Association of C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) with vascular dementia

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Association of C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) with vascular dementia: A meta-analysis

Running title

MTHFR C677T and risk of vascular dementia

Highlights

1. Meta-analysis was used to identify association of MTHFRC677T and vascular dementia.

2. Eleven studies containing 945 cases and 1264 controls were included.

3. MTHFR C677T polymorphism might be associated with susceptibility of vascular dementia.

4. The allele T might increase the risk of vascular dementia in Asian region. Abstract

Objectives: The aim of our study was to assess the association of C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) and risk for vascular dementia.

Methods: PubMed, MEDLINE Springer, Elsevier Science Direct, Cochrane Library and Google scholar was searched for relevant trials until June 2014. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the strength of the association between C677T polymorphism and vascular dementia susceptibility. Subgroup analyses were conducted according to geographic location and study size.

Results: Eleven eligible studies including 2209 participants (Case group 945; Control group 1264) were considered in this meta-analysis. There were significant associations under the overall ORs for TT vs. CC comparison (pooled OR 1.45, 95% CI 1.11-1.89, P < 0.01), recessive model (TT vs. CT + CC, pooled OR 1.40, 95% CI 1.10-1.80, P < 0.01), dominant model (TT + CT vs. CC, pooled OR 1.24, 95% CI 1.04-1.48, P = 0.02) between C677T polymorphism and risk for vascular dementia. No significant associations were found under T-allele comparison (T vs. C, pooled OR 1.22, 95% CI 1.00-1.48, P = 0.05) and CT vs. CC comparison (pooled OR 1.16, 95% CI 0.96-1.41, P > 0.05). Moreover, significant association between C677T polymorphism and vascular dementia was detected in Asian region.

Conclusions: This meta-analysis suggests that C677T polymorphism of MTHFR might be associated with susceptibility of vascular dementia and the allele T might increase the risk of vascular dementia in Aisan populations.

Key words: Vascular dementia; MTHFR C677T;; Polymorphism; Meta-analysis

Introduction

Vascular dementia is the most severe form of vascular cognitive impairment (VCI) and the second most common form of dementia after Alzheimer’s disease (AD) [1, 2]. Similar to AD, the rate of vascular dementia increases with age, it is common among the elderly but can also occur in younger people [3]. Vascular dementia is induced by cerebrovascular lesions with progressive deterioration in memory, thinking, behavior, motor, and/or cognitive functions [4-6]. As a typical complex disease, the genetic basis of vascular dementia has been scarcely known [3, 4]. It was suspected that the genetic architecture of vascular dementia was considerably complex and studies has been done to identify genes related to vascular dementia [4, 7]. Among them, the gene that encodes the methylenetetrahydrofolate reductase (MTHFR) enzyme has been recently investigated as a factor for susceptibility to vascular dementia [8].

A common polymorphism for MTHFR is at base 677 of the gene with a substitution of C to T. The study by Liu et al. [9]reported that the MTHFR C677T polymorphism (mainly TT genotype) was associated with developing vascular dementia in general populations or Asian populations, but the size effect of the association of C677T polymorphism of MTHFR and risk for vascular dementia were small. However, several studies have reported no association between C677T polymorphism and vascular dementia [15]. In order to achieve an integrative understanding the associations between C677T polymorphism and the risk of vascular dementia, a systematic meta-analysis was conducted by collecting and sorting the previous published findings.

Material and methods

Source of material

We identified eligible studies by searching PubMed, MEDLINE and EMBASE, Springer, Elsevier Science Direct, Cochrane Library and Google scholar (the last report was update in September 2013). The following key words were used for searching: “methylenetetrahydrofolate reductase” or “C677T” or “MTHFR” and “dementia” or “vascular dementia” or “VD” or “VaD” and “polymorphism” or “variants”. Meanwhile, the reference lists from retrieved articles were checked to identify additional appropriate studies. We only recruited data from the full-published English paper, not any meeting or conference abstract.

Search methods

Six investigators independently searched the electronic databases. An independent PubMed and MEDLINE search was done by A and B with the same method. An independent Springer and Elsevier Science Direct search was done by C and D with the same method. An independent Cochrane Library and Google scholar search was done by E and F with the same method. The abstracts were reviewed independently by two investigators (A and D) to determine if they met eligibility criteria for inclusion. References in the studies were reviewed by C and F to identify additional studies. Where discrepancies occurred, a third investigator (by E) did additional assessment.

Included and excluded Standards of studies

Studies meeting the following criteria were included: (1) the studied subjects were patients with vascular dementia (retrospective studies or cross-sectional studies, etc.); (2) the objects were human beings, participants’ age were not limited; (3) studies evaluated the association between C677T polymorphism and risk for vascular dementia; (4) sufficient genotype data were present to calculate the odds ratio, sample size were not limited.

