Genetic variation in folate metabolism is associated with the risk of conotruncal heart defects in a Chinese population

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Abstract

Background

Conotruncal heart defects (CTDs) are a subgroup of congenital heart defects that are considered to be the most common type of birth defect worldwide. Genetic disturbances in folate metabolism may increase the risk of CTDs.

Methods

We evaluated five single-nucleotide polymorphisms (SNPs) in genes related to folic acid metabolism: methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), solute carrier family 19, member 1 (SLC19A1 G80A), methionine synthase (MTR A2576G), and methionine synthase reductase (MTRR A66G), as risk factors for CTDs including various types of malformation, in a total of 193 mothers with CTD-affected offspring and 234 healthy controls in a Chinese population.

Results

Logistic regression analyses revealed that subjects carrying the TT genotype of MTHFR C677T, the C allele of MTHFR A1298C, and the AA genotype of SLC19A1 G80A had significant 2.47-fold (TT vs. CC, OR [95% CI] = 2.47 [1.42–4.32], p = 0.009), 2.05–2.20-fold (AC vs. AA, 2.05 [1.28–3.21], p = 0.0023; CC vs AA, 2.20 [1.38–3.58], p = 0.0011), and 1.68-fold (AA vs. GG, 1.68 [1.02–2.70], p = 0.0371) increased risk of CTDs, respectively. Subjects carrying both variant genotypes of MTHFR A1298C and SLC19A1 G80A had a higher (3.23 [1.71–6.02], p = 0.0002) increased risk for CTDs. Moreover, the MTHFR C677T, MTHFR A1298C, and MTRR A66G polymorphisms were found to be significantly associated with the risk of certain subtypes of CTD.

Conclusions

Our data suggest that maternal folate-related SNPs might be associated with the risk of CTDs in offspring.

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Most cited references 27

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Congenital heart disease in the general population: changing prevalence and age distribution.

Ariane J Marelli, Andrew S Mackie, Raluca Ionescu-Ittu … (2007)

Empirical data on the changing epidemiology of congenital heart disease (CHD) are scant. We determined the prevalence, age distribution, and proportion of adults and children with severe and other forms of CHD in the general population from 1985 to 2000. Where healthcare access is universal, we used administrative databases that systematically recorded all diagnoses and claims. Diagnostic codes conformed to the International Classification of Disease, ninth revision. Severe CHD was defined as tetralogy of Fallot, truncus arteriosus, transposition complexes, endocardial cushion defects, and univentricular heart. Prevalence of severe and other CHD lesions was determined in 1985, 1990, 1995, and 2000 using population numbers in Quebec. Children were subjects <18 years of age. The prevalence was 4.09 per 1000 adults in the year 2000 for all CHD and 0.38 per 1000 (9%) for those with severe lesions. Female subjects accounted for 57% of the adult CHD population. The median age of all patients with severe CHD was 11 years (interquartile range, 4 to 22 years) in 1985 and 17 years (interquartile range, 10 to 28 years) in 2000 (P<0.0001). The prevalence of severe CHD increased from 1985 to 2000, but the increase in adults was significantly higher than that observed in children. In the year 2000, 49% of those alive with severe CHD were adults. The prevalence in adults and median age of patients with severe CHD increased in the general population from 1985 to 2000. In 2000, there were nearly equal numbers of adults and children with severe CHD.

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Seeking causes: Classifying and evaluating congenital heart defects in etiologic studies.

Tiffany Riehle‐Colarusso, Sadia Malik, L Botto … (2007)

Classification and analysis of congenital heart defects (CHD) in etiologic studies is particularly challenging because of diversity of cardiac phenotypes and underlying developmental mechanisms. We describe an approach to classification for risk assessment of CHD based on developmental and epidemiologic considerations, and apply it to data from the National Birth Defect Prevention Study (NBDPS). The classification system incorporated the three dimensions of cardiac phenotype, cardiac complexity, and extracardiac anomalies. The system was designed to facilitate the assessment of simple isolated defects and common associations. A team with cardiologic expertise applied the system to a large sample from the NBDPS. Of the 4,703 cases of CHDs in the NBDPS with birth years 1997 through 2002, 63.6% were simple, isolated cases. Specific associations of CHDs represented the majority of the remainder. The mapping strategy generated relatively large samples for most cardiac phenotypes and provided enough detail to isolate important subgroups of CHDs that may differ by etiology or mechanism. Classification of CHDs that considers cardiac and extracardiac phenotypes is practically feasible, and yields manageable groups of well-characterized phenotypes. Although best suited for large studies, this approach to classification and analysis can be a flexible and powerful tool in many types of etiologic studies of heart defects.

