Clinical, genetic, and epidemiological factors in neural tube defects.

We examined clinical, genetic, and epidemiologic factors among 512 probands with nonsyndromal neural tube defects (NTDs). Data were analyzed after grouping the probands in four different ways with respect to pathological features and putative pathogenic mechanisms. Apparently unrelated congenital anomalies occurred more frequently among probands with craniorachischisis (62%), encephalocele (30%), or multiple NTDs (25%) than among probands with anencephaly (14.7%) or spina bifida (10.1%) (P much less than .0001). Unrelated congenital anomalies occurred less often among probands with low spina bifida (6.7%) than among probands with high spina bifida (19.5%). NTDs were seen in 7.8% of the siblings of probands with high spina bifida but in only 0.7% of the siblings of probands with low spina bifida, in 2.2% of the siblings of anencephalic probands, and in none of the siblings of probands with craniorachischisis, encephalocele, or multiple NTDS (P less than .001). In all 16 families in which two siblings had NTDs, both had either defects of the type associated with abnormal primary neurulation or defects of the type associated with abnormal canalization. High spina bifida and multiple NTDs were found more frequently than expected among the Sikh probands (P less than .02). The frequency of non-NTD congenital anomalies was higher among siblings of Sikh probands (8.8%) than among siblings of other probands (2.4%) (P less than .05). This excess was due to the occurrence of hydrocephalus without spina bifida in four of 68 siblings of Sikh probands.     

Birth defects in Arkansas: Is folic acid fortification making a difference?

BACKGROUND: Since 1998, fortification of grain products with folic acid has been mandated in the United States, in an effort to reduce the prevalence of neural tube defects (NTDs). Published reports have shown a reduction in the prevalence of spina bifida since fortification was mandated, but no published studies have reported a reduction in birth defects, other than NTDs, that are postulated to be associated with folic acid deficiency. This study was performed to determine if fortification has reduced the prevalence of NTDs and other birth defects in Arkansas. METHODS: Using data from the Arkansas Reproductive Health Monitoring System, prevalences were computed for thirteen specific birth defects with prior evidence supporting a protective effect of folic acid or multivitamins. Prevalences were calculated using data for live births to Arkansas residents for 1993-2000. Exposure to folic acid fortification was classified by birth year as "pre-fortification" (1993-1995), "transition" (1996-1998) or "post-fortification" (1999-2000). Logistic regression analysis was used to compute crude and adjusted prevalence odds ratios comparing the identified time periods. RESULTS: Prevalences decreased between the pre- and post-fortification periods for spina bifida, orofacial clefts, limb reduction defects, omphalocele, and Down syndrome, but only the decrease in spina bifida was statistically significant (prevalence odds ratio 0.56; 95% confidence interval, 0.37, 0.83). CONCLUSION: In Arkansas, the prevalence of spina bifida has decreased since folic acid fortification of foods was implemented. Similar studies by other birth defects surveillance systems are needed to confirm a preventive effect of fortification for malformations other than spina bifida.     

Trends in the postfortification prevalence of spina bifida and anencephaly in the United States

BACKGROUND: The prevalence of NTDs in the US declined significantly after mandatory folic acid fortification; however, it is not known if the prevalence of NTDs has continued to decrease in recent years relative to the period immediately following the fortification mandate. METHODS: Population‐based data from 21 birth defects surveillance systems were used to examine trends in the birth prevalence of spina bifida and anencephaly during 1999–2000, 2001–2002, and 2003–2004. Prevalence data were stratified by non‐Hispanic White, non‐Hispanic Black, and Hispanic race or ethnicity. Prevalence ratios were calculated by dividing the birth prevalences during the later time periods (2001–2002 and 2003–2004) by the birth prevalences during 1999–2000. RESULTS: During 1999–2004, 3,311 cases of spina bifida and 2,116 cases of anencephaly were reported. Hispanic infants had the highest prevalences of NTDs for all years. For all infants, the combined birth prevalences of spina bifida and anencephaly decreased 10% from the 1999–2000 period to the 2003–2004 period. The decline in spina bifida (3%) was not significant; however the decline in anencephaly (20%) was statistically significant. CONCLUSIONS: While the prevalences of spina bifida and anencephaly in the United States have declined since folic acid fortification in the food supply began, these data suggest that reductions in the prevalence of anencephaly continued during 2001–2004 and that racial and ethnic and other disparities remain. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Anencephaly and spina bifida among Hispanics: Maternal,sociodemographic, and acculturation factors in the National Birth Defects Prevention Study

