(Circulation. 1999;100:2406.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Methylenetetrahydrofolate Reductase Genotypes and Early-Onset Coronary Artery Disease
From the Departments of Cardiology (A.M., Y.B., Y.A.), Medicine D (S.L.), and Medical Genetics (T.S., N.M., M.S.), Rabin Medical Center, Beilinson Campus, Petah-Tiqva, and The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Correspondence to Aviv Mager, MD, Department of Cardiology, Rabin Medical Center, Beilinson Campus, Petah-Tiqva 49100, Israel.
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Abstract |
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Background—Homozygosity for the common (677C
T) mutation in the
methylenetetrahydrofolate reductase
(MTHFR) gene is associated with hyperhomocysteinemia, but there is
uncertainty as to the association between this mutation and
coronary artery disease (CAD). This study examined the
association between MTHFR genotypes and age at onset of
CAD.
Methods and Results—Patients (n=169) with documented myocardial
infarction or angiographically documented CAD who were aged 
55 years
at onset of CAD symptoms and DNA samples from control subjects (n=313)
were studied. The prevalence of homozygosity among patients with early
CAD onset (aged 45 years) was 28%, which was significantly higher
than that in patients with later onset (13%) and in control subjects
(14%) (odds ratio 2.4, 95% CI 1.24 to 4.69, P=0.006,
and odds ratio 2.7, 95% CI 1.15 to 6.42, P=0.01,
respectively). Plasma folate was lower in TT homozygotes who had early
CAD onset than in those with later onset (P=0.005).
Among patients with plasma folate in the lowest quintile (12.6
nmol/L), 31% were homozygotes, as were 45% of those with low plasma
folate and early CAD onset. There was no difference in the prevalence
of traditional risk factors among genotypes. The frequency of
homozygosity in patients with 1 risk factor was higher than in those
with 
2 risk factors (30% versus 12%, P<0.05). In
multiple regression analysis, TT homozygosity and plasma folate
were independently associated with CAD, but the impact of folate was
small.
Conclusions—Homozygosity for the 677CT mutation of MTHFR is
common and is associated with an increased risk of premature CAD in
this population.
Key Words: genetics • coronary disease • risk factors • myocardial infarction
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hyperhomocysteinemia confers an increased risk of coronary artery disease (CAD),1 2 3 stroke,4 and deep vein thrombosis5 and is a strong predictor of mortality among patients with ischemic heart disease.6 Methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the main circulatory form of folate and the methyl donor for homocysteine remethylation, thus regulating the fasting plasma homocysteine level. A common point mutation (677C
T)
in the MTHFR gene renders the enzyme thermolabile and less
active.7 8 9 Homozygosity for this mutation is associated
with mild hyperhomocysteinemia,7 10 11 12 13 14 particularly among
those with low plasma folate levels.10 13 15 16 However,
there is uncertainty as to the association between this mutation and
CAD.8 10 11 12 13 14 16 17 18 19 20 21 22 23 24 25 The present study, undertaken in
Israel, examined the association between homozygosity for this mutation
and age at onset of CAD. |
Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We studied 169 Israeli Jewish patients (26 women and 143 men) from our Post Myocardial Infarction Clinic who were aged
55 years
when they first developed symptoms of CAD and who had angiographically
documented CAD (>50% stenosis of at least one epicardial
coronary artery) or had suffered a myocardial infarction
diagnosed by clinical, ECG, and enzymatic criteria. All the patients
were interviewed, and data involving smoking habits, body weight,
premature CAD in first-degree relatives, use of medications including
vitamins, age at onset of CAD symptoms, anginal status, previous
myocardial infarction, hypertension, diabetes mellitus, and
dyslipidemia were recorded. After a 6-hour fast, blood
was drawn from participants for determination of MTHFR
genotype, lipid profile, creatinine, and plasma
levels of folate and vitamin B12. All
participants underwent coronary angiography for purposes
unrelated to the present study. Each angiogram was reviewed for
determination of the number of lesions with >50% stenosis and
the number of involved coronary arteries. Patients were
allocated to 2 groups according to their age at onset of CAD symptoms:
early onset, 45 years; later onset, 46 to 55 years. For control, DNA
samples were collected from 313 random Jewish males and females who
underwent prenatal screening testing in the genetic clinic at our
center. All were aged <45 years and had no history of CAD. Coronary risk factors included diabetes mellitus, hypertension, dyslipidemia, smoking, obesity, and family history of premature CAD. The following definitions were used: hypertension, blood pressure >140/90 mm Hg or antihypertensive treatment; dyslipidemia, LDL >130 mg%, HDL <35 mg%, triglycerides >300 mg%, or lipid-lowering treatment; smoking, current or recent (<1 year before CAD onset); obesity, body mass index >29; and known coagulation disorders (eg, presence of antiphospholipid antibodies) necessitating anticoagulation.
