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Huiping Zhu

Publications and source records attributed to Huiping Zhu.

At least 19 recordsLinked to original sources
PubMed2007

Fetal and maternal MTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts.

The association between maternal folate intake and risk of nonsyndromic oral clefts has been studied among many populations with conflicting results. The methylenetetrahydrofolate reductase gene (MTHFR) plays a major role in folate metabolism, and several polymorphisms, including C677T, are common in European populations. Data from a French study (1998-2001) let us investigate the roles of maternal dietary folate intake and the MTHFR polymorphism and their interaction on the risk of cleft lip with/without cleft palate (CL/P) and cleft palate only (CP). We used both case-control (164 CL/P, 76 CP, 236 controls; 148, 59, 168 of whom, respectively, had an available genotype) and case-parent (143 CL/P and 56 CP families) study designs and distinguished the role of the child's genotype and maternally mediated effects on risks. This study observed a beneficial effect of mothers' dietary folate intake on their offspring's risk (odds ratio (OR)(< or = 230 microg/day) = ref; for CL/P, OR([230-314 microg/day]) = 0.56, 95% confidence interval = 0.3-0.9, OR(>314 microg/day) = 0.64, 0.4-1.1; for CP, OR([230-314 microg/day]) = 1.15, 0.6-2.2, OR(>314 microg/day) = 0.70, 0.3-1.4). We observed a reduced risk associated with the TT genotype of the child in the case-control analysis (OR(CC) = ref; for CL/P, OR(TT) = 0.54, 0.3-1.1; for CP, OR(TT) = 0.33, 0.1-1.0); this genotype, either fetal or maternal, was not statistically significant in the case-parent analysis. A frequency of TT genotype higher in our control group than previously reported in France can partly explain the risk reduction observed in case-control comparison. Interactions were not statistically significant. Stratified case-parent analysis showed, however, slight heterogeneity in the role of TT genotype according to folate intake. The modest sample size limits this study, which nonetheless provides new estimate of the possible impact of dietary folate intake and MTHFR polymorphism on oral clefts.

Case-Control Studies↗
PubMed2007

Infant C677T MTHFR polymorphism and severe mental retardation.

BACKGROUND: We investigated whether infants with homozygous genotype TT of the MTHFR gene were at increased risk of severe mental retardation. METHODS: One hundred children with severe mental retardation (cases) were investigated from a large geographic-based study of infants born in California in 1992-1993. Cases were compared to 743 randomly selected nonmalformed control infants born in California during 1987-1991. DNA was extracted from newborn screening filter papers. Cases and controls were genotyped TT if homozygous for the MTHFR C677T allele, CT if heterozygous for the C677T allele, and CC if homozygous for the C677 (wild type) allele. RESULTS: Overall, case and control infants had similar percentages of TT and CT genotypes. Percentages between cases and controls differed somewhat across race/ethnic groups. Elevated ORs of 1.9 (95% CI: 0.7-5.0) and 2.6 (95% CI: 1.1-5.8) were observed for the TT and CT genotypes, respectively, among Hispanic children. Observed results were not substantially altered for analyses that removed 41 case children who also had structural birth defects. CONCLUSIONS: Folate-related mechanisms are important to investigate for etiologies of birth defects, and such lines of inquiry may be revealing for mental retardation given the relationships between mental retardation and birth defects and potential relationships between folate, DNA methylation, and mental retardation.

Alleles↗
PubMed2007

Screening for novel PAX3 polymorphisms and risks of spina bifida.

BACKGROUND: PAX3 plays an important role in mammalian embryonic development. Known mutations in PAX3 are etiologically associated with Waardenburg syndrome and syndromic neural tube defects (NTDs). Mutations in the murine homologue, pax3, are responsible for the phenotype of splotch mice, in which nullizygotes are 100% penetrant for NTDs. METHODS: The study sample included 74 infants with spina bifida (cases) and 87 nonmalformed infant controls. The conserved paired-box domain as well as the upstream genomic region of PAX3 were subjected to resequencing and those identified SNPs were evaluated as haplotypes. The associations of haplotypes for selected gene regions and the risks of spina bifida were further studied. RESULTS: Nineteen SNPs were observed; 15 observed in controls had been submitted to the National Center for Biotechnology Information (NCBI) database with allele frequencies. The PAX3 gene variant T-1186C (rs16863657) and its related haplotype, TCTCCGCCC of nine SNPs, were found to be associated with an increased risk of spina bifida, with an OR of 3.5 (95% CI: 1.2-10.0) among Hispanic Whites. CONCLUSIONS: Our analyses indicated that PAX3 SNPs were not strong risk factors for human spina bifida. However, additional follow-up of the PAX3 gene variant T-1186C (rs16863657) and its related haplotype, TCTCCGCCC, may be important in other populations.

