Association of methylenetetrahydrofolate reductase gene 677C > T polymorphism and Down syndrome
- 387 Downloads
The association between Down syndrome (DS) and maternal polymorphisms in genes encoding folic acid metabolizing enzymes remains a controversial issue. A meta-analysis was performed to evaluate the association of maternal MTHFR 677C > T polymorphism and the risk of having a child with DS. Case–control studies were screened from major literature databases. Twenty articles from 13 countries worldwide, with a total of 2,101 DS and 2,702 control mothers, attended the inclusion criteria. We found a 50 % increase for the association of maternal homozygous TT genotype and DS in both fixed (OR = 1.51; 95 % CI 1.22–1.87) and random effects models (OR 1.54; 95 % 1.15–2.05). Similarly, a significant pooled OR was found for the heterozygote CT, with an OR 1.26; 95 % CI 1.10–1.43 (fixed effects model) and OR 1.28; 95 % 1.08–1.51 (random effects model). As ultra-violet B solar radiation highly depends on latitude, and can promote, in less pigmented skin, intravascular folate photolysis, we stratified the analysis by latitude region, defining as Tropical (between 23.5° S and 23.5° N), Sub-Tropical (between 23.5° and 40° N and S), and Northern (≥40o N). Significant association was only found for Sub-Tropical area, both using fixed and random effect models. In conclusion, MTHFR 677C > T polymorphism is a moderate risk factor for DS for some populations, and populations located in Sub-Tropical region seem to be at greater risk. Latitude, ethnicity, skin pigmentation, and red blood cell folate are important variables to be considered in future studies.
KeywordsDown syndrome risk MTHFR 677C > T Meta-analysis Latitude UVB Folate
This study was supported by Grants from Fundação de Auxílio à Pesquisa do Estado do Rio de Janeiro, Brazil (E-26/110.427/2011; E-26/102.797/2012), and Conselho Nacional de Desenvolvimento e Pesquisa, Brazil (476978/2008-4; 308885/2006-6; 573993/2008-4).
Conflict of interest
- 1.Epstein CJ (2001) Down syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease 8e. McGraw-Hill, New York, pp 1223–1256Google Scholar
- 4.Guéant JL, Guéant-Rodriguez RM, Anello G, Bosco P, Brunaud L, Romano C, Ferri R, Romano A, Candito M, Namour B (2003) Genetic determinants of folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome? Clin Chem Lab Med 11:1473–1477Google Scholar
- 8.Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, Oliviero O, Jacques PF, Rosenberg IH, Corrocher R, Selhub J (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci USA 99:5606–5611PubMedCrossRefGoogle Scholar
- 10.James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB, Yi P, Tafoya DL, Swenson DH, Wilson VL, Gaylor DW (1999) Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am J Clin Nutr 70:495–501PubMedGoogle Scholar
- 24.Chango A, Fillon-Emery N, Mircher C, Bléhaut H, Lambert D, Herbeth B, James SJ, Réthoré MO, Nicolas JP (2005) 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 94:166–169PubMedCrossRefGoogle Scholar
- 27.Pozzi E, Vergani P, Dalprá L, Combi R, Silvestri D, Crosti F, Dell Orto M, Valsecchi MG (2009) Maternal polymorphisms for methyltetrahydrofolate reductase and methionine synthetase reductase and risk of children with Down syndrome. Am J Obstet Gynecol 200:e1–e6 Epub 2009 Feb 28PubMedCrossRefGoogle Scholar
- 28.Vraneković J, Babić Bozović I, Starcević Cizmarević N, Buretić-Tomljanović A, Ristić S, Petrović O, Kapović M, Brajenović-Milić B (2010) Functional inference of methylenetetrahydrofolate reductase gene polymorphisms on enzyme stability as a potential risk factor for Down syndrome in Croatia. Dis Markers 28:293–298PubMedGoogle Scholar
- 37.Clarke R, Bennett DA, Parish S, Verhoef P, Dötsch-Klerk M, Lathrop M, Xu P, Nordestgaard BG, Holm H, Hopewell JC, Saleheen D, Tanaka T, Anand SS, Chambers JC, Kleber ME, Ouwehand WH, Yamada Y, Elbers C, Peters B, Stewart AF, Reilly MM, Thorand B, Yusuf S, Engert JC, Assimes TL, Kooner J, Danesh J, Watkins H, Samani NJ, Collins R, Peto R (2012) MTHFR Studies Collaborative Group. Homocysteine and coronary heart disease: meta-analysis of MTHFR case–control studies, avoiding publication bias. PLoS Med 9:e1001177 Epub 2012 Feb 21PubMedCrossRefGoogle Scholar
- 40.Jablonski NG (1992) Sun, skin colour and spina bifida: an exploration of the relationship between ultraviolet light and neural tube defects. Proc Australas Soc Hum Biol 5:455–462Google Scholar
- 49.Bosco P, Gueant-Rodriguez RM, Anello G, Barone C, Namour F, Caraci F, Romano A, Romano C, Gueant JLl (2003) Methionine synthase (MTR) 2756 (A - > G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. Am J Med Genet 121A:219–224PubMedCrossRefGoogle Scholar