Ala67Thr polymorphism in the Agouti‐related peptide gene is associated with inherited leanness in humans
Bibliographic record
Abstract
A role for melanocortin signaling in the regulation of body weight in humans has been clearly established. Haploinsufficiency of the type 4 melanocortin receptor is associated with early-onset obesity, implying that this receptor provides an important tonic inhibition of weight gain. Agouti-related peptide (AGRP) is an endogenous antagonist of melanocortin signaling. Therefore, loss of AGRP function could lead to the expression of a lean phenotype. We investigated the potential role of AGRP in human weight regulation by examining the association between the Ala67Thr AGRP polymorphism and indices of body composition. Significant associations were found between homozygosity for this mutation (n = 8) and body composition phenotype in 874 subjects of the Quebec family study (QFS). By PCR-RFLP analysis, we have identified eight individuals who are homozygous for the 67Thr variant allele within the QFS population, where none were observed in SAFHS. The eight QFS homozygote individuals have lower weight (-16%; P = 0.02), body mass index (-17%; P = 0.01), fat free mass (-9%; P = 0.002), fat mass (FM) (-20%; P = 0.04), and leptin (-20%; P = 0.02) when compared to those carrying at least one 67Ala allele. Individuals homozygous for the 67Thr allele had a BMI that was either at or slightly below an ideal range for their age. Thus, the Ala67Thr AGRP polymorphism is associated with lower body weight in humans, with the largest effect being observed on body FM. We did not observe any difference in the stability or cellular distribution of the mutant protein in a heterologous expression system, thus the mechanism of this effect requires further investigation.
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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 | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 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".