Case-Control Studies↗
PubMed2006

CHKA and PCYT1A gene polymorphisms, choline intake and spina bifida risk in a California population.

BACKGROUND: Neural tube defects (NTDs) are among the most common of all human congenital defects. Over the last two decades, accumulating evidence has made it clear that periconceptional intake of folic acid can significantly reduce the risk of NTD affected pregnancies. This beneficial effect may be related to the ability of folates to donate methyl groups for critical physiological reactions. Choline is an essential nutrient and it is also a methyl donor critical for the maintenance of cell membrane integrity and methyl metabolism. Perturbations in choline metabolism in vitro have been shown to induce NTDs in mouse embryos. METHODS: This study investigated whether single nucleotide polymorphisms (SNPs) in human choline kinase A (CHKA) gene and CTP:phosphocholine cytidylytransferase (PCYT1A) gene were risk factors for spina bifida. Fluorescence-based allelic discrimination analysis was performed for the two CHKA intronic SNPs hCV1562388 (rs7928739) and hCV1562393, and PCYT1A SNP rs939883 and rs3772109. The study population consisted of 103 infants with spina bifida and 338 non-malformed control infants who were born in selected California counties in the period 1989-1991. RESULTS: The CHKA SNP hCV1562388 genotypes with at least one C allele were associated with a reduced risk of spina bifida (odds ratio = 0.60, 95%CI = 0.38-0.94). The PCYT1A SNP rs939883 genotype AA was associated with a twofold increased risk of spina bifida (odds ratio = 1.89, 95% CI = 0.97-3.67). These gene-only effects were not substantially modified by analytic consideration to maternal periconceptional choline intake. CONCLUSION: Our analyses showed genotype effects of CHKA and PCYT1A genes on spina bifida risk, but did not show evidence of gene-nutrient interactions. The underlying mechanisms are yet to be resolved.

California↗
PubMed2006

Arsenic-induced gene expression changes in the neural tube of folate transport defective mouse embryos.

Arsenic injected intraperitoneally (i.p.) during early organogenesis to small pregnant laboratory rodents (mouse, rat, and hamster) induces several congenital defects in the progeny. Among those abnormalities consistently and predominantly observed are exencephaly and encephalocele. These severe defects of the central nervous system originate from a corrupted process of neurulation and are better known as neural tube defects (NTDs). In order to understand the mechanism of arsenate-induced NTDs, we designed studies in which highly sensitive Folr2 nullizygous mice were injected intraperitoneally with sodium arsenate at the beginning of the neural tube formation process. This specific knockout mouse and the arsenic exposure conditions were chosen as they were known to provide a high incidence of exencephaly in exposed embryos. We have applied gene expression technology to the anterior neural tube. This allowed us to study arsenic-induced changes in patterns of gene expression that may contribute to the development of neural tube defects in these mice. Using extensive data analysis approaches including hierarchical clustering and gene ontology analysis, we identified several candidate genes as well as important ontology groups that may be responsible for arsenic's teratogenicity. Changes in the expression of several genes in response to arsenic treatment in our model had previously been demonstrated by other investigators to also induce NTDs in murine model systems. These include: engrailed 1 (En-1), platelet derived growth factor receptor alpha (Pdgfralpha) and ephrinA7 (EphA7). We also found several gene ontology groups that could be implicated in arsenic's underlying teratogenicity: morphogenesis, oxidative phosporylation, redox response, and regulation of I-kappaB kinase/NF-kappaB cascade. Additionally, we revealed new target genes which may be responsible for arsenic disrupted oxidative phosphorylation.

Abnormalities, Drug-Induced↗
PubMed2005

A known functional polymorphism (Ile120Val) of the human PCMT1 gene and risk of spina bifida.