Genetic and Biochemical Analysis
DNA was isolated from peripheral leukocytes with a
DNA Isolation Kit for Mammalian Blood (Boehringer-Mannheim).
Screening for the 677C T substitution was performed by polymerase
chain reaction of genomic DNA, followed by HinfI digestion
and agarose gel electrophoresis as described by Frosst et
al.7 Plasma cobalamin (vitamin
B12) and folate levels were measured by
radioimmunoassay techniques.
The study was approved by the Ethics Committee of the Rabin Medical Center, and informed consent was obtained from each participant.
Statistical Analysis
Genotype distributions were examined by
2 analysis. Comparison of biological
parameters between the patients with early CAD onset and
later onset was performed by the Wilcoxon rank sum method, and
comparison of plasma folate levels according to MTHFR genotype
was performed by Kruskal-Wallis ANOVA. Logistic regression
analysis was used to calculate the odds ratio (OR) and
associated 95% CIs for the frequency of the homozygous
genotype (TT) among patients with early and later CAD
onset.
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Results |
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The overall frequency of the T (mutant) allele was significantly higher among patients (44.1%) compared with control subjects (36.3%) (OR 1.38, 95% CI 1.05 to 1.83, P=0.02). The distribution of each MTHFR genotype in the 2 groups of patients and in control subjects is shown in Table 1
. The prevalence of TT homozygotes was
significantly higher among patients with early CAD onset than in
control subjects (OR 2.4, 95% CI 1.24 to 4.69, P=0.006) or
in patients with later CAD onset (OR 2.7, 95% CI 1.15 to 6.42,
P=0.01). There was no difference in the prevalence of TT
homozygotes between the group of patients with later CAD onset and
control subjects (P=0.87).
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Table 2 summarizes the patients’
characteristics according to age at CAD onset. The mean level of plasma
folate was significantly lower in patients with early CAD onset
compared with those with later onset (P=0.02). There were no
significant differences between the 2 groups in the mean levels of
vitamin B12, the prevalence of traditional risk
factors, the mean number of coronary lesions with 50%
luminal diameter stenosis, and the mean number of the involved
vessels.
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Table 3 summarizes the patients’
characteristics according to MTHFR genotype. There were no
significant differences between TT homozygotes and patients with other
genotypes in the mean level of vitamin
B12, the prevalence of traditional risk factors,
the number of coronary lesions with 50% luminal diameter
stenosis, and the number of involved vessels.
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Plasma folate was measured in all participants. Ten patients were current multivitamin users and were excluded from further analysis. The mean plasma level of folate in the 159 multivitamin nonusers was 20.1±6.9 nmol/L.
Table 4 indicates the plasma folate
levels by genotype for patients with early and later CAD onset.
Patients with early CAD onset homozygous for the T allele had lower
plasma folate levels than did those with later onset and the TT
genotype (P=0.005) and those with early onset and a
homozygous normal (CC) genotype (P=0.03). Plasma
folate levels did not differ significantly among genotypes in
patients with later onset of CAD. The TT genotype was markedly
overrepresented among patients with plasma folate levels in
the lowest quintile (12.6 nmol/L) (Table 5).
