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ISSN: 2157-7412
Journal of Genetic Syndromes & Gene Therapy

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Folate Metabolism and Genetic Variant in Down Syndrome: A Meta-Analysis

Ambreen Asim1, Sarita Agarwal1*, Sakil Subhash Kulkarni2 and Inusha Panigrahi2

1Department of Genetics, SGPGIMS Lucknow-226014, India

2Department of Pediatrics, PGIMER, Chandigarh-160012, India

*Corresponding Author:
Sarita Agarwal
Sanjay Gandhi Post Graduate Institute of Medical Sciences
Lucknow, Uttar Pradesh, India
Tel: +91 0522-2494358
E-mail: [email protected]

Received date: August 26, 2015; Accepted date: September 30, 2015; Published date: October 07, 2015

Citation: Asim A, Agarwal S, Kulkarni SS, Panigrahi I (2015) Folate Metabolism and Genetic Variant in Down Syndrome: A Meta-Analysis. J Genet Syndr Gene Ther 6:270. doi:10.4172/2157-7412.1000270

Copyright: © 2015 Asim A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Objectives: Studies investigating the association between gene polymorphisms involved in homocysteine/folate metabolism and Down syndrome (DS) have reported contradictory or inconclusive results. A meta- analysis of 25 studies on association between MTHFR and MTRR polymorphism and DS including 1, 934/2,081/ cases/controls for MTHFR C677T polymorphism, 1,404/1,632/ cases/control for MTHFR A1298C polymorphism and 859 /1,132/cases/ control for MTRR A66G polymorphism was carried out. Study design: Studies were identified by searching the PubMed database for relevant articles published. Case – control studies were chosen, and odds ratio (OR) with confidence interval (CI) were used to assess the strength of association. Results: The overall results suggested that the variant genotypes MTHFR C677T were associated with DS risk (homozygote, TT vs. CC: OR=2.991; 95% CI: 1.321-3.558; P=0.001 and co dominant model, CT vs. CC: OR=1.1616 (1.216-1.845; P=0.0001). The result of the variant genotypes MTHFR A1298C showed its association with the DS risk (homozygote, AA vs. CC: OR=1.428; 95% CI: 1.016-1.849; P=0.0067).In the stratified analysis, results obtained in variant genotype of MTHFR C677T A66G had increased risk of DS in Caucasian subjects in codominant and dominant model while the increased risk was found in dominant models for Brazilian and Asian subjects. Again, for MTHFR A1298C variant, increased risk was found in Caucasian subject in co-dominant, dominant and recessive models and in co-dominant model for Brazilian population. The results also show that in A66G variant of MTRR had increased risk of DS in both Caucasian and Brazilian subjects in dominant model. Conclusion: This meta-analysis supports the idea that MTHFR C677T and MTHFR A1298C genotype is associated with increased risk for DS.

Keywords

Down syndrome; Folate metabolism; Gene polymorphisms; Genotype

Introduction

Down syndrome (DS) is one of the commonest disorders with huge medical and social cost. The major cause of DS is the presence of three copies of genes located on chromosome 21.This change is attributed due to abnormal segregation of during meiosis with maternal non disjunction in around 90% of the cases primarily during meiosis I in the maturing oocyte, before conception [1].

The relationships between non disjunction and abnormal folate metabolism have gained interest recent years. The abnormal folate and methyl metabolism lead to DNA hypomethylation and abnormal chromosomal segregation leading to DNA breaks and aberrant chromosome segregation [2,3].

Studies have shown that MTHFR (methylenetetrahydrofolate reductase) and MTRR (methionine synthase reductase) are the two gene identified as one of the risk factors of DS which are involved in folate metabolism [4-10].

Case–control studies that have investigated the association between DS and MTHFR C677T and A1298C and MTRR A66G polymorphisms have provided inconclusive results. This may be because each study involved small numbers of cases and controls due to which enough information was not available to demonstrate association. In order to shed some light on these inconclusive results, as well as to decrease the uncertainty in the effect size of the risk, a meta-analysis is performed in this article relating the MTHFR C677T, MTHFR A1298C and MTRR A66G gene polymorphisms with DS.

