we contrasted the effect of the LDL-C PRS, measured LDL-C and FH variant carrier status on risk of ischemic heart disease among 3010 cases and 38 738 controls. RESULTS: Among the 41 748 whole-exome sequenced White British individuals, 1-SD increase in the LDL-C PRS was associated with elevated LDL-C among both FH variant carriers (0.34 [95% CI, 0.22-0.47] mmol/L) and noncarriers (0.42 [95% CI, 0.42-0.43] mmol/L). Among individuals with severe hypercholesterolemia, FH variant carriers were enriched in those with a low LDL-C PRS (odds ratio, 2.20 [95% CI, 1.66-2.71] per SD). Each SD increase in the LDL-C PRS was associated with risk of ischemic heart disease to the comparable magnitude as measured LDL-C (odds ratio, 1.24 [95% CI, 1.20-1.29] and odds ratio, 1.15 [95% CI, 1.09-1.23], respectively). The LDL-C PRS was not strongly associated with other traditional ischemic heart disease risk factors. CONCLUSIONS: An LDL-C PRS could be used to identify individuals with a higher probability of harboring FH variants. The association between ischemic heart disease and the LDL-C PRS was comparable to measured LDL-C, likely because the PRS reflects lifetime exposure to LDL-C levels.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 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) | 0.000 | 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 it