Methylation & Detox SNPs (MTHFR, COMT, GST) - References

Methylation & Detox SNPs (MTHFR, COMT, GST) — Literature Dossier

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Landmark Peer-Reviewed Studies

1. McNulty et al. (2006) — Riboflavin (FAD) Rescues MTHFR 677TT Thermolabile Activity

• Citation: McNulty, H., Dowey, L. R. C., Strain, J. J., Dunne, A., Ward, M., Molloy, A. M., … & Scott, J. M. (2006). Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C$\to$T polymorphism. Circulation, 113(1), 74–80.
• Identifiers: DOI: 10.1161/CIRCULATIONAHA.105.580332 (DOI · SciDB · Scholar) | PMID: 16380544 (PubMed · Europe PMC)
• Study Design & Cohort: Double-blind, randomized, placebo-controlled intervention trial stratified by MTHFR C677T genotype (CC, CT, TT; $N=97$ healthy adults selected from a screened cohort of $N=680$).
• Quantitative Findings & Diagnostic Thresholds:
  • Twelve weeks of riboflavin supplementation ($1.6\text{ mg/day}$) decreased plasma homocysteine by 22% (from $16.1$ to $12.5\mu \text{mol/L}$, $p=0.003$) overall in the MTHFR 677TT group, and by 40% (from $22.0$ to $13.2\mu \text{mol/L}$, $p=0.010$) in TT individuals with lower baseline riboflavin, with zero effect in CC or CT genotypes, confirming FAD cofactor stabilization of the variant enzyme.

2. Horigan et al. (2010) — Genotype-Specific Blood Pressure Lowering by Riboflavin in MTHFR 677TT

• Citation: Horigan, G., McNulty, H., Ward, M., Strain, J. J., Purvis, J., & Scott, J. M. (2010). Riboflavin lowers blood pressure in patients with premature cardiovascular disease Homozygous for the 677C$\to$T polymorphism in MTHFR. Journal of Hypertension, 28(3), 478–486.
• Identifiers: DOI: 10.1097/HJH.0b013e328334c126 (DOI · SciDB · Scholar) | PMID: 20090556 (PubMed · Europe PMC)
• Study Design & Cohort: Randomized, double-blind, placebo-controlled trial ($N=181$ patients with premature CVD screened by MTHFR C677T genotype).
• Quantitative Findings & Diagnostic Thresholds:
  • In MTHFR 677TT homozygotes, riboflavin ($1.6\text{ mg/day}$ for 16 weeks) reduced systolic blood pressure by $13.1\text{ mmHg}$ (from $144.0\pm 17.5$ to $130.9\pm 14.3\text{ mmHg}$, $p<0.01$) and diastolic blood pressure by $7.9\text{ mmHg}$ ($p<0.01$), exceeding the efficacy of standard antihypertensive monotherapy in this genetic subgroup.

3. Egan et al. (2001) — COMT Val158Met Genotype and Prefrontal Dopamine Physiology

• Citation: Egan, M. F., Goldberg, T. E., Kolachana, B. S., Callicott, J. H., Mazzanti, C. M., Straub, R. E., … & Weinberger, D. R. (2001). Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proceedings of the National Academy of Sciences, 98(12), 6917–6922.
• Identifiers: DOI: 10.1073/pnas.111134598 (DOI · SciDB · Scholar) | PMID: 11381111 (PubMed · Europe PMC) | PMCID: PMC34453 (PMC Full Text)
• Study Design & Cohort: Neuroimaging (fMRI) and neurocognitive study ($N=493$ participants) evaluating the functional polymorphism rs4680 (Val158Met) in Catechol-O-Methyltransferase.
• Quantitative Findings & Diagnostic Thresholds:
  • The Met/Met (A/A) low-activity allele (3–4-fold lower enzymatic catabolism of synaptic dopamine) accounted for 4.1% of total variance ($p=0.004$) in Wisconsin Card Sorting Test executive perseverative errors and demonstrated significantly greater prefrontal cortical efficiency (lower fMRI BOLD activation required for equivalent working memory accuracy, $p<0.001$) under non-stressed conditions.

4. da Costa et al. (2006) — PEMT SNPs Confer High Susceptibility to Choline Deficiency Organ Dysfunction

• Citation: da Costa, K. A., Kozyreva, O. G., Song, J., Galanko, J. A., Fischer, L. M., & Zeisel, S. H. (2006). Common genetic polymorphisms affect the human requirement for the nutrient choline. The FASEB Journal, 20(9), 1336–1344.
• Identifiers: DOI: 10.1096/fj.06-5734com (DOI · SciDB · Scholar) | PMID: 16816108 (PubMed · Europe PMC) | PMCID: PMC1574369 (PMC Full Text)
• Study Design & Cohort: Controlled inpatient metabolic ward depletion-repletion clinical study ($N=57$ adults placed on a low-choline diet $<50\text{ mg/day}$ for up to 42 days).
• Quantitative Findings & Diagnostic Thresholds:
  • Carriers of the PEMT promoter SNP rs12325817 (C allele) had an Odds Ratio of $25.0$ ($p=0.002$; 78% penetrance) for developing clinical fatty liver or muscle damage (elevated ALT/AST or CPK) when deprived of dietary choline, because PEMT fails to induce de novo hepatic phosphatidylcholine synthesis via S-adenosylmethionine methylation.