Meta-analysis of Methylenetetrahydrofolate reductase maternal gene in Down syndrome: increased susceptibility in women carriers of the MTHFR 677T allele

Abstract

Because a number of data studies include some controversial results about Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Down syndrome (DS), we performed a meta-analysis to determine a more precise estimation of this association. Studies were searched on PubMed, EMBASE and Lilacs-Scielo, up to April 2013, and they were eligible if they included case mothers (DSM) that have gave birth to children with DS, and controls mothers (CM) that have gave birth to healthy children without chromosomal abnormality, syndrome or malformation. The combined odds ratio with 95% confidence intervals was calculated by fixed or random effects models to assess the strength of associations. Potential sources of heterogeneity between studies were evaluated using Q test and the I(2). Publication bias was estimated using Begg's test and Egger's linear regression test. Sensitivity analyses were performed by using allelic, dominant, recessive and codominant genetic models, Hardy-Weinberg equilibrium (HWE) and ethnicity. Twenty-two studies with 2,223 DSM and 2,807 CM were included for MTHFR C677T and 15 studies with 1,601 DSM and 1,849 CM were included for MTHFR A1298C. Overall analysis suggests an association of the MTHFR C677T polymorphism with maternal risk for DS. Moreover, no association between the MTHFR A1298C polymorphism and maternal risk for DS was found. There is also evidence of higher heterogeneity, with I(2) test values ranging from 8 to 89%. No evidence of publication bias was found. Taken together, our meta-analysis implied that the T allele carriers might carry an increased maternal risk for DS.

Turner syndrome and genetic polymorphism: a systematic review

“…28---30 The results regarding the contribution of these polymorphisms to the etiology of TS are conflicting, as the C677T SNP was associated with TS in one study, 28 whereas in the others it was A1298C. 47 The genetic polymorphisms analyzed here seem to influence the severity of the clinical manifestations of TS, as well as response to treatment. 47 The genetic polymorphisms analyzed here seem to influence the severity of the clinical manifestations of TS, as well as response to treatment.…”

Gene Polymorphisms That Predispose Women for Down Syndrome Child Birth

“…It was reported initially [17] in the year 1999, that increased plasma hcy level and an increased frequency of both MTHFR 677CT and TT genotypes among the mothers of DS individuals are strongly linked and since then this polymorphism has been tested in more than 30 case-control studies across the globe and confirmed this association with very few exceptions. As far as published literatures are concerned five large meta-analyses have been done till date between the year 2013 and 2014 to address this issue [18][19][20][21][22], with the latest one that includes data from 34 case-control studies for a total of 3.098 women having DS child and 4.852 control mothers [21]. The outcome of all these meta-analyses suggest that the overall risk as represented by odds ratio (OR), for the birth of a child with Trisomy21 to the women who are carriers of the 677 T allele ranges from 1.2 to 1.5 according to the various genetic models under investigation, i.e., allele contrast, dominant, recessive, co-dominant, etc.…”

“…The outcome of all these meta-analyses suggest that the overall risk as represented by odds ratio (OR), for the birth of a child with Trisomy21 to the women who are carriers of the 677 T allele ranges from 1.2 to 1.5 according to the various genetic models under investigation, i.e., allele contrast, dominant, recessive, co-dominant, etc. Subsequent data stratification into ethnic groups revealed that the risk is higher in Asians (OR = 1.5), and lower in Caucasians and/or other groups (OR usually ranging between 1.0 and 1.4) [19,20,22]. The meta-analyses performed by Wu et al [19]; Yang et al [20]; Rai et al [21]; Victorino et al [22] revealed that the frequency of the MTHFR 677 T allele is higher in Caucasian mother of DS child (ranging from 35.6 to 41.5%), followed by Brazilians (ranging from 33.5 to 33.9%), and lower in Asian populations (ranging from 20.0 to 32.3%).…”

“…Subsequent data stratification into ethnic groups revealed that the risk is higher in Asians (OR = 1.5), and lower in Caucasians and/or other groups (OR usually ranging between 1.0 and 1.4) [19,20,22]. The meta-analyses performed by Wu et al [19]; Yang et al [20]; Rai et al [21]; Victorino et al [22] revealed that the frequency of the MTHFR 677 T allele is higher in Caucasian mother of DS child (ranging from 35.6 to 41.5%), followed by Brazilians (ranging from 33.5 to 33.9%), and lower in Asian populations (ranging from 20.0 to 32.3%). When epidemiological data were stratified according to the geographic origin of the mothers and found that the higher risk in Asians (OR = 1.53; 95% CI = 1.29-1.82), followed by Americans (OR = 1.23; 95% CI = 1.07-1.39), and the association remain insignificant for Europeans (OR = 1.04; 95% CI = 0.93-1.16) [21].…”

“…When the data was stratified according to latitude, exhibited a significant association of the MTHFR 677C > T polymorphism with DS birth insub-tropical populations (both TT vs. CC and CT vs. CC carriers), followed by tropical regions (only CT vs. CC carriers), but no significant effect was evident in the population from northern temperate region of the globe. These observations suggest complex gene-environment interactions, which might be a product of differences in allele frequencies among different populations in association with different nutritional status and exposure to environmental factors, such as solar radiation, that could interfere with folate bioavailability [16,23,18,22]. Interestingly, scientists have observed association of the MTHFR 677C > T polymorphism with both chromosome 13 and 21 malsegregation events in lymphocytes from the mothers of DS child [23,24].…”