BACKGROUND : We used data from the multisite National Birth Defects Prevention Study for expected delivery dates from October 1997 through 2003, to determine whether the increased risk in anencephaly and spina bifida (neural tube defects (NTDs)) in Hispanics was explained by selected sociodemographic, acculturation, and other maternal characteristics. METHODS : For each type of defect, we examined the association with selected maternal characteristics stratified by race/ethnicity and the association with Hispanic parents' acculturation level, relative to non‐Hispanic whites. We used logistic regression and calculated crude odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS : Hispanic mothers who reported the highest level of income were 80% less likely to deliver babies with spina bifida. In addition, highly educated Hispanic and white mothers had 76 and 35% lower risk, respectively. Other factors showing differing effects for spina bifida in Hispanics included maternal age, parity, and gestational diabetes. For spina bifida there was no significant elevated risk for U.S.–born Hispanics, relative to whites, but for anencephaly, corresponding ORs ranged from 1.9 to 2.3. The highest risk for spina bifida was observed for recent Hispanic immigrant parents from Mexico or Central America residing in the United States <5 years (OR = 3.28, 95% CI = 1.46–7.37). CONCLUSIONS : Less acculturated Hispanic parents seemed to be at highest risk of NTDs. For anencephaly, U.S.–born and English‐speaking Hispanic parents were also at increased risk. Finally, from an etiologic standpoint, spina bifida and anencephaly appeared to be etiologically heterogeneous from these analyses. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

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.     

Disruption of PDGFRalpha-initiated PI3K activation and migration of somite derivatives leads to spina bifida

Spina bifida, or failure of the vertebrae to close at the midline, is a common congenital malformation in humans that is often synonymous with neural tube defects (NTDs). However, it is likely that other etiologies exist. Genetic disruption of platelet-derived growth factor receptor (PDGFR) alpha results in spina bifida, but the underlying mechanism has not been identified. To elucidate the cause of this birth defect in PDGFRalpha mutant embryos, we examined the developmental processes involved in vertebrae formation. Exposure of chick embryos to the PDGFR inhibitor imatinib mesylate resulted in spina bifida in the absence of NTDs. We next examined embryos with a tissue-specific deletion of the receptor. We found that loss of the receptor from chondrocytes did not recapitulate the spina bifida phenotype. By contrast, loss of the receptor from all sclerotome and dermatome derivatives or disruption of PDGFRalpha-driven phosphatidyl-inositol 3' kinase (PI3K) activity resulted in spina bifida. Furthermore, we identified a migration defect in the sclerotome as the cause of the abnormal vertebral development. We found that primary cells from these mice exhibited defects in PAK1 activation and paxillin localization. Taken together, these results indicate that PDGFRalpha downstream effectors, especially PI3K, are essential for cell migration of a somite-derived dorsal mesenchyme and disruption of receptor signaling in these cells leads to spina bifida.     

Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects

BACKGROUND: The number of mouse mutants and strains with neural tube closure defects (NTDs) now exceeds 190, including 155 involving known genes, 33 with unidentified genes, and eight "multifactorial" strains. METHODS: The emerging patterns of mouse NTDs are considered in relation to the unknown genetics of the common human NTDs, anencephaly, and spina bifida aperta. RESULTS: Of the 150 mouse mutants that survive past midgestation, 20% have risk of either exencephaly and spina bifida aperta or both, parallel to the majority of human NTDs, whereas 70% have only exencephaly, 5% have only spina bifida, and 5% have craniorachischisis. The primary defect in most mouse NTDs is failure of neural fold elevation. Most null mutations (>90%) produce syndromes of multiple affected structures with high penetrance in homozygotes, whereas the "multifactorial" strains and several null-mutant heterozygotes and mutants with partial gene function (hypomorphs) have low-penetrance nonsyndromic NTDs, like the majority of human NTDs. The normal functions of the mutated genes are diverse, with clusters in pathways of actin function, apoptosis, and chromatin methylation and structure. The female excess observed in human anencephaly is found in all mouse exencephaly mutants for which gender has been studied. Maternal agents, including folate, methionine, inositol, or alternative commercial diets, have specific preventative effects in eight mutants and strains. CONCLUSIONS: If the human homologs of the mouse NTD mutants contribute to risk of common human NTDs, it seems likely to be in multifactorial combinations of hypomorphs and low-penetrance heterozygotes, as exemplified by mouse digenic mutants and the oligogenic SELH/Bc strain.     

