GENETIC TESTING AND MOLECULAR BIOMARKERS
Volume 17, Number 1, 2013
ª Mary Ann Liebert, Inc.
Pp. 69–73
DOI: 10.1089/gtmb.2012.0200
MTRR 66A > G Polymorphism as Maternal Risk Factor
for Down Syndrome: A Meta-Analysis
Márcia R. Amorim1 and Marcelo A. Costa Lima2
Down syndrome (DS) is the most common cause of mental retardation. Recent reports have investigated possible genetic factors that may increase maternal risk for DS. Methionine synthase reductase (5-methyltetrahydrofolate-homocysteine methyltransferase reductase MTRR) plays an important role in folic acid pathway and
a common polymorphism (c.66A > G) has been associated with DS but results were controversial. This metaanalysis summarizes the available data concerning this association. Online major databases were searched to
identify case-control studies regarding MTRR 66A > G polymorphism and DS. Crude odds ratios (OR) and 95%
confidence intervals (CI) were calculated for maternal risk to have a DS child both using fixed and random
effects (RE) models. Eleven articles from six populations were identified, including 1226 DS mothers and 1533
control mothers. Heterogeneity among studies was significant (Q = 29.7, DF = 10, p = 0.001; I2 = 66.3%). The
pooled OR in a RE model showed an increase in the risk of having a DS child associated with the G allele (OR
1.23, 95% CI 1.02–1.49). The fixed effect pooled OR was 1.19 (95% CI 1.08–1.31). This meta-analysis indicates that
maternal MTRR 66A > G polymorphism is associated with an increased risk of having a DS child.
Introduction
most studied genes are methylenetetrahydrofolate reductase
(MTHFR) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, also known as methionine synthase reductase (MTRR). Results of the association between
single nucleotide polymorphisms within these genes and the
risk of DS are controversial and discrepancies among reports
have been explained mostly by the nutritional environment
and genetic characteristics of the populations (Guéant et al.,
2003).
The MTRR gene was mapped to chromosome 5p15.2–15.3
(Leclerc et al., 1998) and encodes an enzyme responsible for
restoration of methionine synthase (MTR) activity by reductive methylation of cobalamin, leading to methionine synthesis and production of S-adenosylmethionine, which is the
main cellular methyl donor for transmethylation reactions
(Wolthers and Scrutton, 2007). A common polymorphism in
human MTRR is an adenine to guanine transition at position
66 (c.66A > G), which results in replacement of isoleucine with
methionine at residue 22 (p.I22M) (Wilson et al., 1999). This
substitution decreases the ability of MTRR to restore MTR
activity in vivo (Olteanu et al., 2002).
In the last decade several reports have evaluated the association between MTRR 66A > G polymorphism and an increased risk of having a DS child, and the results are
controversial. This meta-analysis summarizes published data
concerning this association.
D
own syndrome (DS) is the most common genetic cause
of mental retardation in humans. This chromosomal
abnormality occurs in 1/700 liveborn infants, with a wide
spectrum of clinical phenotypes (Epstein et al., 1991). To date,
only maternal age has been associated with an increased risk
of DS (Epstein, 2001), however the causative mechanisms
involved in the age-dependent occurrence of meiotic missegregation are still unclear. The facts that most DS children
are born from younger women (Eskes, 2006), and the incidence of trisomy of chromosome 21 differs between populations (Wiseman et al., 2009) indicate the concurrence of other
genetic components to increase the susceptibility to disjunction errors.
It has been proposed that an altered maternal folate metabolism could be associated to centromeric DNA hypomethylation and chromosomal nondisjunction ( James et al.,
1999). Abnormal folate metabolism could also counteract the
overexpression of the three copies of the cystathionine beta
synthase gene (CBS) in the trisomy 21 fetus, assuring folate
availability for both DNA synthesis and methylation (Hobbs
et al., 2000).
From the original paper of James et al. (1999) to date,
several reports have investigated the influence of folate
pathway polymorphisms on maternal risk for DS and the
1
Departamento de Biologia Geral, Instituto de Biologia, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil.
Departamento de Genética, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro,
Brazil.
