Full Text:   <1907>

CLC number: R394

On-line Access: 

Received: 2007-11-24

Revision Accepted: 2008-01-07

Crosschecked: 0000-00-00

Cited: 30

Clicked: 4309

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
1. Reference List
Open peer comments

Journal of Zhejiang University SCIENCE B 2008 Vol.9 No.2 P.93~99


Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome in China

Author(s):  Shao-shuai WANG, Fu-yuan QIAO, Ling FENG, Juan-juan LV

Affiliation(s):  Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

Corresponding email(s):   wangshaoshuaitj@yahoo.com.cn

Key Words:  Tetrahydrofllate dehydrogenase, Ligases, Down syndrome, Folate

Shao-shuai WANG, Fu-yuan QIAO, Ling FENG, Juan-juan LV. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome in China[J]. Journal of Zhejiang University Science B, 2008, 9(2): 93~99.

@article{title="Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome in China",
author="Shao-shuai WANG, Fu-yuan QIAO, Ling FENG, Juan-juan LV",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome in China
%A Shao-shuai WANG
%A Fu-yuan QIAO
%A Ling FENG
%A Juan-juan LV
%J Journal of Zhejiang University SCIENCE B
%V 9
%N 2
%P 93~99
%@ 1673-1581
%D 2008
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B0710599

T1 - Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome in China
A1 - Shao-shuai WANG
A1 - Fu-yuan QIAO
A1 - Ling FENG
A1 - Juan-juan LV
J0 - Journal of Zhejiang University Science B
VL - 9
IS - 2
SP - 93
EP - 99
%@ 1673-1581
Y1 - 2008
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B0710599

Objective: To explore the relationship between genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), the central enzymes in folate metabolism that affects DNA methylation and synthesis, and the risk of down syndrome in China. Methods: Genomic DNA was isolated from the peripheral lymphocytes of 64 mothers of children with down syndrome and 70 age matched control subjects. Polymerase chain reaction and restriction fragment length polymorphism were used to examine the polymorphisms of MTHFR 677C→T, MTRR 66A→G and the relationship between these genotypes and the risk of down syndrome was analyzed. Results: The results show that the MTHFR 677C→T polymorphism is more prevalent among mothers of children with down syndrome than among control mothers, with an odds ratio of 3.78 (95% confidence interval (CI), 1.78~8.47). In addition, the homozygous MTRR 66A→G polymorphism was independently associated with a 5.2-fold increase in estimated risk (95% CI, 1.90~14.22). The combined presence of both polymorphisms was associated with a greater risk of down syndrome than the presence of either alone, with an odds ratio of 6.0 (95% CI, 2.058~17.496). The two polymorphisms appear to act without a multiplicative interaction. Conclusion: MTHFR and MTRR gene mutation alleles are related to down syndrome, and CT, TT and GG gene mutation types increase the risk of down syndrome.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1] Acácio, G.L., Barini, R., Bertuzzo, C.S., Couto, E.C., Annichino-Bizzacchi, J.M., Júnior, W.P., 2005. Methylenetetrahydrofolate reductase gene polymorphisms and their association with trisomy 21. Prenat. Diagn., 25(13):1196-1199.

[2] Botto, L.D., Yang, Q., 2000. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A huge review. Am. J. Epidemiol., 151:862-877.

[3] Boué, J., Boué, A., Lazar, P., Gueguen, S., 1975. Retrospective and prospective epidemiological studies of 1506 karotyped spontaneous abortions. Teratology, 12(1):11-26.

[4] Brown, C.A., McKinney, K.Q., Young, K.B., Norton, H.J., 1999. The C677T methylenetetrahydrofolate reductase polymorphism influences the homocysteine-lowering effect of hormone replacement therapy. Mol. Genet. Metab., 67(1):43-48.

[5] Duthie, S.J., Narayanan, S., Brand, G.M., Pirie, L., Grant, G., 2002. Impact of folate deficiency on DNA stability. J. Nutr., 132(8 Suppl.):2444S-2449S.

