MTHFR Genetic Polymorphism As a Risk Factor in Egyptian Mothers with Down Syndrome Children

Recent reports linking Down syndrome (DS) to maternal polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) gene locus have generated great interest among investigators in the field. The present study aimed at evaluation of MTHFR 677C/T and 1298A/C polymorphisms in the MTHFR gene as maternal risk factors for DS. Forty two mothers of proven DS outcomes and forty eight control mothers with normal offspring were included. Complete medical and nutritional histories for all mothers were taken with special emphasis on folate intake. Folic acid intake from food or vitamin supplements was significantly low (below the Recommended Daily Allowance) in the group of case mothers compared to control mothers. Frequencies of MTHFR 677T and MTHFR 1298C alleles were significantly higher among case mothers (32.1% and 57.1%, respectively) compared to control mothers (18.7% and 32.3%, respectively). Heterozygous and homozygous genotype frequencies of MTHFR at position 677 (CT and TT) were higher among case mothers than controls (40.5% versus 25% and 11.9% versus 6.2%, respectively) with an odds ratio of 2.34 (95% confidence interval [CI] 0.93–5.89) and 2.75 (95% CI 0.95–12.77), respectively. Interestingly, the homozygous genotype frequency (CC) at position 1298 was significantly higher in case mothers than in controls (33.3% versus 2.1% respectively) with an odds ratio of 31.5 (95% CI 3.51 to 282.33) indicating that this polymorphism may have more genetic impact than 677 polymorphism. Heterozygous genotype (AC) did not show significant difference between the two groups. We here report on the first pilot study of the possible genetic association between DS and MTHFR 1298A/C genotypes among Egyptians. Further extended studies are recommended to confirm the present work.

[1]  H. Hiza,et al.  Nutrient content of the U.S. food supply, 2005 , 2008 .

[2]  P. Mastroiacovo,et al.  Analysis of seven maternal polymorphisms of genes involved in homocysteine/folate metabolism and risk of Down syndrome offspring , 2006, Genetics in Medicine.

[3]  F. Coppedè,et al.  Folate gene polymorphisms and the risk of Down syndrome pregnancies in young Italian women , 2006, American journal of medical genetics. Part A.

[4]  E. Bermejo,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? , 2006, American journal of medical genetics. Part A.

[5]  R. Raman,et al.  MTHFR C677T and A1298C polymorphisms are risk factors for Down's syndrome in Indian mothers , 2006, Journal of Human Genetics.

[6]  J. Annichino-Bizzacchi,et al.  Methylenetetrahydrofolate reductase gene polymorphisms and their association with trisomy 21 , 2005, Prenatal diagnosis.

[7]  D. Brunoni,et al.  Relationship between polymorphisms in genes involved in homocysteine metabolism and maternal risk for Down syndrome in Brazil , 2005, American journal of medical genetics. Part A.

[8]  R. Castro,et al.  5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T and 1298A→C mutations are associated with DNA hypomethylation , 2004, Journal of Medical Genetics.

[9]  Y. Alanay,et al.  Methylenetetrahydrofolate reductase enzyme polymorphisms as maternal risk for down syndrome among Turkish women , 2004, American journal of medical genetics. Part A.

[10]  Ricardo Barini,et al.  [Mutations in the methylene-tetrahydrofolate reductase gene and Down syndrome]. , 2002, Cadernos de saude publica.

[11]  J. Oury,et al.  Methylenetetrahydrofolate Reductase Polymorphism in the Etiology of Down Syndrome , 2002, Pediatric Research.

[12]  V. Gatta,et al.  C677T mutation in the 5,10-MTHFR gene and risk of Down syndrome in Italy , 2002, European Journal of Human Genetics.

[13]  Y. Ikeda,et al.  The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and Africans. , 2002, American journal of human genetics.

[14]  A. Parle‐McDermott,et al.  MTRR and MTHFR polymorphism: link to Down syndrome? , 2002, American journal of medical genetics.

[15]  S. Schwartz,et al.  Maternal folate polymorphisms and the etiology of human nondisjunction. , 2001, American journal of human genetics.

[16]  K. Nakashima,et al.  The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine. , 2000, American journal of medical genetics.

[17]  R. Rozen,et al.  Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. , 2000, American journal of human genetics.

[18]  V. L. Wilson,et al.  Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. , 1999, The American journal of clinical nutrition.

[19]  Zhoutao Chen,et al.  Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR) , 1998, Mammalian Genome.

[20]  R. Rozen,et al.  A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. , 1998, Molecular genetics and metabolism.

[21]  J. Clegg,et al.  Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. , 1998, American journal of human genetics.

[22]  F. Gabreëls,et al.  A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? , 1998, American journal of human genetics.

[23]  E. Fisher,et al.  Down syndrome genetics: unravelling a multifactorial disorder. , 1996, Human molecular genetics.

[24]  R. Steegers-Theunissen,et al.  Periconceptional vitamin profiles are not suitable for identifying women at risk for neural tube defects. , 1993, The Journal of nutrition.

[25]  S. Premakumari,et al.  Energy and protein requirements. , 1986, WHO chronicle.

[26]  P. Polani.  Down's Anomaly , 1967, Nature.

[27]  S. Naushad,et al.  Prevalence of methylene tetrahydrofolate reductase polymorphism in South Indian population , 2004 .

[28]  J. Bocchini,et al.  Absence of association of fetal MTHFR C677T polymorphism with prenatal Down syndrome pregnancies , 2003, European Journal of Human Genetics.

[29]  R. Matthews,et al.  A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase , 1995, Nature Genetics.

[30]  N. Raper.  Nutrient Content of the U.S. Food Supply , 1991 .

[31]  Joint Fao,et al.  Energy and protein requirements. Report of a joint FAO/WHO/UNU Expert Consultation. , 1985, World Health Organization technical report series.

[32]  L. Penrose,et al.  Down's anomaly , 1976 .