2
69
70
AMORIM AND COSTA LIMA
Methods and Analyses
Eligible studies were identified by searches in major literature databases (PubMed at www.ncbi.nlm.nih.gov/pubmed
and Web of Science at www.isiknowledge.com), using the
following keywords, alone and combined: ‘‘A66G,’’
‘‘66A > G,’’ ‘‘MTRR,’’ ‘‘methionine synthase reductase,’’ ‘‘5methyltetrahydrofolate-homocysteine methyltransferase reductase’’ and ‘‘Down syndrome’’ or ‘‘trisomy 21.’’ SCIELO (at
www.scielo.org) was also screened using the same keywords
in English, Portuguese and Spanish in order to assure the
recovery of papers published in Latin American journals not
indexed in the other databases. We included studies that met
the following criteria: (1) case-control studies; (2) use of validated genotyping methods to identify the polymorphism; (3)
availability of MTRR genotypes for Down syndrome mothers
(DSM) and control mothers (CM), and (4) written in English,
Portuguese or Spanish. Both authors have reviewed independently each article. Crude odds ratios (OR) and 95%
confidence intervals (CI) for having a DS child were calculated
comparing GG and/or AG with AA and comparing G allele
with A allele. Heterogeneity among studies was tested considering that when there is heterogeneity among studies, the
pooled OR is preferably estimated using the random effects
(RE) model instead of fixed effects (FE) model. Q-statistics and
I2 metrics were calculated as described (Cochran, 1954; Higgins and Thompson, 2002). Statistical analyses were performed using Meta-Disk (version 1.4). The frequencies were
evaluated for accordance to Hardy–Weinberg equilibrium
(HWE) using the w2 test.
Results
We screened major bibliographic databases searching for
articles focusing on the association of maternal MTRR
66A > G polymorphism and DS. We found 11 reports that
met the inclusion criteria conducted in populations of different ethnic backgrounds from seven countries: United
States and Canada (Hobbs et al., 2000), Ireland (O’Leary et al.,
2002), France (Chango et al., 2005), China (Wang et al., 2008),
Italy (Scala et al., 2006; Coppedè et al., 2009; Pozzi et al., 2009)
and Brazil (da Silva et al., 2005; Santos-Rebouças et al., 2008;
Brandalize et al., 2010; Zampieri et al., 2012). The reports
included 1233 DS and 1533 CM and details of the studies are
presented in Table 1.
The observed genotype frequencies were evaluated for
accordance to HWE. The distribution of genotypes were in
agreement with HWE in all studies but one (Chango et al.,
2005) (w2 = 12.19, p = 0.002).
The frequency of heterozygous genotype was the highest in
both DSM and CM, ranging from 42.7% to 60.0% in DSM and
45.4% to 56.3% in CM. The genotype and allele frequencies are
shown in Table 2.
Overall analysis of the association between the mutant allele and an increase in risk of DS has revealed significant
heterogeneity among studies (Q = 29.7; DF = 10; I2 = 66.3%;
p = 0.001), and the RE pooled OR was significant, indicating a
20% increase (OR 1.23; 95% CI 1.02, 1.49) in the risk of having
a DS child (Fig. 1).
We also evaluated the association using different interaction models; recessive (GG vs. AG + AA), dominant (GG + AG
vs. AA) and codominant (both GG vs. AA and AG vs. AA).
The heterogeneity between-studies was significant using the
recessive (Q = 25.8, DF = 10, p = 0.004, I2 = 61.2%) and dominant (Q = 19.1, DF = 10; p = 0.04, I2 = 47.6) models. No heterogeneity was observed when AG genotype was compared to
AA (Q = 12.2, DF = 10, p = 0.27, I2 = 17.8%) and the FE pooled
OR was significant (OR 1.21, 95% CI 1.02–1.44) (Table 3).
Discussion
DS is an important public health issue and most DS individuals need special services (education, medical, and social)
for the duration of their lives. Since the first report of a possible association between genetic polymorphisms in folatemetabolizing encoding genes and an increased DS risk ( James
et al., 1999), several studies have investigated this hypothesis.
The distributions of MTRR 66A > G genotypes vary greatly
according to genetic background. The higher frequencies of
MTRR GG genotype were described in Caucasians and Indians ranging from 28% to 35%, and the lowest (less than 7.5%)
were observed in Latin descent populations (Rady et al., 2002;
Yang et al., 2008; Rai et al., 2011). We also observed differences
in MTRR GG genotype frequencies among groups of different
ethnicities, ranging from 14.7% in the Chinese population to
40.3% in French population.
