Serum Homocysteine and Methylene Tetrahydrofolate Reductase Gene Polymorphism: Implications in Cardiovascular Disease
Claudio Cortese, Corradino Motti, Stefano Bertolini*, Sergio Bernardini, Renato Massoud, Giorgio Federici.
Dept. of Internal Medicine, Univ. of Tor Vergata, Rome; *Dept. of Internal Medicine, Univ. of Genoa, Genoa, Italy
Homocysteine is emerging as an important new risk factor for cardiovascular disease. Its metabolism represents an interesting model of gene-gene and gene-environment interaction. Homocysteine is a thiol compound which derives from methionine and follows two main metabolic pathways:1) remethylation to methionine requiring folate and vitamin B12 as cofactors; 2)transsulfuration to cystathionine and cysteine requiring vitamin B6 as cofactor. Elevations in homocysteine levels may be caused by deficiencies in cofactor levels and/or genetic defects in enzymes involved in homocysteine metabolism. In particular, a common polymorphism in the gene for the 5,10-methylene tetrahydrofolate reductase (MTHFR) (C677T, Ala->Val) is associated with thermolability and decreased activity of the enzyme. Subjects carrying the Val allele are exposed to the risk of developing a mild-to-moderate hyperhomocysteinemia, which has been recognized as an additive and independent risk factor for atherosclerosis in several epidemiological studies. The genetic effect caused by the MTHFR polymorphism is blunted in women in premenopausal age (probably because of estrogen levels) and in subjects who exhibit serum levels of folate and/or vitamin B12 above the 50th percentile of distribution in the general population. Because of the complexity of the interactions underlying the variability in homocysteine levels, we have explored a unique study model by investigating the risk-related role of homocysteine and MTHFR gene polymorphism in a cohort of well-characterized individuals already affected by a genetic burden related to atherosclerosis. 447 Italian subjects affected by heterozygous familial hypercholesterolemia, a genetic condition caused by defects in the LDL receptor gene, have been studied for the presence of moderate hyperhomocysteinemia and of the Val allele of the MTHFR polymorphism. Our results demonstrate that in this population sample serum homocysteine levels are an independent predictor of coronary heart disease risk in males (OR: 1.8) along with arterial hypertension and LDL cholesterol, whereas in females only LDL cholesterol emerges as independent predictor of coronary events. MTHFR polymorphism is not "per se" an independent contributor to the CHD risk, although it strongly influences the levels of serum homocysteine.