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Indian Journal of Human Genetics
Medknow Publications on behalf of Indian Society of Human Genetics
ISSN: 0971-6866 EISSN: 1998-362x
Vol. 13, Num. 2, 2007, pp. 76-77

Indian Journal of Human Genetics, Vol. 13, No. 2, May-August, 2007, pp. 76-77

Letter To Editor

Risk of Down syndrome conferred by MTHFR C677T polymorphism: Ethnic variations

Manovikas Biomedical Research and Diagnostic Centre, 482, Madudah, Plot I-24, Sec.-J, E.M. Bypass, Kolkata - 700107
Correspondence Address:Manovikas Biomedical Research and Diagnostic Centre, 482, Madudah, Plot I-24, Sec.-J, E.M. Bypass, Kolkata - 700 107,

Code Number: hg07018


Down syndrome (DS) well known for trisomy of the 21 st chromosome (MIM 190685) is a complex genetic disorder with prevalence of 1/800 live births. Chromosomal non-disjunction during meiosis, mostly in mothers with DS child, was hypothesized to be the cause for trisomy 21. [1] Studies on human cell line have shown that DNA hypomethylation can induce chromosomal instability. [2]

One of the most crucial enzyme in methionine cycle is Methylenetetrahydrofolate reductase ( MTHFR ; E.C. [MIM 236250]) that reduces 5,10-methylenetetrahydrofolate (5,10-methylene THF) into 5-methyltetrahydrofolate (5-methyl-THF). MTHFR regulates DNA replication by supplying 5-methyl-THF, a primary form of circulatory folate, which is a substrate for methionine formation and required for de novo nucleotide biosynthesis. Reduced activity of MTHFR along with low plasma folate level was hypothesized to be a risk factor for meiotic non-disjunction and risk of having DS child. [3]

Association of MTHFR C677T (rs#1801133) polymorphism with risk of DS have been much discussed; [3],[4] the mutant T allele, associated with reduction in enzymatic activity, was found to be a risk factor for DS.

Our family-based association analysis (75 DS families from West Bengal, 22.82°N, 88.2°E) revealed preferential transmission of wild type C677 allele to DS children (Haplotype-based Haplotype relative risk analysis, χ2 =3.83, p=0.05; Transmission disequilibrium test, χ2 =5.76, P =0.016); paternal transmission of C allele from heterozygous CT father was significant (χ2 =5.56, P =0.018), while no significant difference in maternal transmission was observed (χ2 =3.33, P =0.068). No difference in allelic frequencies was observed (χ2 =0.065, P =0.968) between DS mother (n=68; C=0.846, T=0.154) and control mother (n=59; C=0.839, T=0.161).

An earlier report from Varanasi (25.33°N, 83°E), [4] a north-eastern state of India, had shown strong association of 677T with Indian DS patients and 677T allele was considered as a risk factor for DS contributed by either parent. However data obtained in our study, based on eastern Indian population, do not support the conclusions made by earlier investigators; allelic frequencies were not much different in parents of DS patients as compared to controls. Any preferential transmission of T allele was also not observed.

As Indian population is heterogeneous with large number of ethnic groups, differences in allele frequencies among ethnic groups from different geographical locations are not surprising. However, the present study warrants consideration of 677T polymorphism as a risk factor for DS in Indian mothers. Role of 677T in connection with the "hypomethylation theory" should be explored further, in different ethnic groups.


1.Antonarakis SE, Petersen MB, McInnis MG, Adelsberger PA, Schinzel AA, Binkert F, et al . The meiotic stage of non-disjunction in trisomy 21: Determination by using DNA polymorphisms. Am J Hum Genet 1992;50:544-50.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Harrison JJ, Anisowicz A, Gadi IG, Raffeld M, Sager R. Azacytidine-induced tumorigenesis of CHEF/18 cells: Correlated DNA methylation and chromosome changes. Proc Natl Acad Sci USA 1983; 80:6606-10.  Back to cited text no. 2    
3.James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB, et al . Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factor for Down syndrome. Am J Clin Nutr 1999;70:495-501.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Rai AK, Singh S, Mehta S, Kumar A, Pandey LK, Raman R. MTHFR C677T and A1298C polymorphisms are risk factors for Down's syndrome in Indian mothers. J Hum Genet 2006;51:278-83.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]

Copyright 2007 - Indian Journal of Human Genetics

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