association between mthfr c677t polymorphism and
TRANSCRIPT
CLINICAL STUDY
Association Between MTHFR C677T Polymorphism andCongenital Heart Disease
A PRISMA-Compliant Meta-Analysis
Peng-Fei Liu,1* MD, Bing Ding,1* MD, Jun-Yi Zhang,1 MD, Xiao-Fei Mei,1 MD, Fei Li,1 MD,
Peng Wu,1 MD, Chun-Hao Mei,1 MD, Ya-Feng Zhou,1 PhD and Tan Chen,1 PhD
SummaryMany published studies have evaluated the association between the 5,10-methylenetetrahydrofolate reduc-
tase (MTHFR) C677T (rs1801133) polymorphism and the risk of congenital heart disease (CHD); however, the
specific conclusion is still controversial.
To get a more accurate conclusion, we used a meta-analysis to evaluate the association between the
MTHFR gene C677T polymorphism and the risk of CHD.
Based on the design-based search strategy, a comprehensive literature search was conducted on PubMed,
OVID, Cochrane Library, Embase, Wanfang, CNKI, and Web of Science. We selected the Newcastle-Ottawa
Scale (NOS) to assess the quality of the included studies. We performed a heterogeneity test on the results of
the study and calculated the combined odds ratios (ORs) and its corresponding 95% confidence intervals (95%
CIs) under a random- or fixed-effect model. Subgroup analyses were conducted by ethnicity, source of controls,
sample size, and genotyping method. Sensitivity analysis was used to insure authenticity of this meta-analysis
result. Egger’s test and Begg’s funnel plot were performed to detect publication bias.
Eventually, our meta-analysis included 15 eligible studies. We observed a significant correlation between
the MTHFR C677T polymorphism and the development of CHD in the recessive model (OR: 1.35, 95% CI:
1.06-1.71, P = 0.006) for the overall population. In subgroups stratified by ethnicity and source of controls,
subgroup analyses indicated similar associations in Asians and hospital-based groups, but not for Caucasians
and population-based groups. Egger’s test and Begg’s funnel plot demonstrated no significant publication bias
in our study.
Our analysis identified that MTHFR C677T allele is a risk genetic for CHD development, especially in
Asians compared with Caucasians.
(Int Heart J 2020; 61: 553-561)
Key words: Single nucleotide polymorphism, rs1801133
Congenital heart disease (CHD) is a common vari-
ety of structural abnormality in newborns, with a
prevalence of approximately 1:100 live births.1,2)
Many CHDs are caused by the interaction of genetic and
environmental factors, although the exact cause for it is
quite complex and still unclear.3) Folic acid plays a very
important role in the development of the cardiovascular
system.4) It is known that the lack of folic acid leads to
hyperhomocysteinemia, which has been described as a
possible risk factor for CHD.5,6)
The 5,10-methylenetetrahydrofolate reductase
(MTHFR) encoded by the MTHFR gene located at 1p36.3
is an important enzyme in homocysteine metabolism, con-
verting 5,10-methylenetetrahydrofolate into 5-
methyltetrahydrofolate in the process of methyltetrahydro-
folate.7) The MTHFR C677T mutation has been proved to
reduce the activity of enzyme and increase the level of
plasma homocysteine.7)
The relationship between the MTHFR gene polymor-
phism and the risk of CHD was first analyzed by Wen-
strom et al.8) In recent years, several articles have been
published on the relationship between the polymorphism
(C677T) and the risk of CHD. However, the conclusion is
still inconsistent. Thus, to provide a more comprehensive
result, we performed the present meta-analysis based on
15 trials9-23) to evaluate the association between MTHFR
From the 1Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, China.
*These authors contributed equally to this work.
This work was supported by grants from the National Natural Science Foundation of China (81873486,81770327), Natural Scientific Fund of Jiangsu prov-
ince (BK20161226), Jiangsu Province’s Key Provincial Talents Program (ZDRCA2016043), Jiangsu Province’s 333 High-Level Talents Project (BRA
2017539), and Jiangsu Provincial Medical Innovation Team (NO.CXTDA2017009). The funders had no roles in study design, data collection and analysis, de-
cision to publish, or preparation of the manuscript.
Address for correspondence: Tan Chen, PhD or Ya-Feng Zhou, PhD, Department of Cardiology, The First Affiliated Hospital of Soochow University, 188
Shizi Road, Suzhou, Jiangsu, 215006, China. E-mail: [email protected] or [email protected]
Received for publication July 26, 2019. Revised and accepted November 27, 2019.