Mini-review: toward understanding mechanisms of genetic neural tube defects in mice.

We review the data from studies of mouse mutants that lend insight to the mechanisms that lead to neural tube defects (NTDs). Most of the 50 single-gene mutations that cause neural tube defects (NTDs) in mice also cause severe embryonic-lethal syndromes, in which exencephaly is a nonspecific feature. In a few mutants (e.g., Trp53, Macs, Mlp or Sp), other defects may be present, but affected fetuses can survive to birth. Multifactorial genetic causes, as are present in the curly tail stock (15-20% spina bifida), or the SELH/Bc strain (15-20% exencephaly), lead to nonsyndromic NTDs. The mutations indicate that "spina bifida occulta," a dorsal gap in the vertebral arches over an intact neural tube, is usually genetically and developmentally unrelated to exencephaly or "spina bifida" (aperta). Almost all exencephaly or spina bifida aperta of genetic origin is caused by failure of neural fold elevation. The developmental mechanisms in genetic NTDs are considered in terms of distinct rostro-caudal zones along the neural folds that likely differ in mechanism of elevation. Failure of elevation leads to: split face (zone A), exencephaly (zone B), rachischisis (all of zone D), or spina bifida (caudal zone D). The developmental mechanisms leading to these genetic NTDs are heterogeneous, even within one zone. At the tissue level, the mutants show that the mechanism of failure of elevation can involve, e.g., (1) slow growth of adjacent tethered tissue (curly tail), (2) defective forebrain mesenchyme (Cart1 or twist), (3) defective basal lamina in surface ectoderm (Lama5), (4) excessive breadth of floorplate and notochord (Lp), (5) abnormal neuroepithelium (Apob, Sp, Tcfap2a), (6) morphological deformation of neural folds (jmj), (7) abnormal neuroepithelial and neural crest cell gap-junction communication (Gja1), or (8) incomplete compensation for a defective step in the elevation sequence (SELH/Bc). At the biochemical level, mutants suggest involvement of: (1) faulty regulation of apoptosis (Trp53 or p300), (2) premature differentiation (Hes1), (3) disruption of actin function (Macs or Mlp), (4) abnormal telomerase complex (Terc), or (5) faulty pyrimidine synthesis (Sp). The NTD preventative effect of maternal dietary supplementation is also heterogeneous, as demonstrated by: (1) methionine (Axd), (2) folic acid or thymidine (Sp), or (3) inositol (curly tail). The heterogeneity of mechanism of mouse NTDs suggests that human NTDs, including the common nonsyndromic anencephaly or spina bifida, may also reflect a variety of genetically caused defects in developmental mechanisms normally responsible for elevation of the neural folds.     

Comparative proteomics of spinal cords of rat fetuses with spina bifida aperta

Neural tube defects (NTDs) are complex congenital anomalies of the central nervous system, with a prevalence of 5 per 10,000 worldwide. However, current therapeutics for NTDs are unsatisfactory. The neurological complications remain the main problem for therapy. Neurological dysfunction could result from the primary defect or injuries to the uncovered neural tissue in the uterus. However, the pathological changes in the uncovered neural tissue have not been described. Here, we present our comparative proteomics study of the spinal cord from rat fetuses with all-trans retinoic-acid-induced spina bifida aperta. Proteins from spinal cords were subjected to 2-D gel electrophoresis, then protein identification by mass spectrometry. We identified 13 proteins with differential expression between normal spinal cords and those with spina bifida aperta. These identified proteins were reported to be involved in signal transduction, cell adhesion and migration, protein folding and apoptosis. We confirmed 4 identified proteins by immunoblot analysis and assessed their mRNA levels by quantitative real-time PCR. This is the first comparative proteomics of spinal cords from rat fetuses with spina bifida aperta. We demonstrate protein alterations that reflect the pathological situation of the uncovered neural tissue, which may help improve the treatment of NTDs.     