Folate binding protein 1 (Folr1) knockout mice with low maternal folate concentrations have been shown to be excellent animal models for human folate-responsive neural tube defects (NTDs). Previous studies using the Folr1 knockout mice revealed that maternal folate supplementation up-regulates the expression of the PCMT1 gene in Folr1 nullizygous neural tube tissue during neural tube closure. PCMT1 encodes the protein repair enzyme l-isoaspartate (d-aspartate) O-methyltransferase (PIMT) that converts abnormal d-aspartyl and l-isoaspartyl residues to the normal l-aspartyl form. PIMT is known to protect certain neural cells from Bax-induced apoptosis. Pcmt1-deficient mice present with abnormal AdoMet/AdoHcy homeostasis. We hypothesized that a known functional polymorphism (Ile120Val) in the human PCMT1 gene is associated with an increased risk of folate-responsive human NTDs. A case-control study was conducted to investigate a possible association between this polymorphism and risk of spina bifida. Compared to the Ile/Ile and Ile/Val genotypes, the homozygous Val/Val genotype showed decreased risk for spina bifida (adjusted odds ratio=0.6, 95% confidence interval: 0.4-0.9). Our results showed that the Ile120Val polymorphism of PCMT1 gene is a genetic modifier for the risk of spina bifida. Val/Val genotype was associated with a reduction in risk for spina bifida.

Adult↗
PubMed2005

Genetic variation in the proto-oncogene SKI and risk for orofacial clefting.

BACKGROUND: SKI is a proto-oncogene that is required for development of the central nervous system and skeletal muscle, and is involved in specifying selected cranial neural-crest-derived craniofacial structures. To identify genetic variants within the SKI gene and investigate the potential association between SKI polymorphisms and risk for orofacial defects, we initially re-sequenced the gene. METHODS: DNA re-sequencing of all seven exons of the SKI gene was performed on 100 control samples. Subsequently, we genotyped 394 samples (148 CLP cases, 99 CP cases, and 147 control infants) for a novel SNP identified in the DNA re-sequencing effort using restriction fragment length polymorphism (RFLP) analysis. RESULTS: We identified one polymorphism in exon 1 of the SKI gene (257C>G) from controls. This SNP resulted in an amino acid change from alanine to glycine (A62G, GenBank Accession No. NM_003036). Among all samples genotyped by the RFLP method, variants (CG, GG) were found in 10.5% of the cases, compared to a prevalence of 17.7% in the controls. The odds ratio was calculated to be 0.6, with a 95% confidence interval (CI) of 0.3-1.0. CONCLUSION: In a population of California infants with craniofacial defects, a novel polymorphism of the SKI gene was found to be associated with a decreased risk for orofacial defects. The function of this polymorphism and how it might confer protection to the embryo against craniofacial malformations is currently under investigation in our laboratory.

Case-Control Studies↗
PubMed2005

Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial defects and congenital heart defects in China.

PURPOSE: This study was designed to investigate whether the risks of congenital heart defects (CHD) and orofacial defects were influenced by a polymorphism of the offspring's RFC1 or by an interaction between the RFC1 gene and maternal periconceptional use of folic acid. METHODS: A case-control study was conducted. A total of 82 families with a child affected by cleft lip with or without cleft palate (CLP), 67 families with a child-affected by CHD, and 100 nonmalformed control families were genotyped using PCR-RFLP. RFC1 G allele was tested through family-based association test. RESULTS: Among mothers who did not use folic acid, the risks of 4.03 (95% CI = 1.33-12.77) for the G80/G80 genotype and 4.14 (95% CI = 1.06-16.82) for the G80/A80 genotype were observed relative to the A80/A80 genotype for CHD offspring. In family-based association tests (FBAT), offspring carrying the G allele for RFC1 is at increased risk for CHD (Z = 2.140, p < .05). No significant association was found between either RFC1 genotype or maternal folic acid supplementation and the risks of CLP. CONCLUSIONS: Our findings suggest that the RFC1 G allele is likely to be an important candidate gene in folate transport and to be associated with risk for CHD. This study found modest evidence for a gene-nutrient interaction between offspring RFC1 genotype and periconceptional intake of folic acid on the risk of congenital heart defects.

Case-Control Studies↗
PubMed2005

Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts?

