Abstract 155: Mutations In ABCA8 Result In HDL Deficiency And Cholesterol Efflux Defects
Bibliographic record
Abstract
The molecular basis of extreme HDL-C levels is incompletely understood. To identify mutations in novel putative HDL genes, we sequenced select genes in 80 unrelated individuals with extreme low HDLc (HDL %ile≤10th) and as controls, 120 individuals with high HDL (HDL %ile≥90th). We identified two variants in ABCA8 in subjects with low HDL-C levels. The E18-2T>C mutation is located in a highly conserved region and gives rise to a disruption of a splice site. The G>C variant occurs at a site conserved in vertebrates, at position 64425884 (build HG18), and results in Pro609Arg substitution. No ABCA8 mutations were identified in HHDL individuals. These represent the first mutations identified in ABCA8, which belongs to the family of ATP binding cassette transporters. Family expansion followed by genotyping identified additional mutation carriers and first degree relative controls in whom segregation analyses were performed. Compared with controls, mutation carriers showed a significant 32.6% decrease in plasma HDLc levels and decreased HDL percentiles (HDLc: controls = 1.23±0.26, mutation carriers = 0.83±0.37, mmol/L, p=0.0007; HDL%ile: controls = 41.8±21.2, mutation carriers = 17.3±19.2, p=0.004, n=23 controls and 12 carriers). No changes in LDLc, triglycerides or BMI were observed. Since mutations in ABCA8 reduce plasma HDLc levels, we assessed the role of ABCA8 in lipid efflux. Cholesterol efflux to lipid-free APOA-I was significantly reduced by 62.1% in fibroblasts from the proband with the E18-2 T>C mutation. In comparison, fibroblasts from heterozygous ABCA1 mutation carriers showed a 30-60% decrease in efflux to APOA-I depending on mutation severity. Wild type and P609R ABCA8 cDNA clones were generated from human liver RNA. A significant ~200% increase in cholesterol efflux to lipid free APOA-I was observed with wild type ABCA8, further suggesting that ABCA8 is a lipid transporter. A significant 75% decrease in the efflux of cholesterol to lipid-free APOA-I (p=0.02) was observed with the mutant P609R ABCA8 protein compared to wild-type. We show here that ABCA8 is a cholesterol transporter, and that mutations in ABCA8 are a novel cause for reduced plasma HDLc levels in humans.
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How this classification was reachedexpand
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 | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".