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The frequency of TT genotype decreased markedly with the
increasing number of traditional risk factors. The frequency of
homozygosity in patients with 0 to 1 risk factors (30%) was higher
than the frequency in patients with 2 risk factors (12%,
P<0.05). A family history of premature CAD was reported by
57% of the patients. As shown in Table 6, there were no differences in the
prevalence of this or any other specific risk factor among MTHFR
genotypes.
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Most of our patients (n=151) had myocardial infarction, whereas only 18 patients developed symptoms only. The proportion of patients with symptoms only did not vary by age or by MTHFR genotype. Therefore, the clinical manifestation of CAD could not have had an impact on our findings.
On multiple regression analysis, TT homozygosity and plasma folate were independently associated with early CAD onset compared with later onset, but the association of plasma folate with early CAD onset was much weaker (OR 2.45, 95% CI 0.99 to 6.1, P=0.05, and OR 1.05, 95% CI 1.00 to 1.10, P=0.04, respectively). Plasma folate was modeled as a continuous variable. When plasma folate was not controlled for, the OR for CAD associated with the TT genotype was 2.63 (95% CI 1.15 to 6.04, P=0.02)
The other variables adjusted for in the model were sex (OR 2.31, 95% CI 0.84 to 6.36, P=0.10) and number of coronary risk factors (OR 1.05, 95% CI 0.87 to 1.28, P=0.59). Because of the low prevalence of coronary risk factors and the small size of some patient groups, we could not adequately control for each of these factors. Confounding was addressed, however, by including a term in the model for the number of risk factors. Although there were no differences in any of these factors among genotypes or age groups, it is possible that the control of confounding in this model was not optimal.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We found a significantly higher frequency of homozygosity for the 677C
T mutation of MTHFR in patients with early CAD onset (aged 45
years) than in patients with later onset or control subjects. The OR
for CAD in this age group was 2.4. Other epidemiological studies that
estimated the risk of CAD associated with the TT genotype
showed conflicting results. Although some
investigators11 14 17 found this mutation to be a
significant risk factor for coronary heart disease (OR of 3.1
to 2.1), others found only a mild increase in the risk of
CAD12 18 or even no increase at
all.10 13 16 19 20 21 22 23 24 25 Summarizing the results of 12 studies,
Verhoef et al13 reported that 8 of them did not find an
increased risk of cardiovascular disease for the TT
genotype despite the fact that homozygosity for this mutation
is associated with elevated fasting homocysteine levels. However,
critical analysis of previous reports highlight certain
methodological differences that could have limited their ability to
demonstrate an association between this mutation and the risk of CAD.
For example, age was not restricted in most of the studies that found
no association between MTHFR polymorphism and
CAD,10 21 22 23 24 25 and most of these studies did not include a
separate analysis of patients with very early onset of
coronary heart disease. Interestingly, only 2
studies16 19 of 4 studies8 14 16 19 that
included mostly younger patients found no association between the TT
genotype and CAD. One of them19 compared the
frequency of homozygosity in CAD patients aged <50 years with control
subjects and did not find a significant difference in TT distribution
between the 2 groups. Another study16 investigated the
risk of myocardial infarction specifically in young women. This patient
population was relatively small, and there were significant differences
in the prevalence of coronary risk factors between the patients
and control subjects. To the best of our knowledge, ours is the first
study to assess the relation between MTHFR polymorphism and CAD in
patients aged <45 years at the time of CAD onset. Our results are
consistent with those of Gallagher et al14 and
Kluitmans et al11 in Irish and Dutch populations,
respectively, and show that the TT mutation is a significant risk
factor for very early onset of CAD in the Israeli population as well.
