MTHFRGene variants C677T, A1298C and association with Down syndrome: A case-control study from South India

Abstract

BACKGROUND:The 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and low folate levels are associated with inhibition of DNA methyltransferase and consequently DNA hypomethylation. The expanding spectrum of common conditions linked with MTHFR polymorphisms includes certain adverse birth outcome, pregnancy complications, cancers, adult cardiovascular diseases and psychiatric disorders, with several of these associations remaining still controversial. Trisomy 21 or Down syndrome (DS) is the most common genetic cause of mental retardation. It stems predominantly from the failure of chromosome 21 to segregate normally during meiosis. Despite substantial research, the molecular mechanisms underlying non-disjunction leading to trisomy 21 are poorly understood.MATERIALS AND METHODS:Two common variants C677T and A1298C of the MTHFR gene were screened in 36 parents with DS children and 60 healthy couples from Tamil Nadu and Karnataka. The MTHFR genotypes were studied by RFLP analysis of PCR-amplified products and confirmed by sequencing.RESULTS:The CT genotype was seen in three each (8.3%) of case mothers and fathers. One case father showed TT genotype. All the control individuals exhibited the wild type CC genotype. A similar frequency for the uncommon allele C of the second polymorphism was recorded in case mothers (0.35) and fathers (0.37) in comparison with the control mothers (0.39) and fathers (0.37).CONCLUSION:This first report on MTHFR C677T and A1298C polymorphisms in trisomy 21 parents from south Indian population revealed that MTHFR 677CT polymorphism was associated with a risk for Down syndrome.

Maternal Methylenetetrahydrofolate Reductase C677T Polymorphism and Down Syndrome Risk: A Meta-Analysis from 34 Studies

“…In thirty four studies included in the present meta-analysis, the smallest case sample size was 26 [39] and highest sample size was 239 [32] . ORs for more than one were reported in twenty four articles [1] , [2] , [4] – [6] , [8] , [13] , [28] – [30] , [32] , [33] , [35] – [39] , [42] , [43] , [46] – [49] , [51] , [52] . Except two studies [28] , [43] , control populations of all articles were in Hardy-Weinberg equilibrium.…”

“…Control population of only two studies [28] , [43] were not in HW equilibrium and heterogeneity did not decreased after exclusion of these studies (p = <0.0001, I 2 = 70.00%). Exclusion of seven studies with small sample size, less than 50 (O’Leary et al [44] , n = 41; Liang et al [34] , n = 30; Mequid et al [38] , n = 42; Cyril et al [42] , n = 36; Coppede et al [48] , n = 29; Tayeb [2] , n = 30; Elsayed et al [39] , n = 26), also did not decreased heterogeneity (P heterogeneity = <0.0001, I 2 = 72.98%). Similarly exclusion of eleven studies with very high p value (O’Leary et al [44] , p = 0.87; Acacio et al [28] , p = 0.40; Scala et al [7] , p = 0.91; Martinez-Frias et al [51] , p = 0.90; Pozzi et al [13] , p = 0.84;Vranekoviz et al [37] , p = 0.43; Bozovic et al [8] , p = 0.58; Tayeb [2] , p = 0.74; Elsayed et al [39] , p = 0.65; Kaur and Kaur [5] , p = 0.52; Pandey et al [43] , p = 0.44) did not decrease heterogeneity but increased odds ratio (OR = 1.29, 95% CI = 1.18−1.41, p = <0.0001).…”

Fission Yeast Methylenetetrahydrofolate Reductase Ensures Mitotic and Meiotic Chromosome Segregation Fidelity

“…However, multiple population-based studies performed across different geographical locations have yet to yield a consensus on the potential connections among the various MTHFR polymorphisms. For example, MTHFR polymorphisms have been associated [ 47 , 48 ] and not associated [ 49 , 50 ] with Down syndrome. However, an extensive literature search for polymorphisms associated with Down syndrome indicates a trend toward phenotypic penetrance that is dependent on the co-occurrence of two or more polymorphisms [ 14 ].…”

Evaluation of c677t and a1298c polymorphism of the methylenetetrahydrofolate reductase gene as a maternal risk factor for trisomy 21 (a monocentric study)

“…To date, the concern for this issue was more intense in Chinese (11,15,18,26) and Indian populations (9,14,20,25). There have also been studies in Brazil (7,12,17) and a few studies in Arab populations, such as in the United Arab Emirates (6), Egypt (13) or Jordan (16).…”

“…Folate deficiency and deficiency of donors of methyl groups at the cellular level are both associated with abnormal methylation in DNA, chromosomal instability, rupture of DNA chains, aberrant chromosomal recombination, abnormal chromosome segregation, and meiotic nondisjunction of chromosomes and aneuploidies (1,4,5). A hypothesis has been advanced that genitors of patients with trisomy 21 (MIM *156570), and consequently possess altered metabolism of folate and homocysteine (2)(3)(4)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Another hypothesis states the involvement of other genes, such as methylenetetrahydrofolate dehydrogenase (5,19).…”