Huo J

Analysis of polymorphisms of genes associated with folate‐mediated one‐carbon metabolism and neural tube defects in Chinese Han Population

BACKGROUND The polymorphism of genes involved in folate-mediated one-carbon metabolism may be a risk factor for neural tube defects (NTDs). In the present study, we aimed to investigate the single nucleotide polymorphisms (SNPs) of the genes BHMT, CUBN, FTCD, GAMT, GART, SARDH, SHMT1, and MUT, and their effect on NTDs in the Chinese Han population. METHODS A total of 270 NTDs cases and 192 controls were enrolled in this study. The SNPs were analyzed with the next-generation sequencing method. The folate levels of brain tissues from 113 available NTDs cases and 123 available controls were measured. RESULTS Next-generation sequencing identified 818 single nucleotide variants, including 214 SNPs used for further analysis. Statistical analysis showed that two independent SNP loci, rs2797840 and rs2073817 in SARDH, may be associated with the susceptibility of NTDs. Specifically, the minor allele G of rs2797840 was significantly associated with NTDs risk in spina bifida subgroup (p value = 0.0348). For subjects whose folate content was measured, the protective allele G of rs2797840 was significantly associated with increased folate content of brain. rs2797840 is within several ENCODE regulatory regions, indicating this SNPs may influence expression of SARDH. CONCLUSION The SNPs rs2797840 and rs2073817 in SARDH may serve as an indicator for the occurrence of NTDs in the Chinese Han population, and rs2797840 may also be an indicator for folate content of brain.

Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects.

Neural tube defects (NTDs) are serious congenital malformations. Excessive maternal homocysteine (Hcy) increases the risk of NTDs, while its mechanism remains elusive. Here we report the role of histone homocysteinylation in neural tube closure (NTC). A total of 39 histone homocysteinylation sites are identified in samples from human embryonic brain tissue using mass spectrometry. Elevated levels of histone KHcy and H3K79Hcy are detected at increased cellular Hcy levels in human fetal brains. Using ChIP-seq and RNA-seq assays, we demonstrate that an increase in H3K79Hcy level down-regulates the expression of selected NTC-related genes including Cecr2, Smarca4, and Dnmt3b. In human NTDs brain tissues, decrease in expression of CECR2, SMARCA4, and DNMT3B is also detected along with high levels of Hcy and H3K79Hcy. Our results suggest that higher levels of Hcy contribute to the onset of NTDs through up-regulation of histone H3K79Hcy, leading to abnormal expressions of selected NTC-related genes.Elevated maternal homocysteine (Hcy) increases the risk for neural tube defects (NTDs) but how this arises is unclear. Here, the authors show that high levels of Hcy on histone H3K79Hcy correlate with NTDs, causing abnormal gene expression (for example Cecr2, Smarca4 and Dnmt3B) linked to neural tube closure.

Altered GNAS imprinting due to folic acid deficiency contributes to poor embryo development and may lead to neural tube defects

Disturbed epigenetic modifications have been linked to the pathogenesis of Neural Tube Defects (NTDs) in those with folate deficiency during pregnancy. However, evidence is lacking to delineate the critical region in epigenome regulated by parental folic acid and mechanisms by which folate deficiency affects normal embryogenesis. Our data from clinical samples revealed the presence of aberrant DNA methylation in GNAS imprinting cluster in NTD samples with low folate concentrations. Results from mouse models indicated that the establishment of GNAS imprinting was influenced by both maternal and paternal folate-deficient diets. Such aberrant GNAS imprinting was present prior to the gametogenesis period. Imprinting in Exon1A/GNAS gDMR was abolished in both spermatozoa and oocytes upon treating with a parental folate-deficient diet (3.6% in spermatozoa, 9.8% in oocytes). Interestingly, loss of imprinting in the GNAS gene cluster altered chromatin structure to an overwhelmingly open structure (58.48% in the folate-free medium group vs. 39.51% in the folate-normal medium group; P < 0.05), and led to a disturbed expression of genes in this region. Furthermore, an elevated cyclic AMP levels was observed in folate acid deficiency group. Our results imply that GNAS imprinting plays major roles in folic acid metabolism regulation during embryogenesis. Aberrant GNAS imprinting is an attribute to NTDs, providing a new perspective for explaining the molecular mechanisms by which folate supplementation in human pregnancy provides protection from NTDs.

A single-nucleotide polymorphism in transferrin is associated with soluble transferrin receptor levels in Chinese adolescents

BACKGROUND AND OBJECTIVES Associations between genetic variants in the hepcidin regulation pathway and iron status have been reported in previous studies. Most of these studies were conducted in populations of European descent and relatively few studies have been conducted in Chinese populations. In this study, we evaluated associations between single-nucleotide polymorphisms (SNPs) in the hepcidin regulation pathway, serum ferritin (SF) and soluble transferrin receptor (sTfR) in Chinese adolescents. METHODS AND STUDY DESIGN In total, 692 students from rural boarding schools were selected from six cities in China. The participants were divided into case and control groups according to criteria for SF and sTfR. Furthermore, 33 SNPs in TMPRSS6, TF, TFR2, BMP2, BMP4, HJV, CYBRD1, HFE, IL6, PCSK7, HAMP, KIAA1468, and SRPRB were selected. Associations between the genetic variants and SF or sTfR were detected. RESULTS For SF, rs4820268 in TMPRSS6 was associated with an SF <25 ng/mL status. Carriers of the G/G genotype of rs4820268 exhibited significantly lower SF levels than A allele carriers did (p=0.047). For sTfR, rs1880669 in TF, rs4901474 in BMP4, and rs7536827 in HJV were significantly associated with an sTfR >=4.4 mg/L status. However, in general linear model analysis, after adjustment for age, sex, and location, only rs1880669 exhibited a stable association with higher sTfR levels (p=0.032). CONCLUSIONS We found rs4820268, in TMPRSS6 that was associated with a low SF level, as previously reported, and a new association between 1880669 in TF and sTfR.