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Oxidative stress and platelet activation in subjects with moderate hyperhomocysteinaemia due to MTHFR 677 C→T

Alfredo Dragani1, Angela Falco, Francesca Santilli

  • 1Department of Haematology, Civil Hospital Pescara, Italy.

Thrombosis and Haemostasis
|July 12, 2012
PubMed

Insights

The methylenetetrahydrofolate reductase (MTHFR) 677 C→T polymorphism is linked to higher homocysteine, increasing cardiovascular risk. Folic acid supplementation can reverse associated lipid peroxidation and platelet activation in carriers.

Area of Science:

  • Biochemistry
  • Genetics
  • Cardiovascular Disease

Background:

  • The methylenetetrahydrofolate reductase (MTHFR) 677 C→T polymorphism is associated with elevated total homocysteine (tHcy) levels.
  • Elevated tHcy is an independent risk factor for cardiovascular disease.
  • Understanding the impact of this polymorphism on oxidative stress and platelet activation is crucial for cardiovascular risk assessment.

Purpose of the Study:

  • To evaluate in vivo lipid peroxidation and platelet activation in carriers versus non-carriers of the MTHFR 677 C→T polymorphism.
  • To investigate the relationship between these markers, tHcy, and folate levels.
  • To explore the causal relationship using methionine loading and folic acid supplementation.

Main Methods:

  • Cross-sectional comparison of 100 MTHFR 677 C→T carriers and 100 non-carriers.
  • Measurement of urinary 8-iso-prostaglandin (PG)F(2α) (lipid peroxidation) and 11-dehydro-thromboxane (TX)B(2) (platelet activation).
  • Inclusion of methionine-loading tests and folic acid supplementation to assess causality and reversibility.

Main Results:

  • Carriers with hyperhomocysteinaemia exhibited higher urinary 8-iso-PGF(2α) and 11-dehydro-TXB(2) compared to non-carriers.
  • High tHcy, low folate, and the MTHFR 677 C→T polymorphism independently predicted increased 8-iso-PGF(2α) excretion.
  • Folic acid supplementation reduced urinary prostanoid metabolites in hyperhomocysteinaemic carriers, indicating partial reversibility.

Conclusions:

  • Hyperhomocysteinaemia linked to the MTHFR 677 C→T polymorphism is associated with increased in vivo lipid peroxidation and platelet activation.
  • These effects are at least partially reversible with folic acid supplementation.
  • An integrated biomarker approach may identify individuals who would benefit most from folate supplementation for cardiovascular risk reduction.

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