Association between MTHFR A1298C polymorphism and neural tube defect susceptibility: a metaanalysis




Objective


To determine whether 5,10-methylenetetrahydrofolate reductase A1298C polymorphism is associated with neural tube defect susceptibility.


Study Design


Computerized literature searches of the PubMed, Embase, and Medline database were conducted to identify all eligible articles. Study subjects were classified as neural tube defect patients, mothers with neural tube defect offspring and fathers with neural tube defect offspring. The pooled odds ratios with 95% confidence interval (CI) were calculated by fixed-effects model or random-effects model.


Results


Twenty-three case-control studies were finally included. The pooled results showed no significant association between 5,10-methylenetetrahydrofolate reductase A1298C polymorphism and neural tube defect susceptibility in any genetic contrast among the 3 groups, except 1 (AC vs AA in neural tube defect patients: odds ratio, 1.16; 95% CI, 1.10–1.32; P = .03), which, however, turned out to be of no statistical significance in the subgroup of the white population (odds ratio, 1.14; 95% CI, 0.98–1.31; P = .08).


Conclusion


This metaanalysis suggests that 5,10-methylenetetrahydrofolate reductase A1298C polymorphism is not associated with neural tube defect susceptibility in the white population.


Neural tube defect (NTD) is among the most common congenital malformations at birth, including a wide range of phenotypes such as anencephaly, spina bifida and encephalocele. The global prevalence of NTD is greatly variable, ranging from 1 to 11 in 1000 births in different populations. The cause of NTD is assumed to be multifactorial, involving a large number of unclear genetic and environmental interactions. Several researchers have demonstrated that vitamin supplementation with folic acid during the maternal periconceptional period can substantially lower the risk of having an NTD infant, leading to intense researches for potential genes involved in its metabolic pathway.


The 5,10-methylenetetrahydrofolate reductase (MTHFR) is one of the pivotal enzymes in folate-dependent metabolism of homocysteine. It catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which participates in the remethylation of homocysteine to methionine. C677T, a common variant in the MTHFR gene, has been described in many populations and its role as a genetic risk factor for NTD has been identified by 2 metaanalyses. However, the MTHFR C677T polymorphism can only partly explain low blood folate in NTD pregnancies. Thus, additional investigations are needed to establish whether another polymorphism, which involves folate level is associated with NTD. A1298C, another variant localized at the edge of the MTHFR gene, is a missense mutation causing the substitution of glutamine by alanine in exon 7. To date, many epidemiologic studies have evaluated the association between MTHFR A1298C polymorphism and NTD risk, but the results remain inconsistent rather than conclusive. Some reported a positive association between A1298C and NTD, whereas others failed to observe such a result.


To resolve this contradiction and investigate a more precise estimation of relationship, a metaanalysis of all available published studies was performed. In this metaanalysis, study subjects were classified as NTD patients, mothers with NTD offspring and fathers with NTD offspring, for the sake of providing the most comprehensive evidence for association of MTHFR A1298C with NTD risk.


Materials and Methods


Publication search


Computerized literature searches of the PubMed, EMBASE, and MEDLINE database (up to May 31, 2011) were conducted to identify all articles that examined the association of the MTHFR gene variant with neural tube defect. A search strategy was used as follows: (“neural tube defect” OR NTD) AND (“methylenetetrahydrofolate reductase” OR “5,10-methylenetetrahydrofolate reductase” OR MTHFR) AND (A1298C OR 1298A>C) AND (polymorphism OR mutation OR variant). All the eligible studies were retrieved, and their bibliographies were checked for further relevant publications. If the same patient population was used in several publications, only the most recent, largest or complete study was included in this metaanalysis. The search results were limited to humans.


Inclusion criteria


Studies meeting the following inclusion criteria were included: (1) evaluation of the association between MTHFR A1298C polymorphism and neural tube defect; (2) case-control studies; (3) genotype distributions in both case and control were available; (4) studies with full text articles; (5) studies published in English; (6) genotype distributions in the control group conformed to the Hardy-Weinberg equilibrium (HWE).


Data extraction


Information was carefully extracted from all the eligible publications independently by 2 of the authors. Unsettled disagreements were resolved by discussion between the 2 authors. If a consensus could not be reached, a third author was consulted to settle the dispute and a final decision was made by the majority of the votes. The following data were collected from each study: first author’s name, year of publication, country, ethnicity, types of NTD, source of control subjects, number of cases and controls, and number of every genotype and allele. If allele frequencies were not given, they were calculated from the corresponding genotype distributions. Different descents were categorized as white, Asian, and African, following the published data derived from the human evolution study.


Statistical methods


To measure the strength of genetic association between MTHFR A1298C polymorphism and NTD risk, the odds ratios (ORs), together with the 95% confidence interval (CI) and the corresponding P value (the P value being significant if < .05) were calculated. The pooled ORs were estimated for allele contrast (C vs A), codominant model (AC vs AA; CC vs AA), dominant model (AC + CC vs AA), and recessive model (CC vs AA + AC). Heterogeneity between the studies was assessed by the Q-test, which follows a χ 2 distribution with degree of freedom (df) equals to the number of analyzed studies minus 1. The fixed-effects model (Mantel-Haenszel method) was used for the metaanalysis with P > .10 for Q-test. Otherwise, the random-effects model (DerSimonian-Laird method) was used. I 2 metric ( I 2 = (Q − df)/Q) was used to measure the quantification of heterogeneity. To assess the possible publication bias, the Begg’s funnel plot and Egger’s linear regression test were carried out. P < .05 was considered representative of statistically significant publication bias. Sensitivity analyses were performed to see if any exclusion of the studies could affect the original results. Subgroup analysis of the studies on the white population was also performed. All the statistical tests were conducted with the statistical software STATA version 10.0 (Stata Corp, College Station, TX).




Results


Study characteristics


Based on the search term and inclusion criteria, a total of 29 studies were preliminarily identified. Of these, 6 studies were excluded for the following reasons: insufficient data, same data available in another study, published in another language, and genotype distributions of control group deviated from the HWE. Therefore, 23 studies were finally included, in which spina bifida, encephalocele, and anencephaly shared top 3 ranking among the reported NTD types. The studies identified and their main characteristics are shown in Table 1 .



TABLE 1

Characteristics of the studies of MTHFR A1298C polymorphism and susceptibility to NTD












































































































































































First author Year Country Ethnicity Source of controls Study subjects
van der Put 1998 Netherlands White HB P/M/F
Stegmann 1999 Germany White PB P
Barber 2000 America White PB P/M
Volcik 2000 America White PB P/M/F
Richter 2001 Germany White PB P
Cunha 2002 Brazil White PB P/M
De Marco 2002 Italy White PB P/M/F
Parle-McDermott 2003 Ireland White HB P/M/F
Perez 2003 Brazil Mixed HB P/M
Felix 2004 Brazil White HB P/M
Gos 2004 Poland White NR P/M/F
Relton 2004 England White HB M
Relton 2004 England White HB P/M
Sadewa 2004 Indonesia Asian PB P/M
Grandone 2006 Italy White NR P/M/F
Dalal 2007 India White NR M
Gonzalez-Herrera 2007 Mexico White NR P/M/F
Munoz 2007 Mexico White HB M
Candito 2008 France Mixed HB M
Behunova 2010 Slovakia Mixed HB P
Eser 2010 Turkey White PB P
Naushad 2010 India White NR M/F
Selvi 2010 Turkey White NR P/M

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May 23, 2017 | Posted by in GYNECOLOGY | Comments Off on Association between MTHFR A1298C polymorphism and neural tube defect susceptibility: a metaanalysis

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