Studies were excluded if one of the following existed: (1) the design was based on family or sibling pairs; (2) the genotype frequency of C677T polymorphism was not reported; (3) study did not detect the association of C677T polymorphism with susceptibility of vascular dementia; (4) there was insufficient information for extraction of data.

Extraction of data

Two investigators (by A and D) extracted the data independently using a data abstraction form. The following data were collected from each studied: the first author’s name, research year of study, year of study publication, location of participants, design of studies, criteria for vascular dementia, participant age, sample size, genotyping methods and source of control group, et al. The result was reviewed by a third investigator (by B). We contacted authors of the primary studies included for additional information if needed. We resolved discrepancies by discussion with our research team or contracting with original investigators.

Meta-analysis methods

This meta-analysis was performed with the STATA 11.0 software (Stata Corporation, College Station, TX, USA). The meta-analysis used the odds ratios (ORs) and its 95% confidence interval (95% CI) as the common measure of the association between MTHFR C677T polymorphism and risk of vascular dementia. Then, stratified analysis was performed basing on sample size and participants’ geographic location, respectively.

We assessed whether genotype frequencies among controls were consistent with Hardy-Weinberg equilibrium (HWE) by using chi-squared goodness-of-fit test and a P-value < 0.05 was considered as significant disequilib­rium. Pooled ORs were calculated for T-allele comparison (T vs. C), co-dominant model (TT vs. CC, CT vs. CC), recessive model (TT vs. CT + CC) and dominant model (TT + CT vs. CC), respectively. The significance of pooled ORs was determined by Z-test and P-value < 0.05 was considered as statistically significant. The chi-square test based Cochran-Q test [16] and I2 statistic [17] was used to assess the within- and between-study variation or heterogeneity. A P < 0.10 or I2 > 50% indicated statistically significant heterogeneity among studies, and then the random-effects model [18] was used to calculated the pooled ORs and 95% CIs. Otherwise, the fixed-effect model [19] was used.

Evaluation of publication bias

We evaluated publication bias using the Egger’s linear regression test [20], which measures funnel plot asymmetry on the natural logarithm scale of the effect size.

Results

Literature collection and study characteristics

The study selection process is shown in Figure 1. According to the criteria defined, 617 potentially relevant studies were identified (156 from PubMed; 102 from MEDLINE; 131 from Springer; 89 from Elsevier Science Direct; 11 from Cochrane Library; 128 from Google Scholar). There were 107 potentially relevant reports after excluding duplicates and irrelevant studies. After screening the abstracts, 62 of these articles was excluded (25 were review articles; 16 not reported C677T gene; 21 not reported vascular dementia). Then 45 studies were left for full publication review. Of these, 34 were excluded (18 for just only reported C677T gene data but not for comparison; 16 provided no available data). Finally, there were 11 studies [8, 10-15, 21-24] in the meta-analysis.

The characteristics of included studies were presented in Tables 1 and 2. The included studies were published between 1998 and 2013. A total of 2209 (Case group 945; Control group 1264) participants were considered in this meta-analysis. The studies’ sample sizes ranged from 42 to 604. Study designs were case-control study, and source of control groups were subjects without cognitive impairment or healthy subjects. Studies had been carried out in European or Asian region. We calculated HWE for all publications and found that every study was con­sistent with Hardy-Weinberg disequilibrium (P > 0.05).

Meta-analysis of the association between C677T polymorphism and risk for vascular dementia

There were no significant heterogeneities under models for TT vs. CC comparison (P > 0.1 and I2 = 28.1%), CT vs. CC comparison (P > 0.1 and I2 = 30.8%), recessive model (TT vs. CT + CC, P > 0.1 and I2 = 30.4%) and dominant model (TT + CT vs. CC, P > 0.1 and I2 = 36.4%), so we used the fixed-effect model to merge data. Significant heterogeneities were observed under model of T-allele (T vs. C, P < 0.1 and I2 = 46.5%), so the random-effects model was used. A summary of the meta-analysis findings of the association between C677T polymorphism and susceptibility to vascular dementia is shown in Table 3. Significant associations were found under the overall ORs for TT vs. CC comparison (pooled OR 1.45, 95% CI 1.11-1.89, P < 0.01), recessive model (TT vs. CT + CC, pooled OR 1.40, 95% CI 1.10-1.80, P < 0.01), dominant model (TT + CT vs. CC, pooled OR 1.24, 95% CI 1.04-1.48, P = 0.02) between C677T polymorphism and risk for vascular dementia. No significant associations were found under the ORs for T-allele comparison (T vs. C, pooled OR 1.22, 95% CI 1.00-1.48, P = 0.05) and CT vs. CC comparison (pooled OR 1.16, 95% CI 0.96-1.41, P > 0.05).