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Model systems for the study of heart development and disease. Cardiac neural crest and conotruncal malformations.

Paul Hutson, P Kirby (2007)

Neural crest cells are multipotential cells that delaminate from the dorsal neural tube and migrate widely throughout the body. A subregion of the cranial neural crest originating between the otocyst and somite 3 has been called "cardiac neural crest" because of the importance of these cells in heart development. Much of what we know about the contribution and function of the cardiac neural crest in cardiovascular development has been learned in the chick embryo using quail-chick chimeras to study neural crest migration and derivatives as well as using ablation of premigratory neural crest cells to study their function. These studies show that cardiac neural crest cells are absolutely required to form the aorticopulmonary septum dividing the cardiac arterial pole into systemic and pulmonary circulations. They support the normal development and patterning of derivatives of the caudal pharyngeal arches and pouches, including the great arteries and the thymus, thyroid and parathyroids. Recently, cardiac neural crest cells have been shown to modulate signaling in the pharynx during the lengthening of the outflow tract by the secondary heart field. Most of the genes associated with cardiac neural crest function have been identified using mouse models. These studies show that the neural crest cells may not be the direct cause of abnormal cardiovascular development but they are a major component in the complex tissue interactions in the caudal pharynx and outflow tract. Since, cardiac neural crest cells span from the caudal pharynx into the outflow tract, they are especially susceptible to any perturbation in or by other cells in these regions. Thus, understanding congenital cardiac outflow malformations in human sequences of malformations as represented by the DiGeorge syndrome will necessarily require understanding development of the cardiac neural crest.

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Author and article information

Contributors

Xike Wang: wangxike2008@sina.com

Haitao Wei: 22898507@qq.com

Ying Tian: 100877611@qq.com

Yue Wu: 1002910157@qq.com

Lei Luo:

ORCID: http://orcid.org/0000-0003-0875-6403

+86-0851-85273958 , linzhongyueliang@163.com

Journal

Journal ID (nlm-ta): BMC Pediatr

Journal ID (iso-abbrev): BMC Pediatr

Title: BMC Pediatrics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2431

Publication date (Electronic): 30 August 2018

Publication date PMC-release: 30 August 2018

Publication date Collection: 2018

Volume: 18

Electronic Location Identifier: 287

Affiliations

[1 ]ISNI 0000 0004 1791 4503, GRID grid.459540.9, Department of paediatrics, , Guizhou Provincial People’s Hospital, ; Guiyang, 550002 China

[2 ]ISNI 0000 0004 1791 4503, GRID grid.459540.9, Department of science and education, , Guizhou Provincial People’s Hospital, ; Guiyang, 550002 China

Author information

Lei Luo http://orcid.org/0000-0003-0875-6403

Article

Publisher ID: 1266

DOI: 10.1186/s12887-018-1266-9

PMC ID: 6117882

PubMed ID: 30165839

SO-VID: d96d6e4a-23a3-438a-bfcd-38eb70dacbcc

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 : 8 June 2018

Date accepted : 24 August 2018

Funding

Funded by: Science and Technology Project of Guizhou Province in China

Award ID: no.[2016]7141 and [2017]1106

Award Recipient : Xike Wang

Funded by: Science and Technology Innovation Talent Team Project of Guizhou Province

Award ID: no.[2015]4019

Award Recipient : Xike Wang

Funded by: high-level innovative talents training project of Guizhou Province

Award ID: no.GZSYQCC[2016]004

Award Recipient : Xike Wang

Custom metadata

ScienceOpen disciplines: Pediatrics

Keywords: conotruncal heart defect,single-nucleotide polymorphism,methionine synthase,methylenetetrahydrofolate reductase,solute carrier family 19

Data availability:

ScienceOpen disciplines: Pediatrics

Keywords: conotruncal heart defect, single-nucleotide polymorphism, methionine synthase, methylenetetrahydrofolate reductase, solute carrier family 19

Genetic variation in folate metabolism is associated with the risk of conotruncal heart defects in a Chinese population

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Abstract

Background

Methods

Results

Conclusions

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Arabidopsis genomics

Most cited references 27

Congenital heart disease in the general population: changing prevalence and age distribution.

Seeking causes: Classifying and evaluating congenital heart defects in etiologic studies.

Model systems for the study of heart development and disease. Cardiac neural crest and conotruncal malformations.

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