Mutations in Planar Cell Polarity Gene SCRIB Are Associated with Spina Bifida

Neural tube defects (NTDs) (OMIM #182940) including anencephaly, spina bifida and craniorachischisis, are severe congenital malformations that affect 0.5–1 in 1,000 live births in the United States, with varying prevalence around the world. Mutations in planar cell polarity (PCP) genes are believed to cause a variety of NTDs in both mice and humans. SCRIB is a PCP-associated gene. Mice that are homozygous for the Scrib p.I285K and circletail (Crc) mutations, present with the most severe form of NTDs, namely craniorachischisis. A recent study reported that mutations in SCRIB were associated with craniorachischisis in humans, but whether SCRIB mutations contribute to increased spina bifida risk is still unknown. We sequenced the SCRIB gene in 192 infants with spina bifida and 190 healthy controls. Among the spina bifida patients, we identified five novel missense mutations that were predicted-to-be-deleterious by the PolyPhen software. Of these five mutations, three of them (p.P1043L, p.P1332L, p.L1520R) significantly affected the subcellular localization of SCRIB. In addition, we demonstrated that the craniorachischisis mouse line-90 mutation I285K, also affected SCRIB subcellular localization. In contrast, only one novel missense mutation (p.A1257T) was detected in control samples, and it was predicted to be benign. This study demonstrated that rare deleterious mutations of SCRIB may contribute to the multifactorial risk for human spina bifida.     

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.     

Neural tube defects among twin births.

To obtain accurate, unbiased rates of neural tube defects (NTDs) in twins, we conducted a population-based study that included live births and fetal deaths in Los Angeles County, California, ascertaining cases by multiple methods. Twenty-eight twin cases yielded a prevalence-at-birth of 1.6/1,000 twin births, which is significantly higher than the singleton prevalence of 1.1/1,000 births. In twins compared with singletons, the prevalences of both encephalocele and anencephaly are increased, whereas spina bifida is decreased. The twin case male/female sex ratio (.55) is lower than the singleton case sex ratio (.77). Concordance is relatively low at 3.7%, but appears to be higher than recently reported recurrence risks in other low prevalence areas. Stillbirths were most common among female cases and like-sex twins. Our study tends to support proposed etiologic theories associating NTDs with females or monozygotic twins, or both. There is increasing evidence that the etiology of NTDs may differ in high and low prevalence areas. We suggest also that twins and singletons may differ in their response to etiologic factors. The variations among anencephaly, spina bifida, and encephalocele in their association with twinning suggest that there may be different factors that influence the development of each specific NTD. The noted differences among the malformations also indicate that some of the variation among results of other studies of NTDs and twinning may be due to case ascertainment. Including spina bifida cases would decrease the proportion of twins in a study population, while including anencephalics would increase the proportion. Importantly, ascertaining fetal deaths would increase the proportion of anencephalics and case females, so studies of NTDs that do not include fetal deaths will show fewer twins than expected. On the basis of our findings and those of Layde et al., excluding encephaloceles will also decrease the number of twins among NTD cases. When investigating etiologic hypotheses for NTDs, these potential biases must be recognized.     

Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China

BACKGROUND: In the past, northern China's Shanxi Province has reported the highest incidence of neural tube defects (NTDs) in the world. However, little is known about the epidemiology of NTDs in this area in recent years. METHODS: Data were collected from a population-based birth defects surveillance system in 4 counties that captures information on all live births, stillbirths of at least 20 weeks' gestation, and pregnancy terminations at any gestational age resulting from prenatal diagnosis of a birth defect. We also surveyed mothers of NTD case patients to determine their use of folic acid before and during early pregnancy. RESULTS: During 2003, 160 NTD cases were identified among 11,534 births (NTD birth prevalence = 138.7/10,000 births). The rates of anencephaly, spina bifida and encephalocele were 65.9, 58.1, and 14.7 per 10,000, respectively, and a female predominance was observed among anencephaly cases (male-to-female relative risk [RR], 0.49; 95% confidence interval [CI], 0.30-0.79), but not among spina bifida (RR, 0.90; 95% CI, 0.55-1.45) and encephalocele (RR, 1.03; 95% CI, 0.40-2.69) cases. The percentages of pregnancy termination following prenatal diagnosis of anencephaly, spina bifida, and encephalocele were 50%, 41.8%, and 35.3%, respectively. NTD birth prevalence tended to be higher among mothers aged <20 or > or =30 years (P = .06) and was markedly associated with lower levels of maternal education (P < .001). Among 143 NTD mothers, only 6 (4.2%) used folic acid supplements during the periconceptional period. CONCLUSIONS: The NTD birth prevalence rate in the study area is among the highest worldwide. Folic acid deficiency may be one important risk factor.     

Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3

The neural tube defects (NTDs) spina bifida and anencephaly are widely prevalent severe birth defects. The mouse mutant curly tail (ct/ct) has served as a model of NTDs for 50 years, even though the responsible genetic defect remained unrecognized. Here we show by gene targeting, mapping and genetic complementation studies that a mouse homolog of the Drosophila grainyhead (grh) gene, grainyhead-like-3 (Grhl3), is a compelling candidate for the gene underlying the curly tail phenotype. The NTDs in Grhl3-null mice are more severe than those in the curly tail strain, as the Grhl3 alleles in ct/ct mice are hypomorphic. Spina bifida in ct/ct mice is folate resistant, but its incidence can be markedly reduced by maternal inositol supplementation periconceptually. The NTDs in Grhl3-/- embryos are also folate resistant, but unlike those in ct/ct mice, they are resistant to inositol. These findings suggest that residual Grhl3 expression in ct/ct mice may be required for inositol rescue of folate-resistant NTDs.     

eNOS基因多态性与神经管畸形的研究进展

神经管畸形(neural tube defects,NTDs)是一类常见的出生缺陷,严重威胁着妇女儿童的身心健康和人口素质的提高,给社会的发展带来沉重负担,可引起孕妇流产、婴儿死亡和终生残疾。NTDs可分为无脑儿、脑膨出和脊柱裂三种类型,其病因和具体的发病机制尚不清楚。国内外多数研究认为,NTDs是一种由基因的多态性和环境因素所引起的严重的基因突变,还不能用一种单一原因来解释该病的发生。目前的研究热点是易感基因与NTDs的关系,内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)基因最近已被认为是导致NTDs发生的重要候选基因。eNOS基因的点突变或成串突变可以导致酶活性的变化,使eNOS的表达上调,引起NO分泌的异常,促进神经元的凋亡,进而导致大脑的发育异常。本文从eNOS基因多态性与NTDs的相关性研究进行综述。     

Maternal flu or fever, medication use, and neural tube defects: a population-based case-control study in Northern China

BACKGROUND: Maternal exposure to flu or fever has been associated with increased risk for neural tube defects (NTDs); however, few studies have considered the effects of medications on the effects of flu or fever. We evaluated the effect of maternal flu or fever, medication use (antibiotics, antipyretics), and their joint effect on NTDs. METHODS: Data came from an ongoing population-based case-control study of infants with external malformations in northern China. The case group included 363 infants with NTDs identified between January 2003 and June 2005. Controls were 523 newborn infants without identified congenital anomalies matched by county, sex, maternal ethnic group, and the closest date of conception for infants with any major external malformation. Data were collected by a trained health worker through face-to-face interviews after delivery. RESULTS: NTD risks were significantly associated with maternal flu or fever (adjusted odds ratio [AOR] = 3.93, 95% CI: 2.48-6.23) and antipyretic use (AOR = 4.86, 95% CI: 1.33-17.78), but not with antibiotic use (AOR = 1.75, 95% CI: 0.91-3.38) after adjusting for potential confounders. NTD risk associated with maternal antipyretic use was markedly higher for anencephaly (AOR = 7.03, 95% CI: 1.70-29.04) than for spina bifida (AOR = 3.98, 95% CI: 0.95-16.74). Mothers with flu or fever who were also using antipyretics showed a markedly higher AOR for anencephaly (14.75 vs. 4.52), spina bifida (16.30 vs. 3.85), and all NTDs combined (13.91 vs. 4.04) than mothers with flu or fever who were not using antipyretics. Maternal antibiotics did not markedly change the effects of flu or fever on anencephaly (4.17 vs. 4.83), spina bifida (5.08 vs. 4.21), and all NTDs combined (5.05 vs. 4.29). CONCLUSIONS: Maternal flu or fever and antipyretic use during the periconceptional period increases the risk for NTDs. Maternal exposure to antipyretics together with flu or fever results in a markedly higher risk of NTDs than exposure to flu or fever alone.     