Materials and Methods

Selection criteria

Studies were selected from the PubMed published before 2014 using the suitable keywords. Case reports, editorials and review articles were excluded from this study. Case–control studies that determined the distributions of the MTHFR C677T, MTHFR A1298C and MTRR A66G genotypes in case and in a control of were eligible for inclusion in the meta-analysis.

Data extraction

The following information was extracted from each study: first author, journal, year of publication, ‘‘race’’ of study population, matching , genotyping method, and the number of cases and controls for the MTHFR C677T, MTHFR A1298C and MTRR A66G genotypes. In our studies, ethnicities were classified as Caucasians, Asians and Brazilians.

Statistical analysis

The association between MTHFR C677T, A1298C and MTRR A66G gene polymorphisms and DS risk was assessed by using the co dominant (677CT vs. CC, 677TT vs. CC; 1298AC vs. AA, 1298CC vs. AA; AG vs. AA, GG vs. AA), the dominant (677CT+TT vs. CC; 1298AC+CC vs. AA; AG+GG vs. AA) and the recessive (677TT vs. CC+CT; 1298CC vs. AA+AC; GG vs. AA+AG) models.

The strength of association of the MTHFR and MTRR gene polymorphisms with DS was measured by the ORs together with the 95% CIs. The Chi-square test was first used to assess whether the distribution of genotypes among controls conformed to the Hardy-Weinberg equilibrium (HWE), with P<0.05 considered a departure from HWE.

Results

Selection of studies

In this meta-analysis, we have identified 25 studies on association between MTHFR and MTRR polymorphism and DS including 1, 934/2,081/ cases/controls for MTHFR C677T polymorphism, 1,404/1,632/ cases/control for MTHFR A1298C polymorphism and 859 /1,132/cases/control for MTRR A66G polymorphism .For MTHFR C677T polymorphism 18 studies was considered in which 10 studies was from Caucasian population, 2 from Brazil and 4 from Asia. For MTHFR A1298C polymorphism, out of 12 studies, 7 studies were form Caucasian population and 2 and 3 from Brazil and Asia respectively. For MTRR A66G polymorphism, we have included only 7 Inc which 4 from Caucasian population, 2 from Brazil and only 1 from Asia (Table 1 and 2).

Meta analysis

The meta-analysis of the 18 populations demonstrated that MTHFR C677T was associated with increased DS risk under the homozygote (TT vs. CC: OR=2.991; 95% CI: 1.321-3.558; P=0.001) (Table 3) and co -dominant model (CT vs. CC: OR=1.1616 (1.216-1.845; P=0.0001) (Table 3).

Ethnicity Country Author Year                   Cases/Controls for C677T   Cases/Controls for A1298C Ref
  N CC CT TT   N AA AC CC
Caucasian USA Hobbs et al 2000 157/140 51/67 84/59 22/14         14
Italy Stuppia et al. 2002 64/112 20/27 32/62 12/23 - - - - 24
Ireland O’Leary 2002 192/41 18/90 21/84 2/18         25
Turkey Bodurologu 2004 152/91 86/58 55/30 11/3 152/91 44/21 97/10 11/0 26
Italy Scala et al. 2006 94/264 31/74 39/125 24/57 94/264 38/128 38/108 17/25 27
Egypt Meguid et al. 2008 42/48 20/33 17/12 5/3 42/48 8/18 20/29 14/1 28
Italy Coppedde et al. 2009 94/113 25/40 52/55 17/18 69/101 37/46 29/48 6/7 8
Croatia Vranekovic et al. 2010 111/141 49/66 49/64 13/11 111/141 48/63 56/68 7/10 -
Jordan Sadiq et al. 2011 53/29 23/23 27/5 3/1 53/29 24/10 29/18 0/1 30
Croatia Bozovic et al. 2011 112/221 46/101 55/97 11/23 112/221 55/101 52/98 5/22 29
Brazilian Brazil Brandalize et al. 2009 239/197 94/86 113/93 32/18 239/197 143/113 84/76 12/8 31
Brazil Santos et al. 2008 103/108 51/49 43/47 9/12 103/108 58/57 40/49 5/2 32
   Asian India Rai et al. 2006 149/165 97/124 40/39 12/2 89/70 28/28 39/37 22/5 33
India Kohli et al. 2008 103/109 74/71 29/32 6/0         34
India Cyril et al. 2009 36/60 33/60 3/0 0 36/60 14/26 19/21 3/13 35
Present study Ambreen et al. 2014 233/242 183/169 40/44 10/29 304/302 216/212 71/75 17/15 -

Table 1: Characteristics of studies included in the meta- analysis for MTHFR gene polymorphisms C667T and A1298°C [14-23,26-30].