We also have performed subgroup analysis stratified by participants’ geographic location and sample size. Geographic location subgroup analyses revealed that significant association were found in Asian region (T vs. C, OR = 1.23, 95% CI = 1.04-1.44; TT vs. CC, OR = 1.46, 95% CI = 1.08-1.96; TT vs. CT + CC, OR =1.42, 95% CI = 1.08-1.87; TT + CT vs. CC, OR = 1.22, 95% CI = 1.00-1.49), but not in European. The subgroup analyses on the basis of sample size showed that the C677T polymorphism was associated with vascular dementia risk. The detailed stratified analysis was shown in table 3.

Publication bias

The Egger’s test was performed to assess the publication bias of the literature. For all samples, no publication bias was found under all models comparison (P-value of Egger’s test > 0.05, Table 4).

Discussion

In our meta-analysis, we combined 11 studies consisting of 2209 (Case group 945; Control group 1264) participants. The result of this meta-analysis showed that C677T polymorphism of MTHFR might be associated with susceptibility of vascular dementia. In the stratified analysis by geographic location, the significant association was found in Asian region but not in European region. This result indicated that the allele T might increase the risk of vascular dementia in Asian region compared to the allele C.

Our result is in accordance with one previously published meta-analysis on vascular dementia by Liu et al. [9] suggesting MTHFR C677T polymorphism was associated with the developing vascular dementia in general populations or Asian populations. In order to provide additional precision to evaluate the genetic susceptibility of MTHFR C677T polymorphism to vascular dementia, our meta-analysis included two newly published articles [8, 24], and the number of participants of this study was higher. Notably, we further performed stratified analysis based on geographic location and study sample size. Subgroup analyses revealed that studies with small samples sizes may be a source of heterogeneity. In addition, the increased significance in Asian region suggested that the allele T might increase the risk of vascular dementia in this region.

The result of this meta-analysis suggested that significant association was observed between MTHFR C677T polymorphism and the risk for vascular dementia in Asian region but not in European region. This geographic difference might be explained by the following reasons. First, the case number in European was small. There only 207 patients compared with 738 patients in Asian region. The observed geographic difference may be due to chance. Therefore, further studies including larger sample sizes in European can be made. Second, significant heterogeneity was observed in the European subgroup, but not in Asian subgroup (Table 3.), which may distort the result. Moreover, vascular dementia is a complex disease. The detailed etiology underlying vascular dementia is still obscure. The differences of genetic effects and the effects of MTHFR C677T polymorphism may be influenced by other genes or by environment factors that vary between geographic locations.

Some limitations of this study should be considered. First of all, only published studies were included in the present meta-analysis. Thus, publication bias may have occurred, although the use of a statistical test did not all show it. In addition, causes of recruited studies were case-control study, and the sample size of the most included studies was small, with only one study over 200 participants. It still need more large sample size studies to test and verify the results of this meta-analysis. Third, it was indicated that vascular dementia also associated with other genetic factors such as ApoE and ACE gene polymorphism [25, 26], non-genetic factors like diet, lifestyle and economic status, can also influence the risk for vascular dementia [3]. However, due to the limited data extracted from the original articles, the effect of gen-gen and gen-environment interactions was not addressed in our meta-analysis.

The meta-analysis suggests that C677T polymorphism of MTHFR might be associated with susceptibility of vascular dementia and the allele T might increase the risk of vascular dementia in Asian region. Further studies with larger sample size and different geographic populations are needed to confirm our results.

Table 1 Characteristics of studies included in the meta-analysis

Study

Year

Country

Geographic location

Criteria for Vascular dementia

Sample size

Source of control

Study Design

Case

Control

Bottiglieri T, et al.

2001

Italy

European

NA

6

36

Subjects without cognitive impairment

Case-control

Chapman J, et al.

1998

Israel

Asian

NINDS-AIREN

41

40

Healthy subjects

Case-control

Jin P, et al.

2013

China

Asian

DSM-IV

304

300

Nondementia cerebral infarction inpatients

Case-control

Mansoori N, et al.

2012

India

Asian

NINDS-AIREN

50

120

Healthy subjects

Case-control

McIlroy SP, et al.

2002

Northern Ireland

European

NINDS-AIREN

76

71

Healthy subjects

Case-control

Nishiyama M, et al.

2000

Japan

Asian

DSM-III-R

35

33

Subjects without dementia

Case-control

Pandey P, et al.

2009

India

Asian

NINDS-AIREN

80

170

Healthy subjects

Case-control

Pollak RD, et al.