[6] Edmonds, L.D., Oakley, G.P., 1981. Congenital malformations surveillance: Two American systems. Int. J. Epidemiol., 10(3):247-252.

[7] Engel, S.M., Olshan, A.F., Siega-Riz, A.M., Savitz, D.A., Chanock, S.J., 2006. Polymorphisms in folate metabolizing genes and risk for spontaneous preterm and small-for-gestational age birth. Am. J. Obstet. Gynecol., 195(5):1231.e1-1231.e11.

[8] Freeman, S., Grantham, M., Hassold, T., Pettay, D., Takaesu, N., 1991. Cytogenetic and molecular studies of human spontaneous abortions. Am. J. Hum. Genet. Suppl. A, 49:9-16.

[9] García-Casal, M.N., Osorio, C., Landaeta, M., Leets, I., Matus, P., Fazzino, F., Marcos, E., 2005. High prevalence of folic acid and vitamin B12 deficiencies in infants, children, adolescents and pregnant women in Venezuela. Eur. J. Clin. Nutr., 59(9):1064-1070.

[10] Geiman, T.M., Sankpal, U.T., Robertson, A.K., Chen, Y., Mazumdar, M., Heale, J.T., Schmiesing, J.A., Kim, W., Yokomori, K., Zhao, Y., et al., 2004. Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery. Nucl. Acids Res., 32(9):2716-2729.

[11] Gomez, H.L., Santillana, S.L., Vallejos, C.S., Velarde, R., Sanchez, J., Wang, X., Bauer, N.L., Hockett, R.D., Chen, V.J., Niyikiza, C., et al., 2006. A phase II trial of pemetrexed in advanced breast cancer: Clinical response and association with molecular target expression. Clin. Cancer Res., 12(3 Pt 1):832-838.

[12] Guéant-Rodriguez, R.M., Rendeli, C., Namour, B., Venuti, L., Romano, A., Anello, G., Bosco, P., Debard, R., Gérard, P., Viola, M., et al., 2003. Transcobalamin and methionine synthase reductase mutated polymorphisms aggravate the risk of neural tube defects in humans. Neurosci. Lett., 344(3):189-192.

[13] Harvey, K.J., Newport, J., 2003. CpG methylation of DNA restricts prereplication complex assembly in Xenopus egg extracts. Mol. Cell. Biol., 23(19):6769-6779.

[14] Hassold, T.J., Jacobs, P.A., 1984. Trisomy in man. Ann. Rev. Genet., 18(1):69-97.

[15] Hunt, P.A., Lemaire-Adkins, R., 1998. Genetic control of mammalian female meiosis. Curr. Top. Dev. Biol., 37:359-381.

[16] James, S.J., Pogribna, M., Pogribny, I.P., Melnyk, S., Hine, R.J., Gibson, J.B., Yi, P., Tafoya, D.L., Swenson, D.H., Wilson, V.L., Gaylor, D.W., 1999. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase (MTHFR) gene may be maternal risk factors for Down syndrome. Am. J. Clin. Nutr., 70:495-501.

[17] James, S.J., Pogribny, I.P., Pogribna, M., Miller, B.J., Jernigan, S., Melnyk, S., 2003. Mechanisms of DNA damage, DNA hypomethylation, and tumor progression in the folate/methyl-deficient rat model of hepatocarcinogenesis. J. Nutr., 133(11 Suppl. 1):3740S-3747S.

[18] Kim, K.H., Choi, J.S., Kim, I.J., Ku, J.L., Park, J.G., 2006. Promoter hypomethylation and reactivation of MAGE-A1 and MAGE-A3 genes in colorectal cancer cell lines and cancer tissues. World J. Gastroenterol., 12(35):5651-5657.

[19] Ko, Y.G., Nishino, K., Hattori, N., Arai, Y., Tanaka, S., Shiota, K., 2005. Stage-by-stage change in DNA methylation status of Dnmt1 locus during mouse early development. J. Biol. Chem., 280(10):9627-9634.

[20] Leclerc, D., Darwich-Codore, H., Rozen, R., 2003. Characterization of a pseudogene for murine methylenetetrahydrofolate reductase. Mol. Cell Biochem., 252(1-2):391-395.

