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2009 | 4 | 4 | 395-408
Article title

Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome - meta-analysis

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Abstracts
EN
Folate metabolism deficiency has been related to increased occurrence of maternal non-disjunction resulting in trisomy 21. Several polymorphisms in genes coding for folate metabolism enzymes have been investigated for association with the maternal risk of Down syndrome (DS) yielding variable results. We performed a meta-analysis of case-control studies obtained through the PubMed database. The studies on polymorphisms in the MTHFR, MTRR, MTR, RFC1 and CBS genes were included. The summary OR demonstrated a statistically significant increased risk of giving birth to a child with DS in mothers carrying the mutant allele of the MTHFR/C677T gene polymorphism (both genetic models) and in mothers homozygous for the mutant allele of the MTRR/A66G polymorphism (recessive genetic model). Analyses of other polymorphisms, MTHFR/A1298C, MTR/A2756G, RFC1/A80G, and CBS/844ins68, resulted in borderline or no statistical significance. In conclusion, our meta-analysis showed the significance of genetic alterations in the folate metabolism genes in maternal susceptibility to DS offspring. Our results suggest that the importance of folate supplementation to women in reproductive age in prevention of non-disjunction be revised. Further genetic studies on a combined effect of multiple folate metabolism genes is recommended. Additionally, more thorough studies on the haplotype analyses of genes is recommended as well, especially in populations that have not yet been investigated thus far.
Publisher
Journal
Year
Volume
4
Issue
4
Pages
395-408
Physical description
Dates
published
1 - 12 - 2009
online
3 - 10 - 2009
References
  • [1] Smith G.F., Berg J.M., Penrose L.S., Down’s anomaly, 2nd ed., Churchill Livingstone, Edinburgh, New York, 1976
  • [2] Hernandez D., Fisher E.M., Down syndrome genetics: unravelling a multifactorial disorder, Hum. Mol. Genet., 1996, 5 Spec No, 1411–1416
  • [3] Antonarakis S.E., Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group, N. Engl. J. Med., 1991, 324, 872–876 http://dx.doi.org/10.1056/NEJM199103283241302[Crossref]
  • [4] Antonarakis S.E., Petersen M.B., McInnis M.G., Adelsberger P.A., Schinzel A.A., Binkert F., et al., The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms, Am. J. Hum. Genet., 1992, 50, 544–550
  • [5] Penrose L.S., The relative effects of paternal and maternal age in mongolism, J. Genet., 1933, 27, 219–224 http://dx.doi.org/10.1007/BF02984413[WoS][Crossref]
  • [6] Jameson J.L., Principles of molecular medicine, Humana Press, Totowa, N.J., 1998
  • [7] Morris J.K., Wald N.J., Mutton D.E., Alberman E., Comparison of models of maternal age-specific risk for Down syndrome live births, Prenat. Diagn., 2003, 23, 252–258 http://dx.doi.org/10.1002/pd.568[Crossref]
  • [8] Yang Q., Sherman S.L., Hassold T.J., Allran K., Taft L., Pettay D., et al., Risk factors for trisomy 21: maternal cigarette smoking and oral contraceptive use in a population-based case-control study, Genet. Med., 1999, 1, 80–88 http://dx.doi.org/10.1097/00125817-199901000-00138[Crossref]
  • [9] Hassold T., Hunt P., To err (meiotically) is human: the genesis of human aneuploidy, Nat. Rev. Genet., 2001, 2, 280–291 http://dx.doi.org/10.1038/35066065[Crossref]
  • [10] James S.J., Pogribna M., Pogribny I.P., Melnyk S., Hine R.J., Gibson J.B., et al., Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome, Am. J. Clin. Nutr., 1999, 70, 495–501
  • [11] Ueland P.M., Hustad S., Schneede J., Refsum H., Vollset S.E., Biological and clinical implications of the MTHFR C677T polymorphism, Trends Pharmacol. Sci., 2001, 22, 195–201 http://dx.doi.org/10.1016/S0165-6147(00)01675-8[Crossref]
  • [12] James S.J., Maternal metabolic phenotype and risk of Down syndrome: beyond genetics, Am. J. Med. Genet. A., 2004, 127A, 1–4 http://dx.doi.org/10.1002/ajmg.a.20648[Crossref]
