Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases
Introduction
Hyperhomocysteinemia is now becoming increasingly accepted as one of the most important risk factors for atherosclerotic occlusive vascular disease and may explain, at least in part, the occurrence of coronary artery disease (CAD) in patients who do not have dyslipidemia, hypertension and other conventional risk factors. A large number of case-control and cross-sectional studies [1], [2] and several prospective studies [3], [4], [5] have demonstrated that mildly elevated plasma total homocysteine (tHcy) measured during fasting is associated with increased risk of occlusive vascular diseases. A recent report indicates that plasma tHcy concentration is a strong predictor of mortality in patients with angiographically confirmed CAD [6].
The majority of epidemiological studies have focused on fasting hyperhomocysteinemia. In addition, tHcy can be measured after methionine loading. Presence of an elevated tHcy 2–6 h after a dose of methionine is known as post-methionine load (PML) hyperhomocysteinemia. Early clinical studies [7], [8], [9] have shown that obligate heterozygous relatives of patients with classic homocystinuria due to cystathionine-β-synthase (CBS, EC 4.2.1.22) deficiency are more likely to have PML hyperhomocysteinemia than fasting hyperhomocysteinemia. Preliminary results from the NHLBI family heart study showed that PML and fasting hyperhomocysteinemia are independent of each other in the majority of individuals and that without methionine loading, approximately 40% of the cases of elevated plasma tHcy could be missed [10]. More recently, the European concerted action project studied 750 cases of atherosclerotic vascular disease and 800 controls with respect to fasting and PML homocysteine and found that among the patients with hyperhomocysteinemia, 27% had only PML hyperhomocysteinemia [2].
Mild hyperhomocysteinemia, whether measured during fasting or after a methionine load, can be caused by micronutrient deficiencies, such as insufficient folate, vitamin B6, and vitamin B12 intake [11], and by impaired renal function [12]. Genetic defects in either the transsulfuration or the remethylation pathways of homocysteine metabolism have also been shown to predispose individuals to elevated plasma homocysteine.
In the transsulfuration pathway, presence of mutations in the CBS gene in the heterozygous carrier state was thought to be the major cause of PML hyperhomocysteinemia [7], [8]; however, two recent studies were unable to confirm this hypothesis [13], [14]. In the remethylation pathway, a ‘thermolabile’ variant form (C677T) of methylenetetrahydrofolate reductase (MTHFR, EC 1.5.1.20) has been reported to be more prevalent in patients with CAD (17%) than controls (5%) [15], [16]; however, recent reports indicate that homozygosity of this mutation is not associated with increased risk of CAD [17], [18], [19], [20], [21]. Deficiency of B12-dependent methionine synthase (MS, EC 2.1.1.13), an enzyme which catalyzes the remethylation of homocysteine to methionine, may also result in hyperhomocysteinemia. Recently, the gene coding for MS has been cloned and sequenced, and several mutations of the MS gene have been identified [22], [23], [24], [25]. The one most prevalent mutation is that of the A2756G transition, resulting in the substitution of aspartic acid by glycine [22].
In the current investigation, we studied a relatively large number of patients with documented premature CAD and controls. We measured tHcy levels during fasting and 4 h PML and determined four common mutations: the T833C and G919A transitions—the two most prevalent mutations of the CBS gene [9], [14], [26], [27], [28]; the C677T mutation of the MTHFR gene; and the A2756G mutation of the MS gene with the objective of (1) to examine the relationships between plasma tHcy levels and premature CAD; and (2) to determine the importance of genetic influence on plasma tHcy levels, both during fasting and 4 h PML.
Section snippets
Subjects
We studied 376 patients (297 males ranging in age from 27 to 65 years, mean age 48.7 years; and 79 females ranging in age from 36 to 62 years, mean age 48.4 years) with premature CAD as documented by angiographically-proven atherosclerosis, and/or one or more episodes of myocardial infarction or coronary artery bypass surgery before the age of 55 years. For the control group, we concurrently recruited 82 apparently healthy individuals, most of whom were either present or past employees of the
Levels of plasma total homocsyteine
Fig. 1 compares the concentrations of plasma fasting and PML rise in tHcy concentration after adjustment for age and gender on 82 apparently healthy controls and 376 patients with premature CAD. The mean geometric fasting tHcy concentration in CAD patients (9.7 μmol/l; 95% CI, 9.3–10.2 μmol/l) was significantly (P=0.007) higher than the mean concentration in controls (8.7 μmol/l; 95% CI, 7.9–9.5 μmol/l). The mean PML rise in tHcy concentration in CAD patients (22.3 μmol/l; 95% CI, 21.3–23.4
Discussion
Most large epidemiological studies of homocysteine metabolism in CAD patients have measured tHcy only in the fasting state. Of the clinical studies which used post-methionine loading, relatively small numbers of patients were involved. Since these studies include patients with different vascular diseases, even smaller numbers of patients studied had documented CAD.
The current investigation of 376 patients represents one of the largest studies of both fasting and PML homocysteine patients with
Acknowledgements
This study was supported in part by a grant from the Minnesota Medical Foundation of the University of Minnesota and by a grant from the American Heart Association, Minnesota Affiliate.
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