A novel functional polymorphism in the uridine diphosphate–glucuronosyltransferase 2B7 promoter with significant impact on promoter activity
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Bibliographic record
Abstract
To clarify the molecular determinants of the metabolic variability of morphine, we searched for genetic polymorphisms in the gene for uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7) and evaluated their functional impact in vitro and in patients with cancer receiving long-term morphine therapy. Genetic analysis revealed the existence of 8 single-nucleotide polymorphisms (SNPs), 6 of which are tightly linked and are at positions -1248, -1241, -1054, -842, -268, and -102 relative to the hepatic start site. In contrast, an SNP at position -66 occurs independently, whereas a novel variation at position -79 appears to be in linkage disequilibrium with the codon 268 SNP (UGT2B7*2). At least 4 haplotypes were observed in white subjects included in the initial SNP screening. On functional in vitro characterization, promoter-reporter gene constructs with the -79 variation displayed 2.5- to 7-fold less activity compared with the wild-type construct in Caco-2 colon cells and HepG2 hepatoma cells, respectively (P =.015 and P <.001, respectively). To investigate a possible effect of the -79 variation in vivo, serum morphine and morphine glucuronide concentrations were measured by liquid chromatography-mass spectrometry in patients with cancer who received long-term oral morphine therapy, and subjects were then genotyped for the -79 polymorphism. Among 175 patients with normal hepatic and renal function, 6 were heterozygous for the -79 variation, and the morphine-6-glucuronide (M6G)/morphine and morphine-3-glucuronide (M3G)/morphine ratios versus those in the 169 noncarriers were 5.9 +/- 3.5 versus 7.1 +/- 7.0 for M6G/morphine (P =.96) and 31.2 +/- 17.1 versus 42.9 +/- 31.2 for M3G/morphine (P =.53), respectively. Further studies in larger samples are needed to make conclusions about the possible clinical relevance of the -79 polymorphism in the UGT2B7 gene.
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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 | 0.003 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.004 |
| 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 it