Spina bifida phenotypes in infants or fetuses of obese mothers

BACKGROUND: A twofold or greater risk of neural tube defect (NTD)-affected pregnancy has been associated with prepregnant obesity, where obesity was defined as body mass index (BMI) of >29 kg/m(2). Risks have been more elevated for spina bifida than for anencephaly. METHODS: We investigated whether finer phenotypic classifications of spina bifida, in combination with other factors, were associated with a BMI of >29 kg/m(2). Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. Interviews were conducted with mothers of 277 spina bifida cases and 517 nonmalformed controls. RESULTS: Women with a BMI of >29 kg/m(2) compared with those 29 kg/m(2) compared with males whose mothers were 相似文献   

Association between maternal COMT gene polymorphisms and fetal neural tube defects risk in a Chinese population

Maternal tea consumption was reported to increase the risk of fetal neural tube defects (NTDs). Catechol‐O‐methyltransferase (COMT) may be involved in the metabolism of polyphenolic methylation of tea, thus influence the risk of fetal NTDs. Methods: A total of 576 fetuses or newborns with NTDs and 594 healthy newborns were included in the case–control study. Information on maternal tea consumption, sociodemographic characteristics, reproductive history, and related behavior was collected through face‐to‐face interviews. Maternal blood samples were collected to examine polymorphisms in COMT, and the possible interaction of COMT and tea consumption was analyzed. RESULTS: After controlling for potential confounders, homozygotes of rs737865 showed an elevated risk for total NTDs (odds ratio [OR] = 2.04, 95% confidence interval [CI], 1.24–3.35) and for the anencephaly subtype (OR = 1.99, 95% CI, 1.17–3.39). The CC genotype of rs4633 was positively associated with the overall risk of NTDs (OR = 3.66, 95% CI, 1.05–12.83). Heterozygotes for rs4680 were associated with a decreased risk of spina bifida (OR = 0.71, 95% CI, 0.51–0.98). The COMT rs4680 A allele was negatively related with the risk of spina bifida, with adjusted OR = 0.64 (95% CI, 0.45–0.89). An interaction between tea consumption (1 to 2 cups/day) and the rs4680AA/AG genotype was found in the spina bifida subtype (P_interaction = .08). Conclusion: Several COMT variants were associated with elevated risk of NTDs in a Chinese population. Maternal tea consumption may be associated with an increased risk for fetal NTDs in genetically susceptible subgroups. Birth Defects Research (Part A) 100:22–29, 2014. © 2013 Wiley Periodicals, Inc.     

Altered Expression of 14-3-3ζ Protein in Spinal Cords of Rat Fetuses with Spina Bifida Aperta

Background

A large number of studies have confirmed that excessive apoptosis is one of the reasons for deficient neuronal function in neural tube defects (NTDs). A previous study from our laboratory used 2-D gel electrophoresis to demonstrate that 14-3-3ζ expression was low in the spinal cords of rat fetuses with spina bifida aperta at embryonic day (E) 17. As a member of the 14-3-3 protein family, 14-3-3ζ plays a crucial role in the determination of cell fate and anti-apoptotic activity. However, neither the expression of 14-3-3ζ in defective spinal cords, nor the correlation between 14-3-3ζ and excessive apoptosis in NTDs has been fully confirmed.

Methodology/Principal Findings

We used immunoblotting and quantitative real-time PCR (qRT-PCR) to quantify the expression of 14-3-3ζ and double immunofluorescence to visualize 14-3-3ζ and apoptosis. We found that, compared with controls, 14-3-3ζ was down-regulated in spina bifida between E12 and E15. Excessive apoptotic cells and low expression of 14-3-3ζ were observed in the dorsal region of spinal cords with spina bifida during the same time period. To initially explore the molecular mechanisms of apoptosis in NTDs, we investigated the expression of microRNA-7 (miR-7), microRNA-375 (miR-375) and microRNA-451 (miR-451), which are known to down-regulate 14-3-3ζ in several different cell types. We also investigated the expression of p53, a molecule that is downstream of 14-3-3ζ and can be down-regulated by it. We discovered that, in contrast to the reduction of 14-3-3ζ expression, the expression of miR-451, miR-375 and p53 increased in spina bifida rat fetuses.

Conclusions/Significance

These data suggest that the reduced expression of 14-3-3ζ plays a role in the excessive apoptosis that occurs in spina bifida and may be partly regulated by the over-expression of miR-451 and miR-375, and the consequent up-regulation of p53 might further promote apoptosis in spina bifida.