Genetic and secondary causes of severe HDL deficiency and cardiovascular disease
Bibliographic record
Abstract
Supplementary key words apoA-I • ABCA1 • lecithin:cholesterol acyltransferase • lipoprotein lipase • high density lipoprotein metabolism • reverse cholesterol metabolism • dyslipidemia • genes in lipid disordersIt has been concluded that genetic HDL deficiency is not causative for atherosclerotic cardiovascular disease (ASCVD), in contrast to genetic hypercholesterolemia associated with elevated levels of LDL cholesterol (LDL-C) or genetic hypertriglyceridemia (1, 2).This assessment has been reported in high-impact journals by a very large number of authors, representing some of the most prominent and well-known scientists in our field.The data generated stem from a very large number of subjects studied with and without ASCVD.The analyses, however, were based entirely on SNPs, mainly in intronic DNA regions, and excluded the four most important genes that regulate HDL cholesterol (HDL-C) levels: ABCA1, LCAT, APOA1, and LPL.The exclusions were justified by study findings that 1) genetic variations at the ABCA1, LCAT, APOA1, and LPL gene loci also affect TG and/or LDL-C levels and 2) an LIPC variant was not associated with ASCVD (1, 2).In our view this justification is flawed.Our recent review of severe HDL deficiency has documented that patients with HDL-C levels <20 mg/dl in the absence of secondary causes may have premature ASCVD, especially if such patients are homozygous or compound heterozygous for mutations in the APOA1 or ABCA1 genes (3).Abstract We assessed secondary and genetic causes of severe HDL deficiency in 258,252 subjects, of whom 370 men (0.33%) and 144 women (0.099%) had HDL cholesterol levels <20 mg/dl.We excluded 206 subjects (40.1%) with significant elevations of triglycerides, C-reactive protein, glycosylated hemoglobin, myeloperoxidase, or liver enzymes and men receiving testosterone.We sequenced 23 lipid-related genes in 201 (65.3%) of 308 eligible subjects.Mutations (23 novel) and selected variants were found at the following gene loci: 1) ABCA1 (26.9%): 2 homozygotes, 7 compound or double heterozygotes, 30 heterozygotes, and 2 homozygotes and 13 heterozygotes with variants rs9282541/p.R230C or rs111292742/c.-279C>G; 2) LCAT (12.4%): 1 homozygote, 3 compound heterozygotes, 13 heterozygotes, and 8 heterozygotes with variant rs4986970/p.S232T; 3) APOA1 (5.0%): 1 homozygote and 9 heterozygotes; and 4) LPL (4.5%): 1 heterozygote and 8 heterozygotes with variant rs268/p.N318S.In addition, 4.5% had other mutations, and 46.8% had no mutations.Atherosclerotic cardiovascular disease (ASCVD) prevalence rates in the ABCA1, LCAT, APOA1, LPL, and mutation-negative groups were 37.0%, 4.0%, 40.0%, 11.1%, and 6.4%, respectively.Severe HDL deficiency is uncommon, with 40.1% having secondary causes and 48.8% of the subjects sequenced having ABCA1, LCAT, APOA1, or LPL mutations or variants, with the highest ASCVD prevalence rates being observed in the ABCA1 and APOA1 groups.-Geller, A. S., E. Y.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.093 | 0.009 |
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".