Released in advance online on J-STAGE May 15, 2020.
doi: 10.1536/ihj.19-389
All rights reserved by the International Heart Journal Association.
553
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May 2020554 LIU, ET AL
Figure 1. The PRISMA flow diagram of the study selection and exclusion.
Table I. Characteristics of the Studies Included for Meta-Analysis
Author Year Country Ethnicity PolymorphismSource of
controls
Genotyping
method
NOS
score
HWE
test
Yan, et al.9) 2003 China Asian MTHFR677 (rs1801133) HB PCR-RFLP 7 0.075
Storti, et al.10) 2003 Italy Caucasian MTHFR677 (rs1801133) HB Direct sequencing 8 0.277
Shaw, et al.11) 2005 America Caucasian MTHFR677 (rs1801133) PB Direct sequencing 9 0.235
Li, et al.12) 2005 China Asian MTHFR677 (rs1801133) HB PCR-RFLP 7 0.684
Zhu, et al.13) 2006 China Asian MTHFR677 (rs1801133) PB PCR-RFLP 7 0.513
van Beynum, et al.14) 2006 Netherlands Caucasian MTHFR677 (rs1801133) PB Direct sequencing 8 0.277
van Driel, et al.15) 2008 Netherlands Caucasian MTHFR677 (rs1801133) PB Direct sequencing 7 0.263
Kuehl, et al.16) 2010 America Caucasian MTHFR677 (rs1801133) PB Direct sequencing 7 0.911
Obermann-Borst, et al.17) 2011 Netherlands Caucasian MTHFR677 (rs1801133) PB Direct sequencing 8 0.682
Wang, et al.18) 2013 China Asian MTHFR677 (rs1801133) HB Direct sequencing 7 0.168
Sahiner, et al.19) 2014 Turkey Asian MTHFR677 (rs1801133) HB Direct sequencing 8 0.059
Li, et al.20) 2015 China Asian MTHFR677 (rs1801133) HB Direct sequencing 9 0.779
Jiang, et al.21) 2015 China Asian MTHFR677 (rs1801133) HB PCR-RFLP 8 0.586
Wang, et al.22) 2016 China Asian MTHFR677 (rs1801133) HB PCR-RFLP 7 0.949
Wang, et al.23) 2018 China Asian MTHFR677 (rs1801133) HB Direct sequencing 7 0.271
Case-control design was used in all the included studies. PCR-RFLP indicates polymerase chain reaction-restriction fragment length polymor-
phism; Year, publication year; NOS, Newcastle-Ottawa Scale; HWE, Hardy-Weinberg equilibrium; HB, hospital-based; and PB, popula-
tion-based.
polymorphism (C677T) and CHD susceptibility. Methods
This updated meta-analysis was organized according
to the Preferred Reporting Items for Systematic Reviews
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Table II. The Results of Newcastle-Ottawa Scale
Selection Comparability Exposure
Yan, et al.9) ★★★ ★★ ★★Storti, et al.10) ★★★★ ★★ ★★Shaw, et al.11) ★★★★ ★★ ★★★Li, et al.12) ★★★ ★★ ★★Zhu, et al.13) ★★★ ★★ ★★Beynum, et al.14) ★★★ ★★ ★★★Driel, et al.15) ★★★★ ★ ★★Gardemann, et al.16) ★★★ ★★ ★★Obermann-Borst, et al.17) ★★★★ ★★ ★★Wang, et al.18) ★★★ ★★ ★★Sahiner, et al.19) ★★★★ ★★ ★★Li, et al.20) ★★★★ ★★ ★★★Jiang, et al.21) ★★★★ ★★ ★★Wang, et al.22) ★★★ ★★ ★★Wang, et al.23) ★★★ ★★ ★★
Table III. MTHFR C677T Polymorphism Genotype Distribution and Allele Frequency in Cases and Controls
Author
Genotype (n) Allele frequency (n, %)
Cases Controls Cases Controls
Total CC CT TT Total CC CT TT C T RAF C T RAF
Yan, et al.9) 207 58 97 52 103 24 57 22 213 201 0.49 105 101 0.49
Storti, et al.10) 128 20 55 53 200 40 108 52 95 161 0.63 188 212 0.53
Shaw, et al.11) 138 16 68 54 434 52 202 180 100 176 0.64 306 562 0.65
Li, et al.12) 210 61 94 55 102 25 57 20 216 204 0.49 107 97 0.48
Zhu, et al.13) 106 27 22 57 103 24 57 22 76 136 0.64 105 101 0.49
van Beynum, et al.14) 144 20 66 58 220 18 104 98 106 182 0.63 140 300 0.68
van Driel, et al.15) 191 27 103 61 251 25 107 119 157 225 0.59 157 345 0.69
Kuehl, et al.16) 107 10 33 64 290 32 124 134 53 161 0.75 188 392 0.68
Obermann-Borst, et al.17) 140 9 66 65 183 15 76 92 84 196 0.70 106 260 0.71
Wang, et al.18) 160 25 76 59 188 35 100 53 126 194 0.61 170 206 0.55
Sahiner, et al.19) 136 14 53 69 93 7 39 47 81 191 0.70 53 133 0.72
Li, et al.20) 150 41 78 31 150 25 66 59 160 140 0.47 116 184 0.61