Ethnicity Country Author Year                   Cases/Controls for  MTRR A66G Ref
         N AA AG GG
  Caucasian USA Hobbs et al. 2000 145/139 26/39 64/68 55/32 14
Ireland O’Leary et al. 2002 48/192 1/35 23/101 24/56 25
USA Chango et al. 2005 119/120 5/6 66/72 48/42 36
Italy Scala et al. 2006 94/264 28/69 46/131 19/57 27
Brazilian Brazil Da Silva et al. 2006 154/158 37/45 92/87 25/26 37
Brazil Brandalize et al. 2010 239/197 42/42 137/111 60/44 31
Asian India Ambreen et al 2014 60/62 2/1 48/59 10/2  

Table 2: Characteristics of studies included in the meta- analysis for MTRR A66G gene polymorphism [14,16,21,24-26,30].

C677T TT vs. CC OR(95% CI ) P value CT vs. CC OR(95% CI ) P value TT vs. CC+CT OR(95% CI ) P value TT+CT vs. CC OR(95% CI ) P value
Total 2.991(1.321,3.558) 0.0001 1.616(1.216,1.845) 0.0001 0.6235(0.5671,0.7474) <0.0001 0.7528(0.8115,0.8503) 0.0001
Caucasian 1.709(1.083 ,1.209) <0.0001 0.6506(0.7610,08841) <0.0001 2.084(1.084,2.574) <0.0001 1.167(1.003,1.354) 0.0409
Brazilian 0.3419 (0.8648,1.489) 0.1365 0.3419 (0.7404) 0.0002 0.4171(0.9009) 0.2282 2.925(1.305,6.031) 0.0029
Asian 0.6790(0.8198,1.004) 0.0557 0.6298 (0.7404,0.915) 0.0002 0.8249(0.9442,1.211) 0.3249 1.563(1.120,1.970) 0.0001

Table 3: ORs and 95% CI for Down syndrome and the MTHFR C677T polymorphism under different genetic models.

A1298C AA vs. CC OR(95% CI )   P value   AC vs. AA OR(95% CI ) P value CC vs. AA+AC OR(95% CI ) P value AC+CC vs. AA OR(95% CI ) P value
Total 1.428(1.016,1.849) 0.0067 0.9649(0.9208,1.122) 0.6432 0.6894(0.5686,0.8849) 0.6481 1.039(0.9496,1.198) 0.6012
Caucasian 1.583(0.9264,1.560) 0.3759 1.280(1.015,1.591) 0.0257 1.803(1.033,2.509) 0.0004 1.111(0.9591,1.138) 0.3185
Brazilian 0.6955(0.9264,1.560) 0.3759 1.192(0.942,1.644) 0.2845 00.6481(0.9519,1.455) 0.2827  1.025(0.8575,1.350) 0.8615
Asian 0.8891(0.9304,1.470) 0.6464 1.00(0.9058,1.345) 1.00  0.8891(0.9519,1.455) 0.6399   0.8834(0.7791,1.2071) 0.4360

Table 4: ORs and 95% CI for Down syndrome and the MTHFR A1298C polymorphism under different genetic models.

The meta-analysis of the 12 populations demonstrated that MTHFR A1298C was associated with increased DS risk under the homozygote (AA vs. CC: OR=1.428; 95% CI: 1.016-1.849; P=0.0067) (Table 4). However, MTRR A66G was not associated with significantly increased risk of DS.

The association of MTHFR (C667T and A1298C polymorphism) and MTRR A66G polymorphism with DS was further stratified by ethnicity. For MTHFR C677T, the positive association was driven by Caucasian codominate model (TT vs. CC: OR=1.709 (1.083, 1.209; P=<0.0001) and in Caucasian dominant and recessive model (TT+CT vs. CC: OR=1.167 (1.003-1.354, P=0.0409 and TT vs. CC+CT: OR= 2.0841(1.084-2.574; P=<0.0001 respectively). The positive association was also driven by Brazilian dominant model (TT+CT vs. CC: OR=2.925 (1.305-6.031; P=0.0029) and also in Asian dominant model (TT+CT vs. CC: OR=1.563 (1.120-1.970; P=0.001) (Table 3).

