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1 From the Department of Biochemistry, Trinity College, Dublin.
See corresponding Perspective on 324.
The homocysteine theory of atherosclerosis, based originally on the presence of cardiovascular disease (CVD) in those with inborn errors of homocysteine metabolism (1), has in recent times had a few reversals. These relate principally to the pattern that has emerged from many studies. Although virtually all the retrospective and most of the prospective case-control studies showed associations between even modest elevation of plasma total homocysteine (tHcy) and CVD, several large and apparently well-conducted prospective studies did not find this association. Furthermore, the presence of the so-called thermolabile polymorphism of the gene for the folate-dependent enzyme methylene tetrahydrofolate reductase (MTHFR), which is known to be associated with elevated tHcy, does not appear to carry a higher risk of CVD. These issues are addressed in 2 Perspectives in this issue of the Journal from opposite standpoints by 2 groups at the forefront of research in this area.
On several grounds, Brattström and Wilcken (2) "have become increasingly doubtful whether modest elevations of plasma homocysteine may be causally involved in the pathogenesis of atherosclerosis." They concede that the high concentration of plasma tHcy seen in the separate inborn errors of the 3 enzymes that control its concentration do cause a primary thrombotic disorder. However, they point out that elevated tHcy in these genetic disorders seems to affect veins more than arteries and has a very different clinical presentation from that usually seen in atherosclerosis (3). Brattström and Wilcken address the now well-established fact that virtually all retrospective and most prospective studies find mild-to-moderate elevation of tHcy in cases with atherosclerosis compared with controls. They point out that in most of these studies the altered risk may be explained by differences in other established risk factors between cases and controls, such as age, sex, smoking status, blood pressure, cholesterol, or amount of exercise. They suggest that these other factors cause atherosclerosis and that elevation of tHcy is just a consequence and not a cause of this disease (4). Calling this a "reverse causality hypothesis," they seek to explain the manner in which atherosclerosis causes elevation of tHcy. To this end they look to the kidney. There is no doubt that this organ is quantitatively important in the catabolism of homocysteine, as shown in animal (5) and human (6) studies in which impaired renal function and renal disease caused tHcy to rise. Impaired renal function is also clearly associated with atherosclerosis. Brattström and Wilcken propose that atherosclerotic changes in the kidney impair the metabolism of homocysteine and that the consequent increase in the plasma concentration of homocysteine is thus a marker and not a cause of atherosclerosis. To support their view, they point to the apparent absence of increased risk of atherosclerosis in subjects with the common C677T MTHFR polymorphism, which has been shown to raise tHcy in the presence of normal renal function.
Ueland et al (7) take a more positive view of the homocysteine theory of atherosclerosis (1). They favor the view that tHcy enhances and exacerbates the risk of atherosclerosis caused by other factors. Unlike Brattström and Wilcken, they do not see the presence of risk factors such as increased blood pressure, as being confounding but propose that the concurrence of these risk factors with elevation in tHcy is an essential part of the etiology of atherosclerosis. They suggest that the absence of increased risk due to the C677T variant of MTFHR is because the numbers examined to date are insufficient.
An essential component of the review by Brattström and Wilcken is that elevation of tHcy is a consequence of impaired renal function that has occurred as a result of atherosclerotic changes in the kidney caused by other risk factors. These authors contend that tHcy is simply an excellent marker of renal metabolism, which is the primary event and which has become impaired as a result of atherosclerotic changes, as yet undetected, being present in the kidney. At its simplest, this concept is not supported by data on the 3 known inborn errors of homocysteine metabolism in which the elevation of tHcy is due to enzyme defects and in which renal metabolism is presumably normal. Brattström and Wilcken believe that this gives rise to a different condition whose clinical presentation is different from atherosclerosis. However, it is difficult to be certain that mild elevation of tHcy for many years would not present itself in the same manner as would higher elevations for shorter periods. This is particularly true if the role of tHcy is only to exacerbate other risk factors, as suggested by Ueland et al.
The contention that underlying renal atherosclerosis is faithfully marked by elevations in tHcy is interesting. However, the concentration of tHcy is clearly dependent on folate status. Thus, one has to envisage that the concentration of tHcy, produced as a result of varying degrees of renal atherosclerosis, will be changed by folic acid. If this theory is correct, then the trials currently in place or planned to intervene with folic acid will reduce the concentration of the putative marker tHcy but will not help lower the risk of the clinical consequences of atherosclerosis. However, other evidence suggests that differences in folate status with consequent differences in tHcy do change risk. This makes it hard to see tHcy as purely a marker. If tHcy is a marker it would seem to mark something that rises or falls with the plasma homocysteine concentration. Attractive candidates are intracellular homocysteine or S-adenosylhomocysteine. Alternatively, tHcy may be a marker for a different faithful confounder. As with the cause of renal disease, it is not clear why confounders such as elevated blood pressure or cholesterol would be faithfully mirrored in tHcy and folate status unless, of course, Ueland et al are correct and tHcy exacerbates the effect of these other risks.
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