  • [13] Friso S., Choi S.W., Girelli D., Mason J.B., Dolnikowski G.G., Bagley P.J., et al., A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status, Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 5606–5611 http://dx.doi.org/10.1073/pnas.062066299
  • [14] Blount B.C., Mack M.M., Wehr C.M., MacGregor J.T., Hiatt R.A., Wang G., et al., Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage, Proc. Natl. Acad. Sci. U. S. A., 1997, 94, 3290–3295 http://dx.doi.org/10.1073/pnas.94.7.3290[Crossref]
  • [15] Berry R.J., Li Z., Erickson J.D., Li S., Moore C.A., Wang H., et al., Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention, N. Engl. J. Med., 1999, 341, 1485–1490 http://dx.doi.org/10.1056/NEJM199911113412001[Crossref]
  • [16] Ray J.G., Meier C., Vermeulen M.J., Cole D.E., Wyatt P.R., Prevalence of trisomy 21 following folic acid food fortification, Am. J. Med. Genet. A., 2003, 120A, 309–313 http://dx.doi.org/10.1002/ajmg.a.20161[Crossref]
  • [17] Martinez-Frias M.L., Perez B., Desviat L.R., Castro M., Leal F., Rodriguez L., et al., Maternal polymorphisms 677C-T and 1298A-C of MTHFR, and 66A-G MTRR genes: is there any relationship between polymorphisms of the folate pathway, maternal homocysteine levels, and the risk for having a child with Down syndrome?, Am. J. Med. Genet. A., 2006, 140, 987–997
  • [18] Martinez-Frias M.L., The biochemical structure and function of methylenetetrahydrofolate reductase provide the rationale to interpret the epidemiological results on the risk for infants with Down syndrome, Am. J. Med. Genet. A., 2008, 146A, 1477–1482 http://dx.doi.org/10.1002/ajmg.a.32308[WoS][Crossref]
  • [19] Grillo L.B., Acacio G.L., Barini R., Pinto W., Jr., Bertuzzo C.S., Mutations in the methylenetetrahydrofolate reductase gene and Down syndrome, Cad. Saude Publica, 2002, 18, 1795–1797 http://dx.doi.org/10.1590/S0102-311X2002000600035[Crossref]
  • [20] Wang W., Xie W., Wang X., The relationship between polymorphism of gene involved in folate metabolism, homocysteine level and risk of Down syndrome, Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2007, 24, 533–537
  • [21] Acacio G.L., Barini R., Bertuzzo C.S., Couto E.C., Annichino-Bizzacchi J.M., Junior W.P., Methylenetetrahydrofolate reductase gene polymorphisms and their association with trisomy 21, Prenat. Diagn., 2005, 25, 1196–1199 http://dx.doi.org/10.1002/pd.1296[Crossref]
  • [22] Zintzaras E., Maternal gene polymorphisms involved in folate metabolism and risk of Down syndrome offspring: a meta-analysis, J. Hum. Genet., 2007, 52, 943–953 http://dx.doi.org/10.1007/s10038-007-0202-x[Crossref]
  • [23] Biselli J.M., Goloni-Bertollo E.M., Zampieri B.L., Haddad R., Eberlin M.N., Pavarino-Bertelli E.C., Genetic polymorphisms involved in folate metabolism and elevated plasma concentrations of homocysteine: maternal risk factors for Down syndrome in Brazil, Genet. Mol. Res., 2008, 7, 33–42 http://dx.doi.org/10.4238/vol7-1gmr388[Crossref]
  • [24] Chadefaux-Vekemans B., Coude M., Muller F., Oury J.F., Chabli A., Jais J., et al., Methylenetetrahydrofolate reductase polymorphism in the etiology of Down syndrome, Pediatr. Res., 2002, 51, 766–767 [Crossref]
  • [25] Meguid N.A., Dardir A.A., Khass M., Hossieny L.E., Ezzat A., El Awady M.K., MTHFR genetic polymorphism as a risk factor in Egyptian mothers with Down syndrome children, Dis. Markers, 2008, 24, 19–26 [Crossref][WoS]
  • [26] Hobbs C.A., Sherman S.L., Yi P., Hopkins S.E., Torfs C.P., Hine R.J., et al., Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome, Am. J. Hum. Genet., 2000, 67, 623–630 http://dx.doi.org/10.1086/303055[Crossref]
  • [27] Frosst P., Blom H.J., Milos R., Goyette P., Sheppard C.A., Matthews R.G., et al., A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase, Nat. Genet., 1995, 10, 111–113 http://dx.doi.org/10.1038/ng0595-111[Crossref]
  • [28] van der Put N.M., Gabreels F., Stevens E.M., Smeitink J.A., Trijbels F.J., Eskes T.K., et al., A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neuraltube defects?, Am. J. Hum. Genet., 1998, 62, 1044–1051 http://dx.doi.org/10.1086/301825[Crossref]