[21] Lezhava, T., Khavison, V., Monaselidze, J., Jokhadze, T., Dvalishvili, N., Bablishvili, N., Barbakadze, S., 2004. Bioregulator Vilon-induced reactivation of chromatin in cultured lymphocytes from old people. Biogerontology, 5(2):73-79.

[22] McCaffrey, R., St Johnston, D., González-Reyes, A., 2006. Drosophila mus301/spindle-C encodes a helicase with an essential role in double-strand DNA break repair and meiotic progression. Genetics, 174(3):1273-1285.

[23] Mosiolek, M., Pasierbek, P., Malarz, J., Moś, M., Joachimiak, A.J., 2005. Rumex acetosa Y chromosomes: Constitutive or facultative hetero-chromatin? Folia Histochem. Cytobiol., 43(3):161-167.

[24] Neglia, M., Bertoni, L., Zoli, W., Giulotto, E., 2003. Amplification of the pericentromeric region of chromosome 1 in a newly established colon carcinoma cell line. Cancer Genet. Cytogenet., 142(2):99-106.

[25] O'Leary, V.B., Mills, J.L., Pangilinan, F., Kirke, P.N., Cox, C., Conley, M., 2005. Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. Mol. Genet. Metab., 85(3):220-227.

[26] Parry, E.M., Parry, J.M., Corso, C., Doherty, A., Haddad, F., Hermine, T.F., 2002. Detection and characterization of mechanisms of action of aneugenic chemicals. Mutagenesis, 17(6):509-521.

[27] Pilsner, J.R., Liu, X., Ahsan, H., Ilievski, V., Slavkovich, V., Levy, D., 2007. Genomic methylation of peripheral blood leukocyte DNA: Influences of arsenic and folate in Bangladeshi adults. Am. J. Clin. Nutr., 86(4):1179-1186.

[28] Pogribny, I.P., James, S.J., Jernigan, S., Pogribna, M., 2004. Genomic hypomethylation is specific for preneoplastic liver in folate/methyl deficient rats and does not occur in non-target tissues. Mutat. Res., 548(1-2):53-59.

[29] Ramírez, N.J., Belalcázar, H.M., Yunis, J.J., Quintero, L.N., Arboleda, G.H., Arboleda, H., 2007. Parental origin, nondisjunction, and recombination of the extra chromosome 21 in Down syndrome: A study in a sample of the Colombian population. Biomedica, 27(1):141-148.

[30] Rosenblatt, D.S., 1999. Folate and homocysteine metabolism and gene polymorphisms in the etiology of Down syndrome. Am. J. Clin. Nutr., 70:429-430.

[31] Smith, G., Berg, J., 1995. Down’s Anomaly, 2nd Ed. Churchill Livingstone, Edinburgh and New York.

[32] Valinluck, V., Tsai, H.H., Rogstad, D.K., Burdzy, A., Bird, A., Sowers, L.C., 2004. Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic. Acids Res., 32(14):4100-4108.

[33] van der Linden, I.J., den Heijer, M., Afman, L.A., Gellekink, H., Vermeulen, S.H., Kluijtmans, L.A., 2006. The methionine synthase reductase 66A→G polymorphism is a maternal risk factor for spina bifida. J. Mol. Med., 84(12):1047-1054.

[34] Warburton, D., 2005. Biological aging and the etiology of aneuploidy. Cytogenet. Genome Res., 111(3-4):266-272.

[35] Zijno, A., Andreoli, C., Leopardi, P., Marcon, F., Rossi, S., Caiola, S., Verdina, A., Galati, R., Cafolla, A., Crebelli, R., 2003. Folate status, metabolic genotype, and biomarkers of genotoxicity in healthy subjects. Carcinogenesis, 24(6):1097-1103.

Open peer comments: Debate/Discuss/Question/Opinion



2010-01-29 10:47:12

This is a very impressive research. It provides an excellent description of polymorphisms in genes involved in folate metabolism as maternal risk factors.

Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - Journal of Zhejiang University-SCIENCE