Jiang, et al.21) 100 16 46 38 100 11 48 41 78 122 0.61 70 130 0.65
Wang, et al.22) 147 60 73 14 168 35 84 49 193 101 0.34 154 182 0.54
Wang, et al.23) 193 60 68 65 234 31 120 83 188 198 0.51 182 286 0.61
Case-control design was used in all the included studies. RAF indicates risk allele frequency.
and Meta-Analyses (PRISMA).24) Because our articles
were based on previously published studies, patients’ in-
formed consent and ethical approval were not required.
Search strategy: This systematic literature search was
conducted by the first two investigators until March 31,
2019 in the PubMed, OVID, Cochrane Library, Embase,
Wanfang, CNKI, and Web of Science without language
limitation. For the literature search, we used a combina-
tion of the following items: methylenetetrahydrofolate re-
ductase or MTHFR and CHD or CHD or birth defects
and polymorphism or Single Nucleotide Polymorphism
(SNP). Furthermore, reference listings of studies included
in our meta-analysis were manually searched for possible
eligible articles.
Inclusion and exclusion criteria: All eligible studies in-
cluded in this study needed to follow the inclusion crite-
ria: studies with case-control designs, report of the asso-
ciation between the MTHFR C677T polymorphism and
the risk of CHD, and articles with sufficient data. The ex-
clusion criteria were as follows: letters, case reports, meta-
analysis, review articles, articles without control group, ar-
ticles with abstract only, and studies without detailed
genotype data.
Data extraction: From each study, the first two research-
ers independently extracted all useful data. Any potential
conflicts were discussed with other authors. The extraction
of study data included the following: first author, publica-
tion year, country of origin, ethnicity, number of cases
and controls, genotype frequency, source of controls,
genotyping method, and Hardy-Weinberg equilibrium
(HWE). We investigated the quality of each study based
on the nine-point Newcastle-Ottawa Scale (NOS).25)
Statistical analysis: In each of the included study, we ex-
amined HWE to assess bias in genotype distribution. We
calculated odds ratios (ORs) and 95% confidence intervals
(95% CIs) for analyses of the C677T polymorphism and
the risk of CHD. The pooled ORs and 95% CIs were cal-
culated in five genetic models: allele model (T versus C),
heterozygote model (TC versus CC), homozygote model
(TT versus CC), dominant model (TT + TC versus CC),
and recessive model (TT versus TC + CC). We used the I2
test to quantify the proportion of the total variation caused
by the heterogeneity. The range of I2 is between 0% and
100%. A value of 0% indicates that no heterogeneity was
observed, a large value indicates an increase in heteroge-
neity, 25% is considered low, 50% is considered moder-
ate, and 75% is considered high heterogeneity. When I2 >
50%, a random-effect model26) should be taken. Otherwise,
the fixed-effect model27) was then adopted. The present
analysis included a wide variety of study designs such as
ethnicity, source of controls, sample size, and genotyping
method. Sensitivity analysis was conducted to detect
whether omitting each study involved in this meta-analysis
will alter the stability of the results. Publication bias was
assessed by drawing Begg’s funnel plot. We also assessed
funnel plot asymmetry via Egger’s test, and P > 0.05
means that there was no statistically significant bias of
publication.28) Our meta-analysis was performed using the
Cochrane Collaboration Review Manager 5.3 software and
Int Heart J
May 2020556 LIU, ET AL
Figure 2. Forest plot from the meta-analysis on the association between the MTHFR C677T (rs1801133) polymorphism and the risk of CHD.
