Review Article Methylene Tetrahydrofolate Reductase Gene and Coronary Artery Disease

Hyperhomocysteinemia has been identified as a risk factor for coronary artery disease (CAD).1-9 In a nested case control study in Norway on 21,826 subjects in general population, hyperhomocysteinemia was clearly identified as an independent risk factor for CAD with no threshold level.9 Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the methylation of homocysteine and its role in this pathway is outlined in Figure. Several inherited enzyme defects that can lead to elevated level of plasma homocysteine have been reported. Defective cystathionine b-synthase was the first to be extensively studied.10 However, defective remethylation of homocysteine due to defective MTHFR was another cause of hyperhomocysteinemia leading to premature vascular disease.11 So far 10 mutations have been identified in the gene for MTHFR12,13 that result into decreased activity of this enzyme, which varies to a great extent. However, a homozygous mutation of the MTHFR gene (677C T; ala val) alters the highly conserved amino acid alanine to valine, which results in compromised activity of MTHFR and leads to reduced methylation of homocysteine, and hence, to hyperhomocysteinemia.14 This variant of MTHFR had increased thermolability and was reported to be associated with the development of CAD.15 Since then the polymorphism of the gene of this enzyme has been a subject of great interest and a number of investigators have reported different results from a number of different populations. The objective of this review is to highlight the results of some of these studies and to emphasize the need to focus on the genetic architecture of CAD in a country, such as, Pakistan where this disease is quite common in the younger population.16 As a general rule, the earlier the onset of a complex disease (which results from interactions between genetic and environmental factors), the greater the role of the genetic make-up.