For MTHFR A1298C polymorphism, the positive association was observed in Caucasian co dominant model (AA vs. CC: 1.583 (0.9264- 1.560; P=0.3759). Similarly, the positive association was also observed in Caucasian and Brazilian codominant model AC vs. AA (OR=1.280 (1.015-1.591; P=0.0257) and OR= 1.192 (0.942-1.644; P=0.2845). The positive association was also driven by Caucasian population in recessive model (CC vs. AA+AC: OR=1.803 (1.03, 2.509; P=0.0004)) (Table 4).

For MTRR A66G polymorphism, the association was observed in both Caucasian and Brazilian population of dominant model (AG+GG vs. AA: (OR=1.533(1.021-2.129; P=0.014”) and (OR= 1.1417(0.999- 2.006; P=0.0487) respectively) (Table 5) (Figures 1-3).

A1298C AA vs. CC OR(95% CI )   P value   AC vs. AA OR(95% CI ) P value CC vs. AA+AC OR(95% CI ) P value AC+CC vs. AA OR(95% CI ) P value
Total 1.428(1.016,1.849) 0.0067 0.9649(0.9208,1.122) 0.6432 0.6894(0.5686,0.8849) 0.6481 1.039(0.9496,1.198) 0.6012
Caucasian 1.583(0.9264,1.560) 0.3759 1.280(1.015,1.591) 0.0257 1.803(1.033,2.509) 0.0004 1.111(0.9591,1.138) 0.3185
Brazilian 0.6955(0.9264,1.560) 0.3759 1.192(0.942,1.644) 0.2845 00.6481(0.9519,1.455) 0.2827  1.025(0.8575,1.350) 0.8615
Asian 0.8891(0.9304,1.470) 0.6464 1.00(0.9058,1.345) 1.00  0.8891(0.9519,1.455) 0.6399   0.8834(0.7791,1.2071) 0.4360

Table 4: ORs and 95% CI for Down syndrome and the MTHFR A1298C polymorphism under different genetic models.

A66G AA vs. GGOR(95% CI ) P value AG vs. AAOR(95% CI ) P value GG vs. AA+AGOR(95% CI ) P value AG+GG vs. AAOR(95% CI ) P value
Total 0.5801(0.6271,0.7640) <0.0001 0.7862(0.6967,0.995) 0.0493 0.6947(0.8680,0.8548) 0.0006 0.7169(0.6323,0.9031) 0.0046
Caucasian 0.6852(0.778,0.9655) 0.0073 0.328(0.987,1.87) 0.1067 0.6367(0.7979,0.8281) 0.0007 1.533(1.021,2.129) 0.0104
Brazilian 0.4914(0.6022.0.7868) 0.0029 0.7851(0.6488,1.124) 0.1863 0.5849(0.8507,0.8667) 0.0071 1.417(0.999,2.006) 0.0487
Asian 0.40(0.0649,6.853) 0.5183 0.7851(0.6488,1.124) 0.1863 0.1667(0.762,0.7965) 0.0127 0.4754(0,9283,5.388) 0.539

Table 5: ORs and 95% CI for Down syndrome and the MTRR A66G polymorphism under different genetic models.

Discussion

Folate is an important vitamin that contributes to cell division and growth and is therefore of particular importance during infancy and pregnancy. Folate deficiency during conception and early pregnancy has been associated with slow growth, anemia, weight loss, digestive disorders, and neural tube defects. It has been suggested that certain polymorphism present on folate metabolizing genes can increase a risk of conceive baby with DS.

James et al in 1999 have reported a folate metabolizing gene, MTHFR as one of the risk factor for DS babies and have also suggested that a significant increase in plasma homocysteine levels exists in mothers of DS babies [9,11].

