PubMed Health⌕ Search

Biomedical subjects

Gary M Shaw

Publications and source records attributed to Gary M Shaw.

At least 19 recordsLinked to original sources
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

Risks of human limb deficiency anomalies associated with 29 SNPs of genes involved in homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation.

This study explored risks of limb deficiency anomalies associated with 29 single nucleotide polymorphisms (SNPs) of genes involved in homocysteine metabolism, coagulation, cell-cell interaction, inflammatory response, and blood pressure regulation. The authors genotyped 96 cases and 437 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Increased risk of limb anomaly was observed for three SNPs: heterozygosity for F5 Arg506Gln, with an odds ratio (OR) of 2.5 (95% confidence interval (CI), 1.0, 6.5); heterozygosity for TNF (-376)G > A, OR 2.1 (0.7, 6.2); and homozygosity for NPPA 2238T > C, OR 4.0 (1.1, 15.4). We hypothesized that effects of variant genotypes in the presence of maternal smoking, and/or in the absence of supplement intake, may exceed effects of any of these factors alone. In particular, findings for polymorphisms in SERPINE1, ITGA2, SELE, TNF, LTA, NPPA, GNB3, and ADRB2 supported the hypotheses, both for smoking and for supplement intake. These results suggest involvement of genetic variation of biologically relevant candidate genes, and gene-environment interaction, for some limb anomalies whose pathogenesis may be related to altered vascular tone or integrity.

Blood Coagulation↗
PubMed2006

Candidate gene polymorphisms do not differ between newborns with stroke and normal controls.

BACKGROUND AND PURPOSE: Neonatal stroke is increasingly recognized with an estimated incidence of one in 4000 live births per year. Pathways involved in the pathophysiology of neonatal stroke are diverse and may include thrombosis and thrombolysis, vascular reactivity, and inflammation. METHODS: We compared frequencies of polymorphisms in genes regulating thrombosis and thrombolysis, nitric oxide, cytokines, vascular tone, and cell adhesion in a hospital-based cohort of 59 newborns with stroke relative to a random sample of 437 California newborns. RESULTS: Of the 31 polymorphisms evaluated, no variant allele was significantly more common than the reference allele in newborns with stroke than in the general population. CONCLUSIONS: Using a series of polymorphisms in pathways implicated in the etiology of stroke, newborns with stroke were not distinguished from a normal control group. Further studies are needed to determine the interaction of genetic polymorphisms with environmental risk factors in the pathogenesis of neonatal stroke.

Adolescent↗
PubMed2006

Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake.

Increasing epidemiologic evidence suggests that genetic susceptibilities contribute to birth defects risks, especially in combination with other environmental exposures. This analysis examines the association of risk of limb deficiency defects with infant genotypes for N-acetyltranferases (NAT1, NAT2), glutathione-S-tranferases (GSTT1, GSTM1), and endothelial nitric oxide synthase (NOS3). The combined effects of infant genotype with maternal smoking and supplement intake were also examined. The authors genotyped 92 cases and 201 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Several of the infant genotypes were associated with an at least 1.5-fold increased risk for limb deficiency defects: homozygosity for the NAT1 1088 and 1095 polymorphisms, heterozygosity and homozygosity for the NOS3 A(-922)G polymorphism, and heterozygosity (but not homozygosity) for the NOS3 G894T polymorphism. The authors hypothesized that the effects of selected variant genotypes in the presence of maternal smoking, or in the absence of supplement intake, may exceed effects of any of these factors alone. A few observations suggested that risks were greatest among infants with variant genotypes, whose mothers also smoked or did not take supplements, but most did not, and risk estimates were imprecise. Further studies exploring genetic susceptibility and combined gene-environment effects with respect to limb development will be important to continued improvement of our understanding of the etiology of limb anomalies.

Arylamine N-Acetyltransferase↗
PubMed2006

Array comparative genomic hybridization in patients with congenital diaphragmatic hernia: mapping of four CDH-critical regions and sequencing of candidate genes at 15q26.1-15q26.2.

