MTHFR A1298C polymorphisms reduce the risk of congenital heart defects: a meta-analysis from 16 case-control studies

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Abstract

Background

Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in the hyperhomocysteinemia, which is a risk factor related to the occurrence of congenital heart defect (CHD). However, the association between MTHFR polymorphism and CHD has been inconclusive.

Methods

We conducted an updated meta-analysis to provide comprehensive evidence on the role of MTHFR A1298C polymorphism in CHD. Databases were searched and a total of 16 studies containing 2207 cases and 2364 controls were included.

Results

We detected that a significant association was found in the recessive model (CC vs. AA + AC: OR = 1.38, 95% CI: 1.10–1.73) for the overall population. Subgroup analysis showed that associations were found in patients without Down Syndrome in genetic models for CC vs. AA (OR = 1.47, 95% CI: 1.01–2.14), CC vs. AC (OR = 1.29, 95% CI: 1.00–1.66) and recessive model (OR = 1.44, 95% CI: 1.14–1.82). We conducted a meta-regression analysis, Galbraith plots and a sensitivity analysis to assess the sources of heterogeneity.

Conclusions

In summary, our present meta-analysis supports the MTHFR 1298C allele as a risk factor for CHD. However, further studies should be conducted to investigate the correlation of plasma homocysteine levels, enzyme activity, and periconceptional folic acid supplementation with the risk of CHD.

Electronic supplementary material

The online version of this article (10.1186/s13052-017-0425-1) contains supplementary material, which is available to authorized users.

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Most cited references 29

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Incidence of congenital heart disease: II. Prenatal incidence.

J. I. Hoffman (1995)

The incidence of congenital heart disease appears to be about 1 per 100 liveborn infants. In infants who die before term, however, there is a much higher incidence of congenital heart disease, with a tendency for an excess of complex lesions. Some but not all of these lesions are associated with gross chromosomal abnormalities, which occur frequently in first-trimester abortions. Most of these chromosomal abnormalities are associated with such maldevelopment of many organ systems that fetal death occurs in utero. Monosomy X (45, XO), has a high association with congenital heart disease. Most fetuses with this abnormality die in utero, but because the abnormality is not inevitably lethal a small increase in survival of these fetuses would cause a large increase in the total incidence of congenital heart disease.

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Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16

Heather J. Cordell, Jamie Bentham, Ana Töpf … (2013)

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls, and included patients from each of the three major clinical CHD categories (septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no regions achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P=9.5×10−7) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N=340 cases), and this was replicated in a further 417 ASD cases and 2520 controls (replication P=5.0×10−5; OR in replication cohort 1.40 [95% CI 1.19-1.65]; combined P=2.6×10−10). Genotype accounted for ~9% of the population attributable risk of ASD.

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Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism.

Torbjørn Fredriksen, Per Ueland, Tom Grotmol … (2007)

Several polymorphisms of genes involved in one-carbon metabolism have been identified. The reported metabolic phenotypes are often based on small studies providing inconsistent results. This large-scale study of 10,601 population-based samples was carried out to investigate the association between a panel of biochemical parameters and genetics variants related to one-carbon metabolism. Concentrations of total homocysteine (tHcy), folate, vitamin B(12) (cobalamin), methylmalonic acid (MMA), vitamin B(2) (riboflavin), vitamin B(6) (PLP), choline, betaine, dimethylglycine (DMG), cystathionine, cysteine, methionine, and creatinine were determined in serum/plasma. All subjects were genotyped for 13 common polymorphisms: methylenetetrahydrofolate reductase (MTHFR) c.665C>T (known as 677C>T; p.Ala222Val) and c.1286A>C (known as 1298A>C; p.Glu429Ala); methionine synthase (MTR) c.2756A>G (p.Asp919Gly); methionine synthase reductase (MTRR) c.66A>G (p.Ile22Met); methylenetetrahydrofolate dehydrogenase (MTHFD1) c.1958G>A (p.Arg653Gln); betaine homocysteine methyltransferase (BHMT) c.716G>A (known as 742G>A; p.Arg239Gln); cystathionine beta-synthase (CBS) c.844_845ins68 and c.699C>T (p.Tyr233Tyr); transcobalamin-II (TCN2) c.67A>G (p.Ile23Val) and c.776C>G (p.Pro259Arg); reduced folate carrier-1 (SLC19A1) c.80G>A (p.Arg27His); and paraoxonase-1 (PON1) c.163T>A (p.Leu55Met) and c.575A>G (p.Gln192Arg). The metabolic profile in terms of the measured vitamins and metabolites were investigated for these 13 polymorphisms. We confirmed the strong associations of MTHFR c.665C>T with tHcy and folate, but also observed significant (P C (associations with tHcy, folate and betaine), MTR c.2756A>G (tHcy), BHMT c.716G>A (DMG), CBS c.844_845ins68 (tHcy, betaine), CBS c.699C>T (tHcy, betaine, cystathionine) and TCN2 c.776C>G (MMA). No associations were observed for the other polymorphisms investigated. (c) 2007 Wiley-Liss, Inc.

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Author and article information

Contributors

Di Yu: 391122912@qq.com

Zhulun Zhuang: zhulunzhuang@126.com

Zhongyuan Wen: 353228540@qq.com

Xiaodong Zang: 963023105@qq.com

Xuming Mo: yd@njmu.edu.cn

Journal

Journal ID (nlm-ta): Ital J Pediatr

Journal ID (iso-abbrev): Ital J Pediatr

Title: Italian Journal of Pediatrics

Publisher: BioMed Central (London )

ISSN (Electronic): 1824-7288

Publication date (Electronic): 4 December 2017

Publication date PMC-release: 4 December 2017

Publication date Collection: 2017

Volume: 43

Electronic Location Identifier: 108

Affiliations

[1 ]GRID grid.452511.6, Department of Cardiothoracic Surgery, , Children’s Hospital of Nanjing Medical University, ; Nanjing, 210008 China

[2 ]GRID grid.452511.6, Department of Cardiovascular Center, , The Second Affiliated Hospital of Nanjing Medical University, ; Nanjing, 210008 China

Article

Publisher ID: 425

DOI: 10.1186/s13052-017-0425-1

PMC ID: 5715640

PubMed ID: 29202788

SO-VID: 66ff4794-3a5e-450f-b167-a477da2a236d

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 30 June 2017

Date accepted : 13 November 2017

Funding

Funded by: Jiangsu Provincial Special Program of Medical Science

Award ID: BL2013003

Award Recipient : Xuming Mo

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81370277 and 81370279

Award Recipient : Xuming Mo

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ScienceOpen disciplines: Pediatrics

Keywords: methylenetetrahydrofolate reductase,polymorphism,congenital heart defects,meta-analysis,risk factor

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ScienceOpen disciplines: Pediatrics

Keywords: methylenetetrahydrofolate reductase, polymorphism, congenital heart defects, meta-analysis, risk factor

MTHFR A1298C polymorphisms reduce the risk of congenital heart defects: a meta-analysis from 16 case-control studies

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Most cited references 29

Incidence of congenital heart disease: II. Prenatal incidence.

Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16

Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism.

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