MTHFR gene contains 11 exons, located on chromosome 1p36.3 which encodes for an enzyme methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate and homocysteine metabolism. MTHFR is composed of an N-terminal catalytic and a C-terminal regulatory domain [12]. It catalyzes the biologically irreversible reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which provides the methyl group for the remethylation of homocysteine to methionine [13]. Several single nucleotide polymorphisms are associated with MTHFR including C677T and A1298C which can affect folate and total homocysteine status. The C677T lies at the catalytic domain and the A1298C position is at the regulatory domain.

The MTHFR C677T, which involves a cytosine (C) to thymine (T) substitution at position 677 which changes amino acid from alanine to valine in the enzyme. The C677T increases thermolability of MTHFR and causes impaired folate binding and reduced activity of the MTHFR enzyme [14]. The MTHFR A1298C is due to adenine(A) to cytosine (C) transversion at nucleotide 1298, which produces a glutamate to alanine substitution. The A1298C polymorphism in the MTHFR gene has also been associated with decreased enzyme activity [4,5].

MTRR gene is located at 5p15.31 which maintains the methionine synthase enzyme at an active stage for the remethylation of homocysteine to methionine [6]. Methionine synthase reductase regenerates a functional methionine synthase via reductive methylation. Single nucleotide polymorphism in MTRR gene like A66G is found to affect the homocystein levels in humans [7,8]. The A66G polymorphism in the MTRR gene causes the substitution of isoleucin with the methionine at codon 22 [9]. This polymorphism might be a genetic risk factor for DS since the methionine synthase reaction is important in maintaining normal folate metabolism and DNA methylation.

The meta-analysis examined the MTHFR and MTRR gene polymorphism and their relationship to risk of DS. The frequency of 677T and 1298C allele was found to be significantly higher among DS children than the other groups indicating that MTHFR C677T and MTHFR A1298C polymorphism in DS children would be expected to play an important role in bringing about DS. Some studies reported significantly increased prevalence of MTHFR C677T polymorphism as important risk factors for DS babies while in contrast some studies had also reported insignificant association [15-18]. For MTHFR A1298C polymorphism, much more contradictory reports have been presented [16,17,19-25]. Differences in ethnicity may be one reason for controversy and high intake of food folate may neutralize the metabolic impact of MTHFR polymorphism [26].

The T and C allele variant of MTHFR C677T and A1298C respectively may increase the thermolability of MTHFR gene thereby leading to production of abrupt homocysteine levels causing hypomethylation. Hypomethylation leads to abnormal chromosomal segregation which in turns leads to the risk of elevated trisomic fetuses. However this mechanism of abrupt homocysteine causing DNA methylation needs further elucidation and other risk factors must be studied properly on larger case –control study which is the main limitations of the study.

The pooled results indicate the homozygous and heterozygous variant of MTHFR C677T polymorphism exerted a risk on DS development (OR=2.991, 95% CI: 1.321-3.558 and OR=1.616, 95% CI: 1.216-1.845, respectively). However, when the analysis was performed by ethnicity, this was not observed in all subgroups except for Caucasian population (OR=1.709; 95% CI: 1,083-1.209). Similarly, when the study was stratified by ethnicity for dominant model, all three sub group showed increased risk of DS but these effect were reduced overall population of DS (OR=07528, 95% CI=0.8115-0.8503).

Again, the pooled results of MTHFR A1298C polymorphism of homozygous variant exerted a risk on DS development (OR=1.428, 95% CI: 1.016-1.849). However, when the analysis was performed by ethnicity, this was not observed in either of the subgroups.

In MTRR A66G polymorphism, reduced risk was observed in all variant but when this risk was stratified in dominant variant, the risk was observed in both Caucasian and Brazilian subgroups (AG+GG vs. AA; OR=1.555, 95% CI: 1.021-2.219 and OR=1.417, 95% CI; 0.999-2.006, respectively) yet this did not produce any overall effect on dominant model. Further well designed large scale case –control studies might be required to validate the association in different population having the risk of DS.

Acknowledgements

The research was financially supported by the Department of Science and Technology, Ministry of Health, Government of India (DST/Inspire fellowship/2012/499). We are highly grateful to Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh for providing the infrastructure for this research. The acknowledgements are highly credited to Dr. Madhu Khuller, Dr. Ram K Marwaha, Dr Reena Das of PGIMER, Chandigarh and the physicians and residents of the Department of Genetics, SGPGIMS, Lucknow, Uttar Pradesh for providing the blood samples of the patients.

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