MTHFR genotype modifies the effect of lead exposure on plasma homocysteine in older adults
Why this work is in the frame
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Bibliographic record
Abstract
Background: Lead exposure appears to elevate homocysteine, a one-carbon metabolite and important risk factor for chronic cardiovascular and neurodegenerative diseases. The influence of genetic susceptibility on lead exposure’s association with homocysteine is unknown. Aims: To determine the joint relation of lead exposure and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, which encodes a key enzyme in one-carbon metabolism, to plasma homocysteine. Methods: From a subcohort of the VA Normative Aging Study (n=876 older men), we obtained data on genotypes of MTHFR, cumulative lead exposure, and repeated measures of recent lead exposure and plasma homocysteine. We used multivariable-adjusted linear regression and linear mixed effects models to assess the interaction of lead exposure and genotype on homocysteine. Results: The association of blood lead concentration with plasma homocysteine varied significantly by MTHFR genotype at five of eleven loci (rs4846049, rs6541003, rs1994798, rs1801133, and rs1801131; P<0.05). For example, among men with the major allele (AA) at rs1801131, an interquartile range (IQR) difference in blood lead concentration (3 ug/dl) was associated with 6.6% higher plasma homocysteine (95% CI: 4.5% to 8.8%), while among men with the minor allele (CC) (resulting in a non-synonymous amino acid change), blood lead level was not associated with homocysteine (an IQR difference in blood lead associated with -1.4% difference in homocysteine, 95% CI: -6.1% to 3.5%). At visit one, participants with two copies of the most frequent (33.6%) MTHFR haplotype had the strongest lead-homocysteine association; an IQR increase in blood lead was associated with a 13.0% increase in homocysteine (95% CI: 6.0-19.9), compared to men with one (9.9%) or zero (4.9%) copies of this haplotype. Conclusions: The MTHFR gene may influence susceptibility to lead-induced elevation in homocysteine. A one-carbon metabolism pathway analysis of lead and homocysteine will also be explored.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.001 |
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