Atherosclerosis 153 2000 161 – 168
The methylenetetrahydrofolate reductase gene is associated with increased cardiovascular risk in Japan, but not in other
populations
Sun Ha Jee
a,
, Terri H. Beaty
b
, Il Suh
c
, Young-sup Yoon
d
, Lawrence J. Appel
b
a
Department of Epidemiology and Disease Control, Yonsei Uni6ersity Graduate School of Health Science and Management, CPO POB
8044
, Seoul, South Korea
b
Department of Epidemiology, Johns Hopkins Uni6ersity School of Hygiene and Public Health, Baltimore, MD, USA
c
Department of Pre6enti6e Medicine and Public Health, Yonsei Uni6ersity College of Medicine, Seoul, South Korea
d
Di6ision of Cardiology, Yonsei Cardio6ascular Center, Yonsei Uni6ersity College of Medicine, Seoul, South Korea Received 7 June 1999; received in revised form 13 December 1999; accepted 14 January 2000
Abstract
The methylenetetrahydrofolate reductase MTHFR gene has been associated with increased risk for cardiovascular disease in some, but not all studies. Our data sources included a MEDLINE search of the literature published before December 1998, a
bibliography review, and expert consultation. Of 23 studies initially identified, 18 9855 persons met the inclusion criteria. Information on sample size, study design, Hardy – Weinberg equilibrium, method of genotype determination, plasma folate and
homocysteine were abstracted by two reviewers using a standardized protocol. The overall odds ratio of the MTHFR gene on cardiovascular disease was estimated using the Mantel – Haenzel method. From 12 studies with angiographically-confirmed
coronary artery disease CAD, the overall odds ratio OR for CAD among those with heterozygous VA was 1.3 95 CI, 1.1 – 1.5, while it was 1.4 1.2 – 1.6 for the homozygous mutant VV compared to those with homozygous normal AA.
However, the overall odds ratio for CAD among those with the VV genotype versus AA genotype was not statistically significant OR: 1.1; 95 CI: 0.9 – 1.3 after excluding three Japanese studies. The corresponding OR for the three Japanese studies was 2.0
1.6 – 2.7. For six studies with myocardial infarction MI, the overall OR of MI was 1.0 0.8 – 1.1 for those with the VA genotype and 0.9 0.7 – 1.1 for those with the VV genotype, respectively; none of these ORs for MI was statistically significant.
The MTHFR gene is associated with increased risk for CAD in Japan, but not in other populations. © 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords
:
Genotype; MTHFR; Coronary artery disease; Myocardial infarction; Racial difference www.elsevier.comlocateatherosclerosis
1. Introduction
Over the past decade, mild hyperhomocysteinemia has been recognized as a risk factor for occlusive arte-
rial disease and thrombosis [1 – 5]. A meta-analysis of 27 studies investigating the relation between fasting total
homocysteine tHcy levels and coronary artery disease CAD yielded an odds ratio of 1.6 for men and 1.8 for
women for every 5 mmoll increase in tHcy plasma levels [6]. Homocysteine levels are influenced by envi-
ronmental folate, vitamin B6, and vitamin B12 intake as well as genetic factors [2,3,7 – 9].
A common mutation of enzyme methylenetetrahy- drofolate reductase MTHFR has been implicated in
the development of hyperhomocysteinemia [10,11] and CAD. A missense mutation in the gene encoding
MTHFR has recently been described as the molecular basis for this defect. MTHFR activity in the VV
genotype has been found to be reduced [12] and tHcy significantly elevated [12,13] compared with the AA
and VA genotypes.
One [24], but not the other [40], meta-analysis has identified a positive association between the MTHFR
gene and increased risk for CAD. Results of these
Corresponding author. Tel.: +
82-2-3615095; fax: +
82-2- 3655118.
E-mail address
:
jsunhayumc.yonsei.ac.kr S.H. Jee. 0021-915000 - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 2 1 - 9 1 5 0 0 0 0 0 3 8 9 - 0
studies have been inconsistent, perhaps because of racial differences, small sample sizes or other design
features. Pooling the results of case-control studies provided a means of exploring the basis for heterogene-
ity in study outcomes.
The objective of this study was to quantitatively summarize the evidence for a relationship between the
MTHFR gene, coronary artery disease and myocardial infarction.
2. Methods
2
.
1
. Study selection Relevant studies in humans were identified by search-
ing the MEDLINE database for the years 1988 through 1998. The search combined the following terms;
methylenetetrahydrofolate reductase MTHFR, homo- cysteine and cardiovascular disease. In addition, refer-
ence lists of identified studies and review articles were examined for other relevant studies. Finally, experts in
the field were surveyed to identify additional studies. Twenty-three case-control studies [14 – 35] were iden-
tified. These articles were reviewed by two authors Jee and Yoon to determine whether they met predeter-
mined criteria for inclusion in our subsequent analysis. Areas of disagreement or uncertainty were adjudicated
by consensus. To be included, a study must have in- cluded the following criteria: [1] been conducted in
humans; [2] assessed MTHFR genotype determination as an exposure using standardized laboratory methods;
[12] and [3] reported the number of cases and controls with the different MTHFR genotypes. Studies [15,18 –
21,23 – 27] of CAD used angiographically — confirmed occlusion as outcomes, while studies of myocardial
infarction MI used WHO criteria for MI [16 – 18] which relies on symptoms, enzyme elevations or electro-
cardiographic
changes, and
clinicalpast history
[14,22,23].
2
.
2
. Data abstraction Information was abstracted on general characteristics
name of first author, year of publication, country of origin, sample size, mean age, gender of participants
and body mass index, study design case and control selection criteria, folate intake, plasma folate and tHcy
in the study population, method of MTHFR genotype determination including information on the polymerase
chain reaction and enzyme used, and information on Hardy – Weinberg equilibrium. If different outcomes
were employed in the same report, they were analyzed as separate studies [18,23]. When cases of CAD or MI
could not be separated, these studies were not included [27 – 34].
2
.
3
. Statistical analysis Alleic and genotypic frequencies were determined
from observed genotype counts, and the expectations of the Hardy – Weinberg equilibrium were evaluated by x
2
analysis. Comparisons between genotypic frequencies were done using x
2
analysis. A meta-analysis consists of tests for association and
homogeneity. Homogeneity testing assesses the homo- geneity of the different odds ratios determined in re-
spective studies. The overall test for association then assesses the significance of the association between the
C677T mutation and CAD or MI for all studies com- bined. To calculate the pooled effects of the MTHFR
gene, each study was assigned a weight consisting of the reciprocal of variance of its odds-ratio estimate [36].
Estimations of the mean odds ratio of cardiovascular disease associated with those having the MTHFR gene
and those with 95 confidence intervals were calculated using the Mantel – Haenszel method [26].
3. Results