2000

Israel

Asian

DSM-IV

85

82

Cognitively intact people

Case-control

Wehr H, et al.

2006

Poland

European

NINDS-AIREN

65

141

Healthy subjects

Case-control

Yoo JH, et al.

2000

South Korea

Asian

NINDS-AIREN

143

217

Healthy subjects

Case-control

Zuliani G, et al.

2001

Italy

European

NINDS-AIREN

60

54

Subjects without dementia

Case-control

NINDS-AIREN, the Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et 1'Enseignement en Neurosciences; DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised Edition; DSM-IV, DSM, Fourth Edition; NA, not available.

Table 2 Genotype frequencies of C677T polymorphism in studies included in the meta-analysis

Study

Year of Publication

Case genotype

Control genotype

HWEa

CC

CT

TT

CC

CT

TT

Chi-square test

P value

Bottiglieri T, et al.

2001

1

3

2

11

17

8

0.09

0.77

Chapman J, et al.

1998

14

20

7

15

16

9

1.32

0.25

Jin P, et al.

2013

132

99

73

152

96

52

3.71

0.06

Mansoori N, et al.

2012

35

14

1

89

29

2

0.04

0.84

McIlroy SP, et al.

2002

31

37

8

50

19

2

0.01

0.90

Nishiyama M, et al.

2000

9

17

9

13

15

5

0.04

0.84

Pandey P, et al.

2009

49

29

2

118

45

7

1.01

0.31

Pollak RD, et al.

2000

34

41

10

29

37

16

0.45

0.5

Wehr H, et al.

2006

34

26

5

63

66

12

0.83

0.36

Yoo JH, et al.

2000

49

58

36

77

114

26

2.72

0.09

Zuliani G, et al.

2001

20

26

14

17

25

12

0.23

0.63

aHWE: Hardy-Weinberg equilibrium, it was evaluated using the goodness-of-fit chi-square test. P-values were presented. P<0.05 was considered representative of a departure from HWE.

Table 3 Meta-analysis of the association between C677T polymorphism and risk for vascular dementia in fixed/random effect model

Groups

No. of studies

T vs. C

TT vs. CC

CT vs. CC

TT vs. CT+CC

TT+CT vs. CC

OR(95%CI)

PA

I2 (%)

PH

OR(95%CI)

PA

I2 (%)

PH

OR(95%CI)

PA

I2 (%)

PH

OR(95%CI)

PA

I2 (%)

PH

OR(95%CI)

PA

I2 (%)

PH

Overall

11

1.22 (1.00, 1.48)

0.05

46.5

0.04

1.45 (1.11, 1.89)

<0.01

28.1

0.18

1.16 (0.96, 1.41)

0.13

30.8

0.15

1.40 (1.10, 1.80)

<0.01

30.4

0.16

1.24 (1.04, 1.48)

0.02

36.4

0.11

Geographic location

Asian

7

1.23 (1.04, 1.44)

0.01

8.6

0.36

1.46 (1.08, 1.96)

0.01

30.5

0.19

1.13 (0.91, 1.41)

0.27

0.0

0.66

1.42 (1.08, 1.87)

0.01

48.0

0.07

1.22 (1.00, 1.49)

0.05

0.0

0.77

European

4

1.34 (0.72, 2.48)

0.36

75.3

<0.01

1.42 (0.76, 2.62)

0.27

42.9

0.15

1.26 (0.85, 1.86)

0.25

70.4

0.02

1.33 (0.75, 2.37)

0.32

0.0

0.43

1.32 (0.91, 1.91)

0.15

75.7

<0.01

Sample size

<200

7

1.26 (0.87, 1.82)

0.22

59.0

0.02

1.20 (0.75, 1.93)

0.45

34.5

0.16

1.40 (1.02, 1.93)

0.04

22.0

0.26

1.07 (0.69, 1.64)

0.78

11.2

0.34

1.38 (1.02, 1.87)

0.04

47.0

0.08

≥200

4

1.23 (1.02, 1.50)

0.03

23.9

0.27

1.58 (1.14, 2.18)

<0.01

17.3

0.31

1.05 (0.82, 1.33)

0.71

37.6

0.19

1.61 (1.19, 2.17)

<0.01

39.8

0.17

1.18 (0.95, 1.46)

0.15

20.5

0.29

OR, odds ratio; CI, confidence interval; PH , P value for between-study heterogeneity; PA, P value for test of the association.

Table 4 Tests for publication bias (Egger’s test) in population (overall)

Comparison

Egger’s test

t

P value

T vs. C

-0.10

0.92

TT vs. CC

-0.40

0.69

CT vs. CC

0.75

0.47

TT vs. CT+CC

-0.81

0.44

TT+CT vs. CC

0.35

0.74

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