Maternal PCMT1 gene polymorphisms and the risk of neural tube defects in a Chinese population of Lvliang high-risk area

Zhao, Hengyu; Wang, Fang; Wang, Jingyuan; Xie, Hua; Guo, Jin; Liu, Chi; Wang, Li; Lü, Xiaolin; Bao, Yihua; Wang, Guoliang; Zhong, Rugang; Niu, Bo; Zhang, Ting

doi:10.1016/j.gene.2012.05.035

Cited by 6 publications

(9 citation statements)

References 43 publications

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“…Previous studies supported that low folate levels, and polymorphism of folate-metabolic genes were risk factors for NTDs in this region [58], [59], [60]. Genes regulating early embryonic development were also identified as risk factors of NTDs in this region [61], [62], [63]. The significant involvement of copy number variants in NTD revealed by this study further suggests the complex genetic heterogeneity underlying NTD pathogenesis in the Shanxi region.…”

Section: Discussionsupporting

confidence: 77%

Detection of Copy Number Variants Reveals Association of Cilia Genes with Neural Tube Defects

et al. 2013

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BackgroundNeural tube defects (NTDs) are one of the most common birth defects caused by a combination of genetic and environmental factors. Currently, little is known about the genetic basis of NTDs although up to 70% of human NTDs were reported to be attributed to genetic factors. Here we performed genome-wide copy number variants (CNVs) detection in a cohort of Chinese NTD patients in order to exam the potential role of CNVs in the pathogenesis of NTDs.MethodsThe genomic DNA from eighty-five NTD cases and seventy-five matched normal controls were subjected for whole genome CNVs analysis. Non-DGV (the Database of Genomic Variants) CNVs from each group were further analyzed for their associations with NTDs. Gene content in non-DGV CNVs as well as participating pathways were examined.ResultsFifty-five and twenty-six non-DGV CNVs were detected in cases and controls respectively. Among them, forty and nineteen CNVs involve genes (genic CNV). Significantly more non-DGV CNVs and non-DGV genic CNVs were detected in NTD patients than in control (41.2% vs. 25.3%, p<0.05 and 37.6% vs. 20%, p<0.05). Non-DGV genic CNVs are associated with a 2.65-fold increased risk for NTDs (95% CI: 1.24–5.87). Interestingly, there are 41 cilia genes involved in non-DGV CNVs from NTD patients which is significantly enriched in cases compared with that in controls (24.7% vs. 9.3%, p<0.05), corresponding with a 3.19-fold increased risk for NTDs (95% CI: 1.27–8.01). Pathway analyses further suggested that two ciliogenesis pathways, tight junction and protein kinase A signaling, are top canonical pathways implicated in NTD-specific CNVs, and these two novel pathways interact with known NTD pathways.ConclusionsEvidence from the genome-wide CNV study suggests that genic CNVs, particularly ciliogenic CNVs are associated with NTDs and two ciliogenesis pathways, tight junction and protein kinase A signaling, are potential pathways involved in NTD pathogenesis.

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Section: Discussionsupporting

confidence: 77%

Detection of Copy Number Variants Reveals Association of Cilia Genes with Neural Tube Defects

et al. 2013

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“…We merged this data set with our previous data (Zhao et al 2012) and analyzed a combined 113 mother-fetus pairs (67 control pairs and 46 case pairs). These combined results showed that the interaction between maternal and fetal genotypes was not significant.…”

Section: Resultsmentioning

confidence: 99%

“…Plasma folate and Hcy concentrations were skewed and were normalized by logarithmic transformation for all analyses. We combined our data with that from our previous study (Zhao et al 2012) to assess the interaction between maternal and fetal genotypes using a logistic regression model. A linear regression model was used to compare log-transformed compound concentrations between the groups and adjust for age, educational level, gravidity, folate supplementation, gestational week, and fetal sex.…”

