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      Parental Genetic Variants, MTHFR 677C>T and MTRR 66A>G, Associated Differently with Fetal Congenital Heart Defect

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          Abstract

          Background

          Congenital heart defect (CHD) is one of the most common birth defects in the world. The methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes are two of the most important candidate genes for fetal CHD. However, the correlations between the two genes and fetal CHD were inconsistent in various reports. Therefore, this study is aimed to evaluate the parental effects of the two genes on fetal CHD via three genetic polymorphisms, MTHFR 677C>T (rs1801133), MTHFR 1298 A>C (rs1801131), and MTRR 66A>G (rs1801394).

          Methods

          Parents with pregnancy history of fetal CHD were divided into two subgroups: ventricular septal defect (VSD) (21) and non-VSD groups (78). VSD, non-VSD, and 114 control parents (controls) were analyzed in this study. Genotyping of these genetic polymorphisms was done by sequencing.

          Results

          The MTHFR 677C>T polymorphism of either mothers or fathers was independently associated with fetal non-VSD ( P < 0.05) but not VSD, while the MTRR 66A>G polymorphism was independently associated with fetal VSD ( P < 0.05) but not non-VSD. No significance was found for MTHFR 1298A>C polymorphism.

          Conclusion

          In either maternal or paternal group, the MTHFR 677C>T polymorphism was independently related to fetal non-VSD, while the MTRR 66A>G polymorphism was independently related to fetal VSD.

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          A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?

          N. van der Put, F. Gabreëls, E Stevens … (1998)
          Recently, we showed that homozygosity for the common 677(C-->T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A-->C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an MboII recognition site and has an allele frequency of .33. This 1298(A-->C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P T) mutation. However, there appears to be an interaction between these two common mutations. When compared with heterozygosity for either the 677(C-->T) or 1298(A-->C) mutations, the combined heterozygosity for the 1298(A-->C) and 677(C-->T) mutations was associated with reduced MTHFR specific activity (ANOVA P T) mutation. This combined heterozygosity was observed in 28% (n =86) of the NTD patients compared with 20% (n =403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9-4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an additional genetic risk factor for NTDs.
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            A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity.

            I Weisberg, P. Tran, B. Christensen … (1998)
            A common mutation in methylenetetrahydrofolate reductase (MTHFR), C677T, results in a thermolabile variant with reduced activity. Homozygous mutant individuals (approximately 10% of North Americans) are predisposed to mild hyperhomocysteinemia, when their folate status is low. This genetic-nutrient interactive effect is believed to increase the risk for neural tube defects and vascular disease. In this communication, we characterize a second common variant in MTHFR (A1298C), an E to A substitution. Homozygosity was observed in approximately 10% of Canadian individuals. This polymorphism was associated with decreased enzyme activity; homozygotes had approximately 60% of control activity in lymphocytes. Heterozygotes for both the C677T and the A1298C mutation, approximately 15% of individuals, had 50-60% of control activity, a value that was lower than that seen in single heterozygotes for the C677T variant. No individuals were homozygous for both mutations. Additional studies of the A1298C mutation, in the absence and presence of the C677T mutation, are warranted, to adequately address the role of this new genetic variant in complex traits. A silent genetic variant, T1317C, was identified in the same exon. It was relatively infrequent (allele frequency 5%) in our study group, but was quite common in a small sample of African individuals (allele frequency 39%). Copyright 1998 Academic Press.
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              Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition.

              S. James, Athma Pai, J Selhub … (2001)
              Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional and/or genetic disruptions in homocysteine metabolism. The most common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. This variant, with mild enzymatic deficiency, is associated with an increased risk for neural tube defects and pregnancy complications and with a decreased risk for colon cancer and leukemia. Although many studies have reported that this variant is also a risk factor for vascular disease, this area of investigation is still controversial. Severe MTHFR deficiency results in homocystinuria, an inborn error of metabolism with neurological and vascular complications. To investigate the in vivo pathogenetic mechanisms of MTHFR deficiency, we generated mice with a knockout of MTHFR: Plasma total homocysteine levels in heterozygous and homozygous knockout mice are 1.6- and 10-fold higher than those in wild-type littermates, respectively. Both heterozygous and homozygous knockouts have either significantly decreased S-adenosylmethionine levels or significantly increased S-adenosylhomocysteine levels, or both, with global DNA hypomethylation. The heterozygous knockout mice appear normal, whereas the homozygotes are smaller and show developmental retardation with cerebellar pathology. Abnormal lipid deposition in the proximal portion of the aorta was observed in older heterozygotes and homozygotes, alluding to an atherogenic effect of hyperhomocysteinemia in these mice.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biomed Res Int
                Journal ID (iso-abbrev): Biomed Res Int
                Journal ID (publisher-id): BMRI
                Title: BioMed Research International
                Publisher: Hindawi
                ISSN (Print): 2314-6133
                ISSN (Electronic): 2314-6141
                Publication date (Print): 2017
                Publication date (Electronic): 3 July 2017
                Volume: 2017
                Electronic Location Identifier: 3043476
                Affiliations
                1The Medical Genetic Center, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450000, China
                2Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
                3Henan Chengxin Institute of Forensic Clinical Judicial Authentication, Zhengzhou 450003, China
                4Department of Cardiology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450000, China
                Author notes
                *Jian-gang Long: jglong@ 123456mail.xjtu.edu.cn and

                Academic Editor: Erich Cosmi

                Author information
                http://orcid.org/0000-0003-4680-8868
                http://orcid.org/0000-0001-6498-9979
                http://orcid.org/0000-0002-9890-2074
                http://orcid.org/0000-0001-9263-2686
                http://orcid.org/0000-0002-6584-3880
                http://orcid.org/0000-0002-7173-7654
                Article
                DOI: 10.1155/2017/3043476
                PMC ID: 5512027
                SO-VID: d6d72a4d-4808-4f30-9953-4384ae24f971
                Copyright © Copyright © 2017 Qian-nan Guo et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 22 December 2016
                Date accepted : 9 May 2017
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81501336
                Funded by: medical science and technology research project of Henan province
                Award ID: 201702156
                Categories
                Subject: Research Article

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