A: allele; B: heterozygote; C: homozygote; D: dominant; E: recessive. CHD, congenital heart disease; CI, confidence interval; OR, odds ratio.
Stata version 15.0 (StataCorp, College Station, TX, USA). Results
Study characteristics: Our systematic research strategy
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Figure 3. Subgroup meta-analysis by ethnicity of the relationship between the MTHFR C677T polymorphism and the risk of CHD. A: allele; B: heterozygote; C: homozygote; D: dominant; E: recessive.
Int Heart J
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Table IV. Subgroup Analyses of the Association between MTHFR C677T Polymorphism and Risk of CHD
Subgroup Number Odds ratio 95% Confidential interval P value I2 (%)
Allele model
Total 15 1.08 (0.89-1.32) 0.000 81.1
ethnicity
Asian 9 1.15 (0.86-1.52) 0.000 84.0
Caucasian 6 1.00 (0.77-1.31) 0.001 76.7
Source of control
HB 9 1.17 (0.89-1.52) 0.258 82.9
PB 6 0.97 (0.73-1.31) 0.860 80.0
Sample size
≥ 300 12 1.14 (0.92-1.40) 0.230 81.6
< 300 3 0.88 (0.54-1.43) 0.600 77.7
Genotyping method
PCR-RFLP 5 1.08 (0.68-1.70) 0.749 87.8
Direct sequencing 10 1.09 (0.88-1.35) 0.445 78.1
Heterozygote model
Total 15 0.90 (0.65-1.22) 0.000 82.1
ethnicity
Asian 9 0.84 (0.52-1.37) 0.000 85.1
Caucasian 6 0.97 (0.65-1.44) 0.000 78.4
Source of control
HB 9 0.94 (0.65-1.37) 0.760 76.1
PB 6 0.82 (0.46-1.44) 0.484 78.3
Sample size
≥ 300 12 1.00 (0.74-1.36) 0.985 90.4
< 300 3 0.53 (0.17-1.67) 0.279 60.9
Genotyping method
PCR-RFLP 5 0.73 (0.30-1.76) 0.483 89.8
Direct sequencing 10 0.98 (0.73-1.32) 0.890 75.2
Homozygote model
Total 15 1.25 (0.86-1.83) 0.000 76.9
ethnicity
Asian 9 1.43 (0.83-2.48) 0.000 81.5
Caucasian 6 1.03 (0.63-1.67) 0.015 64.5
Source of control
HB 9 1.45 (0.84-2.49) 0.182 81.5
PB 6 1.02 (0.62-1.68) 0.941 65.5
Sample size
≥ 300 12 1.34 (0.88-2.04) 0.178 78.6
< 300 3 0.94 (0.40-2.21) 0.883 66.2
Genotyping method
PCR-RFLP 5 0.94 (0.54-3.08) 0.558 85.4
Direct sequencing 10 1.24 (0.81-1.89) 0.316 72.8
Dominant model
Total 15 0.99 (0.73-1.34) 0.000 83.1
ethnicity
Asian 9 1.00 (0.63-1.60) 0.000 86.0
Caucasian 6 0.98 (0.66-1.46) 0.000 80.8
Source of control
HB 9 1.08 (0.72-1.60) 0.721 81.5
PB 6 0.88 (0.53-1.47) 0.626 87.4
Sample size
≥ 300 12 1.09 (0.80-1.50) 0.573 81.5
< 300 3 0.65 (0.25-1.68) 0.369 88.3
Genotyping method
PCR-RFLP 5 0.89 (0.38-2.07) 0.791 90.2
Direct sequencing 10 1.04 (0.77-1.41) 0.779 77.9
Recessive model
Total 15 1.35 (1.06-1.71) 0.006 54.8
ethnicity
Asian 9 1.57 (1.16-2.12) 0.018 56.7
Caucasian 6 1.06 (0.78-1.43) 0.288 19.2
Source of control
HB 9 1.48 (1.06-2.08) 0.023 66.3
PB 6 1.16 (0.88-1.52) 0.291 0.0
Sample size
≥ 300 12 1.34 (1.01-1.78) 0.041 63.9
< 300 3 1.29 (0.83-2.02) 0.253 0.0
Genotyping method
PCR-RFLP 5 1.52 (1.09-2.12) 0.013 36.5
Direct sequencing 10 1.26 (0.91-1.75) 0.168 62.2
PCR-RFLP indicates polymerase chain reaction-restriction fragment length polymorphism; HB, hospital-based; and PB, population-based.