Abnormalities in folate and/or homocysteine metabolism may adversely influence embryonic development, leading to the birth of infants with a variety of congenital malformations, including neural tube defects (NTDs) and craniofacial abnormalities. Based upon suggestive evidence that periconceptional folic acid supplementation is effective in preventing a significant proportion of the aforementioned birth defects, genetic variation in the folate biosynthetic pathways may influence the infant's susceptibility to these birth defects. The goal of our study was to investigate sequence variations in the betaine-homocysteine methyltransferase (BHMT) and betaine-homocysteine methyltransferase (BHMT2) genes as modifiers of risk of spina bifida, cleft palate, and cleft lip and palate. The results of this study indicated that individuals homozygous for the single nucleotide polymorphism R239Q in BHMT did not have elevated risks for spina bifida. Genotype frequencies for the BHMT2 rs626105 polymorphism also did not reveal any elevated risks for spina bifida, and only a modest, imprecise elevation of risk for orofacial clefts. The results of these experiments suggest that variants of the BHMT/BHMT2 genes in infants do not substantially contribute to the risk of spina bifida or orofacial clefts in our study population.

Betaine-Homocysteine S-Methyltransferase↗
PubMed2005

Reduced folate carrier gene is a risk factor for neural tube defects in a Chinese population.

BACKGROUND: There is a considerable body of data demonstrating that periconceptional supplementation of folic acid can prevent a significant proportion of neural tube defects (NTDs). At present, the mechanism by which folic acid exerts its beneficial effect remains unknown. Folate transporter genes, including the reduced folate carrier gene (RFC1), have been proposed as NTD risk factors. METHODS: The study population included 104 nuclear families with NTDs and 100 nonmalformed control families. We investigated the possible association between a common RFC1 polymorphism (A80G) and NTD risk among offspring, as well as potential gene-environment interactions between the infant RFC1 genotype and maternal periconceptional use of folic acid through a population-based case-control study. RESULTS: We observed that the infants of the GG genotype were associated with a 2.56-fold increased risk of NTDs when compared to the AA genotype (odds ratio [OR], 2.56; 95% confidence interval [CI], 1.04-6.36) in our study population. Among mothers who did not utilize folic acid supplements, the risk for having a child with an NTD was 3.30 (95% CI, 1.15-9.65) for offspring with the GG genotype, compared to the reference (AA) genotype. Children who had the GG genotype and whose mothers did not take folic acid had an elevated risk for NTDs (OR, 8.80; 95% CI, 2.83-28.69), compared to offspring with the AA and GA genotypes whose mothers utilized folic acid supplements. CONCLUSIONS: Our findings suggest that the RFC1 G allele is likely to be an important genetic factor in determining folate transport and subsequently may be a risk factor for NTDs in this Chinese population.

Case-Control Studies↗
PubMed2005

Genes encoding catalytic subunits of protein kinase A and risk of spina bifida.

BACKGROUND: PRKACA and PRKACB are genes encoding the cAMP-dependent protein kinase A (PKA) catalytic subunits alpha and beta, respectively. PKA is known to be involved in embryonic development, as it down-regulates the Hedgehog (Hh) signaling pathway, which is critical to normal pattern formation and morphogenesis. The PKA-deficient mouse model, which has only a single catalytic subunit, provided intriguing evidence demonstrating a relationship between decreased PKA activity and risk for posterior neural tube defects (NTDs) in the thoracic to sacral regions of gene-knockout mice. Unlike most other mutant mouse models of NTDs, the PKA-deficient mice develop spina bifida with 100% penetrance. We hypothesized that sequence variations in human genes encoding the catalytic subunits may alter the PKA activity and similarly increase the risk of spina bifida. METHODS: We sequenced the coding regions and the exon/intron boundaries of PRKACA and PRKACB. We also examined 3 common single-nucleotide polymorphisms (SNPs) of these 2 genes by allele discrimination. RESULTS: Five sequence variants in coding region and 2 intronic sequence variants proximal to exons were detected. None of the 3 SNPs examined in the association study appeared to be associated with substantially increased risk for spina bifida. CONCLUSIONS: Our results did not reveal a strong association between these PKA SNPs and spina bifida risk. Nonetheless, it is important to examine the possible gene-gene interactions between PRKACA and PRKACB when evaluating the risk for NTDs, as well as genes encoding regulatory subunits of PKA. In addition, interactions with other genes such as Sonic Hedgehog (SHH) should also be considered for future investigations.

Alleles↗
PubMed2004

Limb deficiency defects, MSX1, and exposure to tobacco smoke.

