MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae

Biochemistry, Trinity College Dublin, Dublin, Leinster, Ireland
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 02/2005; 132(4):365-8. DOI: 10.1002/ajmg.a.30354
Source: PubMed


This study examined the relationship between folate/homocysteine-related genetic polymorphisms: MTHFD1 1958G --> A (R653Q), MTHFR 677C --> T (A222V), MTHFR 1298A --> C (E429A), and risk of severe abruptio placentae. We genotyped 62 women with a pregnancy history complicated by severe abruptio placentae and 184 control pregnancies. Analysis of the MTHFD1 1958G --> A (R653Q) polymorphism showed increased frequency of the 'QQ' homozygote genotype in pregnancies affected by severe abruptio placentae compared to control pregnancies (odds ratio 2.85 (1.47-5.53), P = 0.002). In contrast to previous reports, the MTHFR polymorphisms 677C --> T (A222V) and 1298A --> C (E429A) were not associated with abruptio placentae risk in our cohort, when analyzed either independently or in combination. We conclude that women who are 'QQ' homozygote for the MTHFD1 1258G --> A (R653Q) polymorphism are almost three times more likely to develop severe abruptio placentae during their pregnancy than women who are 'RQ' or 'RR.'

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Available from: Lawrence C. Brody
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    • "However, for the parents with NTDs offspring subgroups, a comparison between groups yielded significant evidence for the overrepresentation of the 1958A allele and AA homozygote among the case mothers, compared with control individuals, suggesting that the AA genotype may have a different effect in the embryo and may have a maternal effect only. It is noteworthy that women who harbor the AA homozygote for the MTHFD1 G1958A polymorphism are almost three times more likely to develop severe abruptio placentae during their pregnancy than women who are ‘GA’ or ‘GG’ [43]. In addition, Parle-McDermott et al. also reported that MTHFD1 1958AA homozygote have a 1.64-fold increased risk of having an unexplained second trimester loss, which suggests that the MTHFD1 1958AA genotype may be an important maternal risk factor to consider during pregnancy [44]. "
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    ABSTRACT: Objectives The methylenetetrahydrofolate dehydrogenase (MTHFD1) gene, as one of the key genes involved in the folate pathway, has been reported to play a critical role in the pathogenesis of neural tube defects (NTDs). However, the results of published studies are contradictory and inconclusive. Thus, this meta-analysis aimed to evaluate the effect of the common polymorphism in the MTHFD1 gene, the G1958A (R653Q, dbSNP ID: rs2236225) variant, on the risk of NTDs in all eligible studies. Methods Relevant literature published before January 3, 2014 was retrieved from the MEDLINE, EMBASE, Cochrane Library, and CBM databases. Pooled crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated to evaluate the association between the MTHFD1 G1958A polymorphism and NTDs risk. Results We performed a meta-analysis of nine studies with a total of 4,302 NTDs patients and 4,238 healthy controls. Our results demonstrated a significant correlation between the MTHFD1 G1958A polymorphism and NTDs in an overall meta-analysis. For family-based studies, the study subjects were classified as NTD cases, mothers with NTDs offspring, and fathers with NTDs offspring. We found no association between any of the fathers’ genotypes and NTDs, whereas there was a clear excess of the 1958A allele in the mothers of children with NTDs compared with controls individuals. Conclusions In summary, our meta-analysis strongly suggests that the MTHFD1 G1958A polymorphism might be associated with maternal risk for NTDs in Caucasian populations. However, the evidence of this association should be interpreted with caution due to the selective nature of publication of genetic association studies.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "Several polymorphisms in the MTHFD1 gene have been reported, including two common SNPs: G1958A (R653Q, rs2236225) and G401A (R134K, rs1950902). The MTHFD1 G1958A polymorphism is located within the 10-formyltetrahydrofolate synthetase domain and may modulate biosynthesis of thymidylate, purine nucleotides, and methionine effecting DNA methylation [11], [14], [15], [16]. The G401A SNP changes an arginine to a lysine in the dehydrogenase/cyclohydrolase domain of MTHFD1 and may affect these activities. "
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    ABSTRACT: Studies investigating the association between single-nucleotide polymorphisms (SNPs) of the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and cancer risk report conflicting results. To derive a more precise estimation of the relationship between MTHFD1 polymorphisms and cancer risk, the present meta-analysis was carried out. A comprehensive search was conducted to determine all the eligible studies about MTHFD1 polymorphisms and cancer risk. Combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association between the MTHFD1 polymorphisms and cancer risk. We investigated by meta-analysis the effects of 2 polymorphisms in MTHFD1: G1958A (17 studies, 12348 cases, 44132 controls) and G401A (20 studies, 8446 cases, 14020 controls). The overall results indicated no major influence of these 2 polymorphisms on cancer risk. For G1958A, a decreased cancer risk was found in acute lymphoblastic leukemia (ALL)/Asians (the dominant: OR = 0.74, 95% CI = 0.58-0.94, P = 0.01; allelic: OR = 0.80, 95% CI = 0.65-0.99, P = 0.04) and other cancers (recessive: OR = 0.80, 95% CI = 0.66-0.96, P = 0.02). For G401A, the data showed that MTHFD1 G401A polymorphism was associated with a decreased colon cancer risk under dominant model (OR = 0.89, 95% CI = 0.80-0.99, P = 0.04). The results suggest that MTHFD1 G1958A polymorphism might be associated with a decreased risk of ALL and other cancers. Meanwhile, the MTHFD1 G401A might play a protective role in the development of colon cancer. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.
    Preview · Article · Jul 2013 · PLoS ONE
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    • "These genes are involved in the rennin-angiotensin system, angiogenesis, and coagulation pathways . While associations between these genes and placental abruption have been described before [14] [15] [16] [17] [18], none of the identified SNPs have been previously associated with placental abruption or other adverse outcomes of pregnancy . One of these SNPs is rs3176123 in the 3'UTR region of the THBD (Thrombomodulin) gene. "
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    ABSTRACT: Accumulating evidence suggests that placental abruption has a complex multifactorial pathogenesis that involves cardiovascular risk and metabolic dysfunction. However, comprehensive assessment of variations in genes involved in cardiometabolic traits associated with the risk of placental abruption is lacking. We conducted a case-control study investigating associations of variations in maternal cardiometabolic genes (characterized using 217,697 SNPs on the Illumina Cardio-Metabo Chip) with risk of placental abruption. A total of 253 abruption cases and 258 controls were selected from among participants enrolled in the Peruvian Abruptio Placentae Epidemiology Study in Lima, Peru. In the genome-wide association analyses, top hits did not surpass genome-wide significance. However, we observed suggestive associations of placental abruption with several SNPs, including SNPs in SMAD2 (P-value=1.88e-6), MIR17HG (P-value=7.8e-6], and DGKB (P-value=8.35e-6] loci. In candidate gene analyses, we observed associations of variations in a priori selected genes involved in coagulation, rennin-angiotensin, angiogenesis, inflammation, and B-vitamin metabolism with the risk of abruption. Our study suggests that variations in maternal cardiovascular and metabolic genes may be associated with risk of placental abruption. Future studies with large sample sizes are warranted.
    Full-text · Article · Dec 2012 · International Journal of Molecular Epidemiology and Genetics
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