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Figure 4. Sensitivity analysis of the association between the MTHFR C677T polymorphism and the risk of CHD. A: allele; B: heterozygote; C: homozygote; D: dominant; E: recessive.
found 639 potentially relevant studies. After removing du-
plicated articles, 329 studies were left for screening and
303 of studies were excluded. Of the remaining 26 stud-
ies, 4 did not provide sufficient data, 3 were unrelated to
MTHFR, and 4 were excluded due to unmatched study
design. Figure 1 shows the specific process of the study
inclusion and exclusion. Finally, a total of 15 studies were
included in this meta-analysis between the C677T poly-
morphism of the MTHFR gene and the risk of CHD, of
which 2257 cases and 2819 controls were compared. The
main characteristics of each study in our meta-analysis are
presented in Table I. The races of these articles were
Asian (n = 9) and Caucasian (n = 6). Our meta-analysis
included six population-based studies3,6-10) and nine
hospital-based studies.1,2,4,5,11-15) The sample sizes for all in-
volved eligible articles ranged from 200 to 572. All stud-
ies involved are consistent with the HWE test. The results
of NOS for all the included studies are shown in Table II.
The NOS scores for all eligible studies in this meta-
analysis exceeded 6 points, indicating that our analysis is
of good quality. Table III shows the genotype distribution
and allele frequency of all included studies.
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May 2020560 LIU, ET AL
Quantitative synthesis: The present meta-analysis exam-
ined five genetic models of the MTHFR C677T polymor-
phism and the risk of CHD. In all eligible studies in the
random-effect model, a significantly increased risk of
CHD was found only in the recessive genetic model (OR
= 1.35, 95% CI = 1.06-1.71, P < 0.001, I2 = 54.8%, Phetero-
geneity = 0.006) in the overall population. However, our
study did not find significant association under allele
model (OR = 1.08, 95% CI = 0.89-1.32, P = 0.413, I2 =
81.1%, Pheterogeneity < 0.001), homozygote model (OR =
1.25, 95% CI = 0.86-1.83, P = 0.241, I2 = 76.9%, Pheterogene-
ity < 0.001), heterozygote model (OR = 0.90, 95% CI =
0.65-1.22, P = 0.487, I2 = 82.1%, Pheterogeneity < 0.001), and
dominant model (OR = 0.99, 95% CI = 0.73-1.34, P =
0.960, I2 = 83.1%, Pheterogeneity < 0.001) (Figure 2). Because
a high degree of heterogeneity was found in the study, we
use subgroup analysis to investigate the sources of hetero-
geneity. In the subgroup analysis of different ethnicity
(Figure 3), remarkable association was also found in
Asians under recessive model (OR = 1.35, 95% CI =
1.06-1.71, P = 0.014, I2 = 56.7%, Pheterogeneity = 0.006).
However, we found no statistical association in Cauca-
sians in recessive model (OR = 1.06, 95% CI = 0.78-1.43,
P = 0.288, I2 = 19.2%, Pheterogeneity = 0.713). We also con-
ducted subgroup analysis based on source of controls,
sample size, and genotyping method. We obtained similar
results in the subgroup analysis under recessive model. In
the source of control subgroup analysis, we found a sig-
nificant relationship in hospital-based controls (OR =
1.48, 95% CI = 1.06-2.08, P = 0.023, I2 = 66.3%,
Pheterogeneity = 0.003), while there is no relevant influence in
population-based controls (OR = 1.16, 95% CI = 0.88-
1.52, P = 0.291, I2 = 0.0%, Pheterogeneity = 0.291). In addi-
tion, in the subgroup analysis of sample size, an obvious
association between C677T mutation and the risk of CHD
was discovered in �300 group (OR = 1.34, 95% CI =
1.01-1.78, P = 0.041, I2 = 63.9%, Pheterogeneity =
0.001); however, the relationship disappeared in <300
group (OR = 1.29, 95% CI = 0.83-2.02, P = 0.253, I2 =
0.0%, Pheterogeneity = 0.822). In addition, this association was
revealed to be stronger in polymerase chain reaction-
restriction fragment length polymorphism group (OR =
1.52, 95% CI = 1.09-2.12, P = 0.013, I2 = 36.5%,
Pheterogeneity = 0.178) nor direct sequencing group (OR =
1.26, 95% CI = 0.91-1.75, P = 0.253, I2 = 62.2%,
Pheterogeneity = 0.005). The detailed results of our subgroup
analysis were listed in Table IV.
