Abstract 20: Evidence of UGT2B7 as a Pharmacogenetic Determinant of Variability in Serum Fenofibric Acid Levels in Human Subjects
Bibliographic record
Abstract
BACKGROUND: Genetic polymorphisms affecting the drug metabolizing gene [UDP-glucuronosyltransferases or UGTs-(specifically UGT2B7 )] have been reported by our group as a significant source of variability in the lipid-lowering response to fenofibrate. Fenofibrate’s lipid-lowering response displays exceptionally high inter-subject variability which may represent one source of the mixed results from outcome based clinical trials such as ACCORD and FIELD. Given the association between lipid response and fenofibric acid serum concentrations, the purpose of this study was to investigate the pharmacokinetic significance of the UGT2B7 promoter SNP (A-327G SNP (rs7662029)) on serum fenofibric acid concentrations in humans. METHODS: Using a genotype guided approach, we prospectively recruited subjects (>18 years) whose genotype was either AA or GG for UGT2B7 A-327G to receive 28 days once daily fenofibrate (145mg). Steady-state area under the serum fenofibrate concentration vs. time curve (AUC 0-24 ) was calculated from 8 determinations on day 28. Fasting lipid profiles where collected at baseline and after fenofibrate administration. RESULTS: 49 (39% male) individuals with a mean (±SD) age of 33 (±11.8) years completed the study. This included 26 with AA and 23 with GG for UGT2B7 A-327G. The mean (±SD) AUC 0-24 was 218.4±98 μg*hr/mL for AA and 300±131 μg*hr/mL for the GG individuals ( p =0.017). Overall, associations between higher AUC 0-24 and percent change in lipid fraction from baseline, were confirmed for TG (r 2 =0.26, p-value= 0.0002), total cholesterol (r 2 =0.12, p=0.014), LDL-C (r 2 =0.17, p= 0.0032,), non-HDL-C (r 2 =0.11, p=0.019) but not HDL-C (NS). Adjusted for BMI, UGT2B7 A-327G explained 22% of the fenofibric acid AUC 0-24 , with AA individuals having 27.3% lower AUC 0-24 compared to GG individuals. CONCLUSIONS: We confirm UGT2B7 A-327G to be a significant determinant of serum fenofibric acid concentrations and hence a potential important source of fenofibrate’s variability in lipid response and/or clinical outcomes.
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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 | 0.002 | 0.003 |
| 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 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".