Hobbs et al. (2000) reported the association of maternal
MTRR 66A > G polymorphism with DS risk in North American population (including samples from 16 United States and
Table 1. Characteristics of the Studies Included in the Meta-Analysis
Author
Year
Population/ethnicity
No. of DSM
No. of CM
pa
Hobbs et al.
O’Leary et al.
Chango et al.
da Silva et al.
Scala et al.
Santos-Rebouças et al.
Wang et al.
Pozzi et al.
Coppedè et al.
Brandalize et al.
Zampieri et al.
2000
2002
2005
2005
2006
2008
2008
2009
2009
2010
2012
North American/Caucasian
Irish/Caucasian
French/Caucasian
Brazilian/Mixed
Italian/Caucasian
Brazilian/Mixed
Chinese/Asian
Italian/Caucasian
Italian/Caucasian
Brazilian/Caucasian
Brazilian/Mixed
145
48
119
154
93
103
64
74
81
239
105
139
192
119
158
257
108
68
184
111
197
185
0.97
0.67
0.01
0.34
0.94
0.63
0.94
0.98
0.42
0.20
1.00
a
p-Value for Hardy–Weinberg equilibrium in CM group.
DSM, Down syndrome mother; CM, control mother.
MTRR 66A > G POLYMORPHISM AND DOWN SYNDROME
71
Table 2. The Distribution of Methionine Synthase Reductase 66A > G Genotypic
and Allelic Frequencies for Down Syndrome Mothers and Control Mothers
MTRR 66A > G genotype [n (%)]
AA
Reference
Hobbs et al.
(2000)
O’Leary et al.
(2002)
Chango et al.
(2005)
da Silva et al.
(2005)
Scala et al.
(2006)
Santos-Rebouças
et al. (2008)
Wang et al.
(2008)
Pozzi et al.
(2009)
Coppedè et al.
(2009)
Brandalize et al.
(2010)
Zampieri et al.
(2012)
DSM
AG
CM
26 (17.9) 39 (28.1)
1 (2.1)
35 (28.1)
6 (5.0)
5 (4.2)
DSM
64 (44.1)
MTRR 66A > G allele [n (%)]
GG
CM
DSM
A
CM
DSM
G
CM
DSM
CM
68 (48.9) 55 (37.9) 32 (23.0) 116 (40,0) 146 (52,5) 174 (60,0) 132 (47,5)
23 (47.9) 101 (52.6) 24 (37.9) 56 (23.0)
25 (26.0) 171 (44.5)
71 (74.0) 213 (55.5)
72 (60.0)
66 (55.5) 42 (35.0) 48 (40.3)
84 (35.0)
37 (24.0) 45 (28.5)
92 (59.7)
87 (55.1) 25 (16.2) 26 (16.5) 166 (53.9) 177 (56.0) 142 (46.1) 139 (44.0)
28 (30.1) 69 (26.8)
46 (49.5) 131 (51.0) 19 (20.4) 57 (22.2) 102 (54.8) 269 (52.3)
84 (45.2) 245 (47.7)
39 (37.9) 31 (28.7)
44 (42.7)
49 (45.4) 20 (19.4) 28 (25.9) 122 (59.2) 111 (51.4)
84 (40.8) 105 (48.6)
10 (15.6) 24 (35.3)
28 (43.8)
34 (50.0) 26 (40.6) 10 (14.7)
48 (37.5)
80 (62.5)
17 (23.0) 64 (34.8)
47 (63.5)
90 (48.9) 10 (13.5) 30 (16.3)
81 (54.7) 218 (59.2)
67 (45.3) 150 (40.8)
20 (24.7) 29 (26.1)
39 (48.1)
62 (55.9) 22 (27.2) 20 (18.0)
79 (48.8) 120 (54.1)
83 (51.2) 102 (45.9)
76 (31.9) 156 (65.0) 162 (68.1)
82 (60.3)
54 (39.7)
42 (17.6) 42 (21.3) 137 (57.3) 111 (56.3) 60 (25.1) 44 (22.3) 221 (46.2) 195 (49.5) 257 (53.8) 199 (50.5)
36 (34.3) 65 (35.1)
53 (50.5)
89 (48.1) 16 (15.2) 31 (16.8) 125 (59.5) 219 (59.2)
Canada). The comparison of genotypic distribution between
DSM and CM indicated an increase of 2.57-fold (95% CI 1.33–
4.99) for women with GG genotype. The risk was increased to
4.08-fold (95% CI 1.94–8.56) when the homozygous GG genotype was combined to MTHFR TT genotype suggesting a
multiplicative effect. This pattern of association was observed
in the Chinese population, where maternal GG genotype increased 5.2-fold (95% CI 2.06–17.50) the risk. The multiplica-
85 (40.5) 151 (40.8)
tive effect of MTHFR TT and MTRR GG genotypes were also
observed, leading to a sixfold (95% CI 2.06–17.50) increased
risk (Wang et al., 2008). An impressive 15-fold (95% CI 1.94–
116.0) increased risk associated with homozygous GG genotype was observed in the Irish population (O’Leary et al., 2002).