Sensitivity analysis: We carried out a sensitivity analysis
to determine if the omission of each study would under-
mine the results of this meta-analysis. Figure 4 shows that
the results of the changes were not obtained after omitting
each study, indicating the stability of our consequence.
Publication bias: When performing a meta-analysis, it’s
no doubt that publication bias is another common problem
to be resolved. Therefore, we used Egger’s test and con-
structed the Begg’s funnel plot to solve this problem. Ob-
viously, from the funnel plot (Supplemental Figure), all
the 15 studies were symmetrically distributed on the two
sides, which indicated no evidence of publication bias in
our meta-analysis (allele model: P = 0.183; heterozygote
model: P = 0.330; homozygote model: P = 0.542; domi-
nant model: P = 0.643; recessive model: P = 0.118).
Discussion
In general, many case-control articles focusing on the
association between the C677T polymorphism and the
risk of CHD have been reported, but the conclusion re-
mains unclear. Due to the conflicting results and small
sample size of individual studies, we performed this pre-
sent meta-analysis to obtain a more accurate relationship
between the MTHFR gene C677T polymorphism and the
risk of CHD.
We included a total of 15 eligible studies9-23) in our
meta-analysis. All of the results revealed that the MTHFR
C677T polymorphism increased the risk of CHD. Because
of a high heterogeneity, we conducted group analysis ac-
cording to ethnicity, sample size, source of control, and
genotyping method. Analysis by ethnicity group showed
an increased susceptibility of CHD and variant alleles in
Asian population of C677T polymorphism under the re-
cessive model. In contrast, no significant association was
found in the Caucasian population. Moreover, the in-
creased risk of the recessive model was also observed in
stratified analyses by source of controls, sample size, and
genotyping method. Among the regarded studies, no evi-
dence showed publication bias in our meta-analysis.
At present, the pathogenesis of CHD has not been
fully recognized. However, studies have indicated that ge-
netic factors are associated with the pathogenesis of coro-
nary heart disease. 3 ) The synthesis of 5-
methyltetrahydrofolate is affected by the MTHFR enzyme
activity, and then, the process of remethylation of homo-
cysteine to methionine is affected, which finally induces
hyperhomocysteinemia.29) In addition, it has been found
that the MTHFR C677T mutation can reduce the activity
of enzyme and increase plasma homocysteine.7) Hyperho-
mocysteinemia can cause neural crest cells to initiate
apoptosis and has been shown to be toxic to heart cells in
animal model experiments.30,31) These previous studies
provide a good explanation for our results that MTHFR
C677T polymorphism is relevant to increase the risk of
CHD. Folic acid has the effect of lowering the concentra-
tion of homocysteine in the human body.32) In addition, a
published study indicated that proper supplementation
with folic acid significantly reduced the risk of CHD.33)
Therefore, supplementing folic acid during pregnancy
should be considered.
Our meta-analysis did have several limitations. First,
all 15 studies were collected only in Chinese and English,
so relevant studies performed in other languages and pos-
sible unpublished articles may be missed. Second, there
were no studies including Africans, which may lead to se-
lection bias. Third, almost all studies did not classify their
cases by types of CHD, which may have various etiolo-
gies. Fourth, several gene polymorphisms may act to-
gether, which may increase the incidence of CHD. In ad-
dition, some confounding factors, such as gender, age,
physical conditions, and living environments, may affect
the final results.
Based on our analysis, we found that the MTHFR C
677T polymorphism is relevant to increase the risk of
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May 2020 561MTHFR AND CONGENITAL HEART DISEASE
CHD in recessive genetic model. The association was
more significant in Asians compared with Caucasians. In
addition, gene-gene and gene-environment interactions
need further study.
Disclosure
Conflicts of interest: None.
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Supplemental Files
Supplemental Figure
Please see supplemental files: https://doi.org/10.1536/ihj.19-389