Genetic Variant in MTRR, but Not MTR, Is Associated with Risk of Congenital Heart Disease: An Integrated Meta-Analysis

Bingxi Cai,Zhenling Wang,Jiao Lou,Beibei Zhu,Ti Zhang,Yu Sun,Rong Zhong,Juntao Ke,Wei Chen,Lifeng Liu,Ranran Song,Na Shen,Li Zou,Sunil K Ahuja

doi:10.1371/journal.pone.0089609

Bingxi Cai, Zhenling Wang + Show 12 more

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https://doi.org/10.1371/journal.pone.0089609

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Abstract

BackgroundCongenital heart disease (CHD) is one of the most common birth defects and the leading cause of deaths among individuals with congenital structural abnormalities worldwide. Both Methionine synthase reductase (MTRR) and Methionine synthase (MTR) are key enzymes involved in the metabolic pathway of homocysteine, which are significant in the earlier period embryogenesis, particularly in the cardiac development. Evidence is mounting for the association between MTRR A66G (rs1801394)/MTR A2756G (rs1805087) and the CHD risk, but results are controversial. Therefore, we conducted a meta-analysis integrating case-control and transmitted disequilibrium test (TDT) studies to obtain more precise estimate of the associations of these two variants with the CHD risk.MethodsTo combine case-control and TDT studies, we used the Catmap package of R software to calculate odds ratios (ORs) and 95% confidence intervals (CIs).ResultsA total of 9 reports were included in the final meta-analysis. Eight of them comprised of 914 cases, 964 controls, and 441 families that were germane to MTRR A66G polymorphism; and 4 reports comprised of 250 cases, 205 controls, and 53 families that were relevant to MTR A2756G polymorphism. The pooled OR for the MTRR 66 G allele versus A allele was 1.35 (95% CI = 1.14–1.59, P<0.001, P heterogeneity = 0.073). For MTR A2756G, the G allele conferred a pooled OR of 1.10 (95% CI = 0.78–1.57, P = 0.597, P heterogeneity = 0.173) compared with the A allele. Sensitivity analyses were carried out to asses the effects of each individual study on the pooled OR, indicating the stability of the outcome. Moreover, positive results were also obtained in all subgroups stratified by study type and ethnicity except the subgroup of TDT studies in MTRR A66G variant.ConclusionsThis meta-analysis demonstrated a suggestive result that the A66G variant in MTRR, but not the A2756G in MTR, may be associated with the increase of CHD risks.

Highlights

Congenital heart disease (CHD), an abnormality in the heart’s structure or function that arises before birth [1], is characterized by defects in the cardiac architecture that interfere with venous drainage, septation of cardiac segments and their sequences, and regular function of valve apparatuses [2]
Search strategy We searched the relevant literatures from Medline, ISI Web of Science, China National Knowledge Infrastructure (CNKI) and Sinomed databases before March 1, 2013
Since the transmitted disequilibrium test (TDT) eliminates concerns regarding the selection of appropriate controls and the distortion of gene frequencies due to population stratification or admixture, it is a more robust and appropriate method for validating genetic [20,34,35], the TDT were included in the final meta-analysis

Summary

Introduction

Congenital heart disease (CHD), an abnormality in the heart’s structure or function that arises before birth [1], is characterized by defects in the cardiac architecture that interfere with venous drainage, septation of cardiac segments and their sequences, and regular function of valve apparatuses [2]. CHD can be classified into three broad categories: cyanotic heart disease, left-sided obstruction defects and septation defects [1] It represents one of the most common birth defects and the leading cause of death from a congenital structural abnormality worldwide affecting approximately 8 per 1000 live births reported by America Heart. Congenital heart disease (CHD) is one of the most common birth defects and the leading cause of deaths among individuals with congenital structural abnormalities worldwide. Both Methionine synthase reductase (MTRR) and Methionine synthase (MTR) are key enzymes involved in the metabolic pathway of homocysteine, which are significant in the earlier period embryogenesis, in the cardiac development. We conducted a meta-analysis integrating case-control and transmitted disequilibrium test (TDT) studies to obtain more precise estimate of the associations of these two variants with the CHD risk

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