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Functional variant in methionine synthase reductase intron-1 is associated with pleiotropic congenital malformations

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Abstract

Congenital malformations, such as neural tube defects (NTDs) and congenital heart disease (CHD), cause significant fetal mortality and childhood morbidity. NTDs are a common congenital anomaly, and are typically induced by higher maternal homocysteine (Hcy) levels and abnormal folate metabolism. The gene encoding methionine synthase reductase (MTRR) is essential for adequate remethylation of Hcy. Previous studies have focused on the coding region of genes involved in one-carbon metabolism, but recent research demonstrates that an allelic change in a non-coding region of MTRR (rs326119) increases the risk of CHD. We hypothesized that this variant might contribute to the etiology of NTDs as well, based on a common role during early embryogenesis. In the present study, 244 neural tube defect cases and 407 controls from northern China were analyzed to determine any association (by χ 2 test) between rs326119 and disease phenotypes. Significant increased risk of anencephaly was seen in MTRR variant rs326119 heterozygote (het) and homozygote (hom) individuals [odds ratios (OR)het = 1.81; ORhom = 2.05)]. Furthermore, this variant was also a risk factor for congenital malformations of the adrenal gland (OR = 1.85), likely due to multiple systemic malformations in the NTDs case population. Our present data indicate that the rs326119 non-coding variant of MTRR has a pleiotropic effect on the development of multiple tissues, especially during early stages in utero. This suggests the allelic state of MTRR is a significant clinical factor affecting Hcy levels and optimal folic supplementation.

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Acknowledgments

This study was funded by the National “973” project (Grant number 2013CB945404) and the National Natural Science Foundation of China, Beijing, China (Grant numbers 81471163 and 81300489).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Committee of Medical Ethics at the Capital Institute of Pediatrics (Beijing, China) and with the 1964 Helsinki declaration and its later amendments.

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    Authors and Affiliations

    1. Department of Biochemistry and Molecular Biology, Ministry of Education Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, 030001, Shanxi, China

      Haiqin Cheng, Zhaoli Bu, Hong Zhao & Jun Xie

    2. Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, 100020, China

      Huili Li, Qin Zhang, Baoling Bai & Ting Zhang

    3. Toronto General Research Institute, University Health Network, Toronto, Canada

      Ren-Ke Li

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    1. Haiqin Cheng
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    Correspondence to Ting Zhang or Jun Xie.

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    Haiqin Cheng and Huili Li have equally contributed to this work.

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    Cheng, H., Li, H., Bu, Z. et al. Functional variant in methionine synthase reductase intron-1 is associated with pleiotropic congenital malformations. Mol Cell Biochem 407, 51–56 (2015). https://doi.org/10.1007/s11010-015-2453-8

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