Homocysteine and coronary heart disease : the role of polymorphic genes and hemostasis

<FONT FACE="Arial"><strong>Background</strong> Homocysteine is a sulfur-containing amino acid formed during catabolism of the essential amino acid methionine. Defects in genes encoding enzymes or sub-optimal intake of B-vitamins (e.g. folate) involved in homocysteine metabolism can lead to cellular accumulation of homocysteine resulting in elevated plasma levels. Numerous epidemiological studies have shown a positive association between elevated homocysteine levels and cardiovascular disease (CVD) risk. However, whether elevated homocysteine is a causal risk factor of CVD is still under debate. In addition, the pathogenic mechanism through which homocysteine would increase CVD risk is still unclear, but one of the proposed mechanisms is that homocysteine would impair hemostasis .<strong>Methods</strong> The epidemiological studies described in this thesis explored the evidence with respect to a causal role of homocysteine in the occurrence of coronary heart disease (CHD) by investigating the association of polymorphic genes with risk of CHD. Two placebo-controlled intervention studies on homocysteine lowering in humans investigated the role of hemostasis as a potential mechanism.<strong>Results</strong> In a meta-analysis we showed that homozygosity for the 677C&gt;T mutation in the gene encoding methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in homocysteine remethylation, was associated with a higher risk of CHD, however only when folate status was low. This might explain why the mutation was associated with increased CHD risk in Europe, but not in North America, where folate intake is higher because of widespread use of vitamin supplements and folate fortification. In a case-control study, we observed an increased risk of CHD for individuals who were homozygous for the 2756A&gt;G mutation in the gene encoding methionine synthase (MS), another enzyme involved in homocysteine remethylation. However, this could not be confirmed by the majority of other published case-control studies. In two trials, B-vitamin or folic acid supplementation had no clear beneficial effect on markers of hemostasis, despite a marked reduction in homocysteine concentrations was observed.<strong>Conclusions</strong> The result of our meta-analysis on the MTHFR 677C&gt;T polymorphism and CHD supports the hypothesis that impaired folate metabolism, leading to high homocysteine concentrations, is causally related to CHD risk. The meta-analysis could not reveal whether it is elevated homocysteine, low folate or impaired methylation that is the true cause of CHD. However, our results suggest that increasing population mean levels of folate would reduce the incidence of CHD. This could be achieved by improving the bioavailability of folate from foods and additional food fortification with folic acid. Provided the folate status is adequate, there is little additional value of screening for MTHFR 677C&gt;T genotype. Homocysteine-lowering through B-vitamin supplementation does not seem to affect hemostasis in healthy volunteers. More research is needed to unravel the pathogenic mechanism