In France, there was no significant difference between
DSM and CM MTRR G allele frequencies (Chango et al.,
2005). The authors emphasized the importance of correlating
FIG. 1. Random effects pooled odds ratio (OR) and 95% confidence intervals forest plot for the association between
methionine synthase reductase 66A > G and Down syndrome in case-control studies. The OR estimates are represented by
solid black circles and the size of the symbol indicates the weight of the respective study in the meta-analysis. The pooled OR
is represented by a solid black diamond.
72
AMORIM AND COSTA LIMA
Table 3. Fixed and Random Effects Derived Odds Ratios, 95% Confidence Intervals and Heterogeneity
for the Association of Methionine Synthase Reductase 66A > G Polymorphisms and Down Syndrome
Method
Fixed effects
Random effects
Model
OR
95% CI
Q
p
I2 (%)
Codominant (GG vs. AA)
Codominant (AG vs. AA)
Recessive (GG vs. AA or AG)
Dominant (GG or AG vs. AA)
Additive (G vs. A)
Codominant (GG vs. AA)
Codominant (AG vs. AA)
Recessive (GG vs. AA or AG)
Dominant (GG or AG vs. AA)
Additive (G vs. A)
1.40
1.21
1.22
1.26
1.19
1.41
1.19
1.24
1.26
1.23
1.14–1.71
1.02–1.44
1.04–1.43
1.07–1.48
1.08–1.31
0.94–2.12
0.95–1.48
0.92–1.67
0.96–1.64
1.02–1.49
27.1
12.2
25.8
19.1
29.7
27.1
12.2
25.8
19.1
29.7
0.003
0.27
0.004
0.04
0.001
0.003
0.27
0.004
0.04
0.001
63.1
17.8
61.2
47.6
66.3
63.1
17.8
61.2
47.6
66.3
CI, confidence interval; OR, odds ratio.
homocysteine (Hcy) and folate levels to increase the sensitivity to detect a correlation between genotype and DS risk.
Four studies were conducted in Brazil. da Silva et al. (2005)
have evaluated five folate metabolizing pathway polymorphisms (MTHFR 677C > T, MTHFR 1298A > C, MTRR
66A > G, MTR 2756A > G and CBS 844ins68) and observed
higher Hcy levels among DSM when compared to CM.
However, the statistical difference was associated only with a
MTHFR TT genotype. For MTRR 66A > G, no difference was
observed for both genotype and allele distributions between
the case and control groups, indicating that this polymorphism did not act as an independent risk factor for
DS. Santos-Rebouças et al. (2008) evaluated folate pathway
polymorphisms combined to nutritional deficiency as maternal risk factor for DS and did not found an independent or
combined association of maternal genotypes to an increase
risk of DS birth. In a sample of mothers of European descent
living in the South region of Brazil, Brandalize et al. (2010) have
evaluated four folate metabolizing polymorphisms (MTR 2756
A > G, MTRR 66A > G, CBS 844ins68 and RFC 80 G > A) and
found that individual polymorphisms are not associated with
DS. Zampieri et al. (2012) have studied 12 polymorphisms in
folate pathway and their influence on serum folate and plasma
methylmalonic acid (MMA) concentrations as an indicator of
high Hcy levels. Although the authors have found that polymorphisms in folate metabolism genes modulate the maternal
risk for bearing a child with DS, no independent association
between MTRR 66A > G polymorphism and DS risk was observed. However, this polymorphism was the only one to affect
MMA concentration, validating the proposed association between the presence of the mutant 66 G allele both in heterozygous and homozygous status with higher Hcy concentrations.