Section: Discussionmentioning

confidence: 99%

“…However, our recent research showed that maternal rs4816 polymorphism might be a potential genetic risk factor for anencephaly, but not for spina bifida (Zhao et al 2012). This result did not fully support the findings of Zhu et al and it is possible that the differences between the study populations (ethnic group, fetus/mother, with or without folic supplementation) may have been the key factors contributing to this apparent discrepancy.…”

Section: Introductionmentioning

confidence: 89%

“…The primers and probes were as described in our previous study (Zhao et al 2012). To ensure genotyping consistency, 10 % of samples were re-genotyped, and 10 % of samples were sequenced directly to validate the accuracy of the genotyping.…”

Section: Genotypingmentioning

confidence: 99%

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PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case–control study in a population with relatively low folate intake

Wang

Guo

et al. 2013

Genes Nutr

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The PCMT1 gene encodes the protein repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase, which is known to protect certain neural cells against Bax-induced apoptosis. Previous studies have produced inconsistent results regarding the effects of PCMT1 (rs4816 and rs4552) polymorphisms on neural tube defects (NTDs). Reduced maternal plasma folate levels and/or elevated homocysteine (Hcy) levels are considered to be risk factors for NTDs. In order to clarify the key factors contributing to the apparent discrepancy and investigate gene-environment interaction, we conducted a case-control study including 121 cases and 146 matched controls to investigate the association between the two PCMT1 polymorphisms in fetuses and the risk of NTDs in the Chinese population of Lvliang, which has low folate intake. Maternal plasma folate and Hcy levels were also measured, and the interaction between fetal PCMT1 gene status and maternal folate metabolites was assessed. Maternal plasma folate concentrations in the NTD group were lower than in controls (10.23 vs. 13.08 nmol/L, adjusted P = 0.059), and Hcy concentrations were significantly higher (14.46 vs. 11.65 lmol/L, adjusted P = 0.026). Fetuses carrying the rs4816 AG ? GG genotype, combined with higher maternal plasma Hcy, had a 6.46-fold (95 % CI 1.15-36.46) increased risk of anencephaly. The results of this study imply that the fetal PCMT1 rs4816 polymorphism may play only a weak role in NTD formation and that gene-environment interactions might be more significant.

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Finding the genetic mechanisms of folate deficiency and neural tube defects—Leaving no stone unturned

Findley

2017

American J of Med Genetics Pt A

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Neural tube defects (NTDs) occur secondary to failed closure of the neural tube between the third and fourth weeks of gestation. The worldwide incidence ranges from 0.3 – 200 per 10,000 births with the United States of American NTD incidence at around 3–6.3 per 10,000 dependent on race and socioeconomic background. Human NTD incidence has fallen by 35–50% in North America due to mandatory folic acid fortification of enriched cereal grain products since 1998. The US Food and Drug Administration has approved the folic acid fortification of corn masa flour with the goal to further reduce the incidence of NTDs, especially among individuals who are Hispanic. However, the genetic mechanisms determining who will benefit most from folate enrichment of the diet remains unclear despite volumes of literature published on studies of association of genes with functions related to folate metabolism and risk of human NTDs. The advances in omics technologies provides hypothesis-free tools to interrogate every single gene within the genome of NTD affected individuals to discover pathogenic variants and methylation targets throughout the affected genome. By identifying genes with expression regulated by presence of folate through transcriptome profiling studies, the genetic mechanisms leading to human NTDs due to folate deficiency may begin to be more efficiently revealed.

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Maternal PCMT1 gene polymorphisms and the risk of neural tube defects in a Chinese population of Lvliang high-risk area

Cited by 6 publications

References 43 publications

Detection of Copy Number Variants Reveals Association of Cilia Genes with Neural Tube Defects

Detection of Copy Number Variants Reveals Association of Cilia Genes with Neural Tube Defects

PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case–control study in a population with relatively low folate intake

Finding the genetic mechanisms of folate deficiency and neural tube defects—Leaving no stone unturned

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