Oxidative stress and platelet activation in subjects with moderate hyperhomocysteinaemia due to MTHFR 677 C→T polymorphism.
The methylenetetrahydrofolate reductase (MTHFR) 677 C→T polymorphism may be associated with elevated total homocysteine (tHcy) levels, an independent risk factor for cardiovascular disease. It was the study objective to evaluate in vivo lipid peroxidation and platelet activation in carriers of the MTHFR 677 C→T polymorphism and in non-carriers, in relation to tHcy and folate levels. A cross-sectional comparison of urinary 8-iso-prostaglandin (PG)F(2α) and 11-dehydro-thromboxane (TX)B(2) (markers of in vivo lipid peroxidation and platelet activation, respectively) was performed in 100 carriers and 100 non-carriers of the polymorphism. A methionine-loading test and folic acid supplementation were performed to investigate the causal relationship of the observed associations. Urinary 8-iso-PGF(2α) and 11-dehydro-TXB(2) were higher in carriers with hyperhomocysteinaemia than in those without hyperhomocysteinaemia (p<0.0001). Hyperhomocysteinaemic carriers had lower folate levels (p=0.0006), higher urinary 8-iso-PGF(2α) (p<0.0001) and 11-dehydro-TXB(2) (p<0.0001) than hyperhomocysteinaemic non-carriers. On multiple regression analysis, high tHcy (p<0.0001), low folate (p<0.04) and MTHFR 677 C→T polymorphism (p<0.001) independently predicted high rates of 8-iso-PGF(2α) excretion. Methionine loading increased plasma tHcy (p=0.002), and both urinary prostanoid metabolites (p=0.002). Folic acid supplementation was associated with decreased urinary 8-iso-PGF(2α) and 11-dehydro-TXB2 excretion (p<0.0003) in the hyperhomocysteinaemic group, but not in the control group, with substantial inter-individual variability related to baseline tHcy level and the extent of its reduction. In conclusion, hyperhomocysteinaemia due to the MTHFR 677 C→T polymorphism is associated with enhanced in vivo lipid peroxidation and platelet activation that are reversible, at least in part, following folic acid supplementation. An integrated biomarker approach may help identifying appropriate candidates for effective folate supplementation.
Department of Haematology, Civil Hospital Pescara, Italy.
Alfredo
A
Dragani
Angela
A
Falco
Francesca
F
Santilli
Stefania
S
Basili
Giancarlo
G
Rolandi
Loredana
L
Cerasa
Stefano
S
Lattanzio
Giovanni
G
Ciabattoni
Carlo
C
Patrono
Giovanni
G
Davì
D015415:Biomarkers; D002318:Cardiovascular Diseases / Q000453:epidemiology; D015897:Comorbidity; D003430:Cross-Sectional Studies; D003920:Diabetes Mellitus / Q000453:epidemiology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D050171:Dyslipidemias / Q000453:epidemiology; D005492:Folic Acid / Q000097:blood / Q000627:therapeutic use; D006712:Homocystinuria / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood* / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D015227:Lipid Peroxidation; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D009128:Muscle Spasticity / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D018384:Oxidative Stress; D015539:Platelet Activation; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000097:blood / Q000453:epidemiology / Q000235:genetics; D012907:Smoking / Q000453:epidemiology; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine
D015415:Biomarkers; C075750:8-epi-prostaglandin F2alpha; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; D005492:Folic Acid; D008715:Methionine; D015237:Dinoprost; D042965:Methylenetetrahydrofolate Reductase (NADPH2)