Three reports concerning MTRR 66A > G polymorphism
and an increased risk of having a DS child were conducted in
the Italian population (Scala et al., 2006; Coppedè et al., 2009;
Pozzi et al., 2009). While Scala et al. (2006) and Coppedè et al.
(2009) did not found association between MTRR 66A > G
polymorphism and DS, Pozzi et al. (2009) have found that the
presence of the mutated G allele increases two-fold the risk
(95% CI 1.11–4.40) for a DS offspring after parity adjustment,
with similar trends when analyses focuses on woman aged
less than 35 years old. On the other hand, the association was
not observed by Coppedè et al. (2009) when a sample of Italian
woman < 35 years at conception was evaluated.
Crude data analysis has showed association of MTRR
66A > G and DS in USA and Canada, Ireland and China
populations (Hobbs et al., 2000; O’Leary et al., 2002; Wang
et al., 2008) while in the remaining studies, all conducted
in Latin European descent populations (Chango et al.,
2005; da Silva et al., 2005; Scala et al., 2006; Santos-Rebouças et al., 2008; Coppedè et al., 2009; Pozzi et al., 2009;
Brandalize et al., 2010; Zampieri et al., 2012), only one
study reported an association of MTRR 66A > G and DS,
after parity adjustment (Pozzi et al., 2009). However, a
previous report on the Italian population in a sample of
greater size has denied this association (Coppedè et al.,
2009).
Controversial results were also observed in meta-analyses
published to date. Zintzaras (2007) condensed the results of
five reports and included 559 DSM and 866 CM and did not
find any evidence for the association between MTRR 66A > G
and DS. On the other hand, a recent report by Rai (2011), using
data extracted from six reports with a total of 623 DSM and
936 CM describe a 1.42-fold increase in DS offspring when
mothers carry G allele. We found a result similar to that described by Rai (2011), with a significant increase of 1.23-fold
(95% CI 1.02–1.47) of having a DS child for woman carrying
MTRR 66G allele.
It was previously proposed that the association of MTHFR
677C > T polymorphism with neural tube defects could be
specific for non-Latin European descent populations (Amorim
et al., 2007). We can imagine a similar scenario for the association between MTRR 66A > G and DS. When non Latin
European descent reports were excluded (three studies), the
RE pooled OR decreases and looses significance (data now
shown). The occurrence or absence of association between a
polymorphism in a gene involved in folate metabolism with
DS could be explained by difference in maternal folate intake,
variation in mutant allele frequency in the population, genetic
heterogeneity of studied population and different gene–
nutrient interaction among populations (Amorim et al., 2007).
Correlation of maternal red blood cell folate with polymorphic genotypes will help to identify the role of these genetic
variants as risk factors for DS, and only few reports perform
this correlation.
The large between-studies heterogeneity we have observed
may be due to discrepancies in study design but it could reflect genuine differences among the studied populations
(Zintzaras, 2007). Our meta-analysis indicates an independent
association between MTRR G allele and an increased risk of
DS, and the populations without Latin European descent
could be at greater risk.
MTRR 66A > G POLYMORPHISM AND DOWN SYNDROME
Acknowledgments
This study was supported by Fundação de Amparo a
Pesquisa do Estado do Rio de Janeiro—FAPERJ, Brazil (No. E26/110.427/2011).
Author Disclosure Statement
None declared.
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Address correspondence to:
Marcelo A. Costa Lima, Ph.D.
Departamento de Genética
Instituto de Biologia Roberto Alcântara Gomes
Universidade do Estado do Rio de Janeiro (UERJ)
Rua São Francisco Xavier 524, PHLC, sala 218
Maracanã CEP 20550-900
Rio de Janeiro
Brazil
E-mail: marlima@uerj.br; marceloacostalima@gmail.com