There is increasing evidence from epidemiologic studies that genetic susceptibilities may modify the teratogenic effects of smoking. A previous study suggested that maternal smoking in the presence of a dinucleotide repeat polymorphism for MSX1 produced an almost fivefold increased risk for limb anomalies, providing evidence for a gene-environment interaction. The current study examined this potential interaction, using case-control data with several methodologic improvements, including a larger sample size and more detailed information on cigarette smoke exposures. Cases (n = 92) were ascertained from pregnancies ending in 1987-1989, and controls (n = 180) were randomly selected from eligible liveborn infants. In telephone interviews, women reported smoking behaviors during the month before pregnancy through the end of the first trimester. Odds ratios (OR) for maternal and paternal smoking ranged from 1.0 to 1.4, risk estimates were imprecise; for example, the OR for maternal smoking >or=20 cigarettes per day, versus none, was 1.3 (95% confidence interval (CI) 0.5-3.4). Relative to the homozygous wildtype, the OR was 1.5 (95% CI 0.7-3.5) for the homozygous variant genotype and 0.8 (95% CI 0.5-1.4) for the heterozygous variant genotype. There was no evidence that maternal smoking or both parents smoking, in combination with a susceptible MSX1 genotype, conferred an additional increase in risk of limb defects. This study did not find a gene-environment interaction between maternal smoking, infant MSX1 CA repeat polymorphism, and risk of limb deficiency defects. This finding contrasts with results of a previous study, which provided initial evidence for such an interaction. Several important methodological differences may have contributed to the differences in findings between the two studies.

Adult↗
PubMed2004

Promoter haplotype combinations for the human PDGFRA gene are associated with risk of neural tube defects.

Recent animal studies suggested that deregulated expression of the platelet-derived growth factor receptor alpha (PDGFRalpha) may contribute to the failure of normal neural tube closure (NTC). There is also suggestive evidence that the promoter haplotype of the PDGFRA is associated with genetic susceptibility in human neural tube defects (NTDs). The purpose of our study was to investigate the association between promoter haplotype combinations of the human PDGFRA gene and risk for NTDs in a Hispanic population from the Texas-Mexico border region. This population has a considerably higher prevalence of NTDs (16/10,000 live births) than that generally reported in the United States (8-10/10,000 live births). In the present study, NTDs were defined as spina bifida or anencephaly. The haplotype of PDGFRA gene promoter was determined by direct DNA sequence analysis. Two novel haplotypes, H2epsilon and H1beta, were found. We observed significant differences among variable haplotype groups from in vitro transient transfection studies in U2-OS osteosarcoma cell and two other cell lines (HeLa cell and MCF7 cell). Result from our case-control study demonstrated that the frequencies of haplotypes with low transcription activity were significantly higher in NTD mothers than that observed in control mothers (odds ratio=2.2, 95% CI=1.0-4.6). Infants with at least one low activity allele showed slightly higher risk (odds ratio=1.5, 95%=0.8-3.1). Our study suggests that the reduced transcriptional activity of PDGFRA gene could increase the risk of having an NTD-affected pregnancy.

Adult↗
PubMed2003

Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial and conotruncal heart defects.

How folate reduces the risks of congenital anomalies is unknown. The authors focused on a gene involved in folate transport-reduced folate carrier-1 gene (RFC1). Using data from a California case-control study (1987-1989 births), the authors investigated whether the risks of orofacial clefts or conotruncal heart defects were influenced by a polymorphism of infant RFC1 or by an interaction between the RFC1 gene and maternal periconceptional use of vitamins containing folic acid. A total of 305 liveborn infants with cleft lip with or without cleft palate, 123 with cleft palate, 163 with conotruncal heart defects, and 364 nonmalformed controls were genotyped. Odds ratios of 1.6 (95% confidence interval: 0.9, 2.8) for the G80/G80 genotype and of 2.3 (95% confidence interval: 1.3, 3.9) for the G80/A80 genotype were observed relative to the A80/A80 genotype for conotruncal defects. Among mothers who did not use vitamins, the risk of conotruncal defects was 2.1 (95% confidence interval: 0.7, 5.9) for infants with genotype G80/G80 compared with those with the A80/A80 genotype. Among mothers who did use vitamins, the risk was 1.3 (95% confidence interval: 0.7, 2.7). Substantially elevated risks for either cleft group were not observed irrespective of genotype and use/nonuse of vitamins. Thus, this study found modest evidence for a gene-nutrient interaction between infant RFC1 genotype and periconceptional intake of vitamins on the risk of conotruncal defects.

California↗