Therefore, it is possible that the TT genotype will emerge as a
risk factor for premature cardiovascular disease in
other populations with a specific genetic background (eg, non–Anglo
Saxon) and in those with low folate intake, such as the Dutch,
Japanese, and Irish populations as well as ours, where folate
supplementation or fortification is not common. Our findings also
suggest that an investigation of the association between the TT
mutation and coronary heart disease specifically in patients
aged 45 years is warranted.
We found lower plasma folate levels in patients homozygous for the
677CT mutation than in those without this genotype. This is
consistent with previous reports of low plasma folate in those
with homozygosity for this mutation.8 10 16 Additionally,
we compared the prevalence of homozygosity between patients with lower
and higher plasma folate levels and found a significantly higher
prevalence among those with plasma folate in the lowest quintile
compared with those with higher levels. There was no difference in the
prevalence of homozygosity between patients with plasma folate below
versus above the median. van Boxmeer et al19 also reported
a lack of difference in the prevalence of homozygosity between patients
with plasma folate below versus above the normal median. However,
analysis of the distribution of MTHFR genotypes in
other folate strata was not performed in the study of van Boxmeer et
al, and folate status was not addressed in any of the studies in which
MTHFR polymorphism was associated with CAD. The marked
overrepresentation of homozygosity among our patients with very
low plasma folate probably indicates that the association between MTHFR
polymorphism and CAD is stronger in those with low plasma folate
levels and that sampling of plasma folate is probably warranted in
patients with early CAD onset.
Folate intake was not assessed in the present study. Mean plasma folate in the group of patients with late CAD onset was 21.4 nmol/L; the normal range in our laboratory has been 6 to 38 nmol/L. In the US population, for comparison, plasma folate levels of 9.8 to 16.1 nmol/L in control subjects and 9.1 to 12.4 nmol/L in CAD patients have been reported. However, given the marked differences in plasma folate in control subjects even among the studies in the US population, it is not clear whether the absolute values of plasma folate in different studies are comparable. Therefore, although folate levels in our patients were higher than those reported in the presumably well-nourished US population, this may not necessarily imply that folate intake in our population was better. Moreover, the lower levels of folate in the group of patients with early CAD onset and the TT genotype still indicate that folate intake in these patients was insufficient.
We found no difference among the genotypes in the frequency of traditional coronary risk factors. This is consistent with previous observations.18 However, there was an inverse relation in our patients between the frequency of the TT genotype and the number of risk factors. This strongly suggests that the association of the TT genotype with CAD is independent of and does not enhance the effect of the classic risk factors.
Our findings are best explained by the effects of the mutation on
folate and homocysteine metabolism. The product of
MTHFR, 5-methyltetrahydrofolate, is the main circulatory form of folate
and the methyl donor for homocysteine remethylation. Homozygosity for
the 677CT mutation is typically associated with lower plasma folate
levels8 10 16 and with higher plasma homocysteine levels,
particularly among those with low plasma
folate,8 10 13 15 16 suggesting that the mutation
itself might affect plasma folate levels and that the effects on both
plasma folate and homocysteine levels may be more marked when folate
intake is low.10 Because there is some variation in MTHFR
activity among those homozygous for the 677CT
mutation,13 the lower plasma folate levels in the group of
patients with early CAD onset and the TT genotype probably
reflect lower MTHFR activity as well as insufficient folate intake and
indicate that plasma homocysteine was increased in these patients. Our
findings may imply, therefore, that the TT genotype, together
with suboptimal folate nutrition, has a major effect on CAD
pathogenesis, because even young people, with few or no risk factors,
are affected, whereas among older people this effect presumably is
"swamped" by other risk factors.
The present study has some limitations. The control group was younger than the patient group; therefore, it is possible that some control subjects could develop CAD at a later stage. This would decrease the significance of our findings. However, because the occurrence of CAD at this age is low, the impact on our results should not be significant. In addition, folate levels were measured in all our patients after CAD onset and often after the patients had participated in health education programs. It is unknown to us whether this may have affected folate intake or plasma folate levels, and further study is necessary.
Received March 30, 1999; revision received July 26, 1999; accepted July 29, 1999.
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