  • [29] Castro R., Rivera I., Ravasco P., Camilo M.E., Jakobs C., Blom H.J., et al., 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T and 1298A→C mutations are associated with DNA hypomethylation, J. Med. Genet., 2004, 41, 454–458 http://dx.doi.org/10.1136/jmg.2003.017244[Crossref]
  • [30] Paz M.F., Avila S., Fraga M.F., Pollan M., Capella G., Peinado M.A., et al., Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors, Cancer Res., 2002, 62, 4519–4524
  • [31] Tsai M.Y., Yang F., Bignell M., Aras O., Hanson N.Q., Relation between plasma homocysteine concentration, the 844ins68 variant of the cystathionine beta-synthase gene, and pyridoxal-5′-phosphate concentration, Mol. Genet. Metab., 1999, 67, 352–356 http://dx.doi.org/10.1006/mgme.1999.2874[Crossref]
  • [32] Chango A., Emery-Fillon N., de Courcy G.P., Lambert D., Pfister M., Rosenblatt D.S., et al., A polymorphism (80G→A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia, Mol. Genet. Metab., 2000, 70, 310–315 http://dx.doi.org/10.1006/mgme.2000.3034[Crossref]
  • [33] Karpen G.H., Allshire R.C., The case for epigenetic effects on centromere identity and function, Trends Genet., 1997, 13, 489–496 http://dx.doi.org/10.1016/S0168-9525(97)01298-5[Crossref]
  • [34] Ji W., Hernandez R., Zhang X.Y., Qu G.Z., Frady A., Varela M., et al., DNA demethylation and pericentromeric rearrangements of chromosome 1, Mutat. Res., 1997, 379, 33–41
  • [35] O’Leary V.B., Parle-McDermott A., Molloy A.M., Kirke P.N., Johnson Z., Conley M., et al., MTRR and MTHFR polymorphism: link to Down syndrome?, Am. J. Med. Genet., 2002, 107, 151–155 http://dx.doi.org/10.1002/ajmg.10121[Crossref]
  • [36] Stuppia L., Gatta V., Gaspari A.R., Antonucci I., Morizio E., Calabrese G., et al., C677T mutation in the 5,10-MTHFR gene and risk of Down syndrome in Italy, Eur. J. Hum. Genet., 2002, 10, 388–390 http://dx.doi.org/10.1038/sj.ejhg.5200819[Crossref]
  • [37] Boduroglu K., Alanay Y., Koldan B., Tuncbilek E., Methylenetetrahydrofolate reductase enzyme polymorphisms as maternal risk for Down syndrome among Turkish women, Am. J. Med. Genet. A., 2004, 127A, 5–10 http://dx.doi.org/10.1002/ajmg.a.20432[Crossref]
  • [38] Chango A., Fillon-Emery N., Mircher C., Blehaut H., Lambert D., Herbeth B., et al., No association between common polymorphisms in genes of folate and homocysteine metabolism and the risk of Down’s syndrome among French mothers, Br. J. Nutr., 2005, 94, 166–169 http://dx.doi.org/10.1079/BJN20051490[Crossref]
  • [39] da Silva L.R., Vergani N., Galdieri Lde C., Ribeiro Porto M.P., Longhitano S.B., Brunoni D., et al., Relationship between polymorphisms in genes involved in homocysteine metabolism and maternal risk for Down syndrome in Brazil, Am. J. Med. Genet. A., 2005, 135, 263–267
  • [40] Rai A.K., Singh S., Mehta S., Kumar A., Pandey L.K., Raman R., MTHFR C677T and A1298C polymorphisms are risk factors for Down’s syndrome in Indian mothers, J. Hum. Genet., 2006, 51, 278–283 http://dx.doi.org/10.1007/s10038-005-0356-3[Crossref]
  • [41] Coppede F., Marini G., Bargagna S., Stuppia L., Minichilli F., Fontana I., et al., Folate gene polymorphisms and the risk of Down syndrome pregnancies in young Italian women, Am. J. Med. Genet. A., 2006, 140, 1083–1091 [Crossref][WoS]
  • [42] Scala I., Granese B., Sellitto M., Salome S., Sammartino A., Pepe A., et al., Analysis of seven maternal polymorphisms of genes involved in homocysteine/folate metabolism and risk of Down syndrome offspring, Genet. Med., 2006, 8, 409–416 [Crossref]
  • [43] Wang S.S., Qiao F.Y., Feng L., Lv J.J., Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome in China, J. Zhejiang Univ. Sci. B, 2008, 9, 93–99 http://dx.doi.org/10.1631/jzus.B0710599[Crossref]
Document Type
Publication order reference
YADDA identifier
bwmeta1.element.-psjd-doi-10_2478_s11536-009-0055-0
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