Congenital diaphragmatic hernia (CDH) is a common birth defect with a high mortality and morbidity. There have been few studies that have assessed copy number changes in CDH. We present array comparative genomic hybridization data for 29 CDH patients to identify and map chromosome aberrations in this disease. Three patients with 15q26.1-15q26.2 deletions had heterogeneous breakpoints that overlapped with the critical 4 Mb region previously delineated for CDH, confirming 15q26.1-15q26.2 as a critical region for CDH. The three other most compelling CDH-critical regions for genomic deletions based on these data and a literature review are located at chromosomes 8p23.1, 4p16.3-4pter, and 1q41-1q42.1. Based on these recurrent deletions at 15q26.1-15q26.2, we hypothesized that loss-of-function mutations in a gene or genes from this region could cause CDH and sequenced six candidate genes from this region in more than 100 patients with CDH. For three of these genes (CHD2, ARRDC4, and RGMA), we identified missense changes and that were not identified in normal controls; however, none of these alterations appeared unambiguously causal with CDH. These data suggest that CDH caused by chromosome deletions at 15q26.2 may arise because of a contiguous gene deletion syndrome or may have a multifactorial etiology. In addition, there is evidence for substantial genetic heterogeneity in CDH and diaphragmatic hernias can be non-penetrant in patients who have deletions involving CDH-critical regions.

Case-Control Studies↗
PubMed2006

Neural tube defects and maternal residential proximity to agricultural pesticide applications.

Residential proximity to applications of agricultural pesticides may be an important source of exposure to agents that have been classified as developmental toxins. Data on two case-control study populations of infants with neural tube defects (NTDs) and nonmalformed controls delivered in California between 1987 and 1991 were pooled to investigate whether maternal residential proximity to applications of specific pesticides or physicochemical groups of pesticides during early gestation increases the risk of these malformations. Maternal residential proximity within 1,000 m of pesticide applications was ascertained by linking mothers' addresses with agricultural pesticide use reports and crop maps. Odds ratios were computed by using conventional single- and multiple-pesticide and hierarchical multiple-pesticide logistic regression. In single-pesticide models, several pesticides were associated with NTDs after adjustment for study population, maternal ethnicity, educational level, cigarette smoking, and vitamin use. In a hierarchical multiple-pesticide model, effect estimates for only benomyl and methomyl suggested a possible association. Elevated risks of NTDs and anencephaly or spina bifida subtypes were also associated with exposures to chemicals classified as amide, benzimidazole, methyl carbamate, or organophosphorus pesticides and with increasing numbers of pesticides. These results suggest that ambient exposure to certain categories of agricultural pesticides may increase the risk of NTDs.

Adult↗
PubMed2006

Epidemiologic characteristics of congenital diaphragmatic hernia among 2.5 million California births, 1989-1997.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a severe birth defect of unknown etiology. The aims of the current report were to extend the literature on the descriptive epidemiology of CDH and to determine whether its mortality rate decreased in California during the study period. METHODS: Using data from a large population-based registry, we ascertained 631 CDH cases from 1989 to 1997. We also classified cases as isolated or nonisolated based on the presence and type of major accompanying malformations. Approximately 2.5 million live and stillbirths occurred during the ascertainment period. Multivariate Poisson regression analysis was applied to examine the time trend and risk factors. RESULTS: The overall prevalence of CDH was 2.49 per 10,000 live and stillbirths and did not vary over the study period. Isolated cases, which accounted for 58% of cases, revealed a prevalence of 1.45 per 10,000. Heart malformations were the most frequent major anomalies accompanying CDH. We observed a lower risk of isolated CDH among blacks. Advanced maternal age groups had a higher risk for nonisolated CDH. Multiparous women tended to have a lower risk for nonisolated CDH. Male infants and multiple births had an increased risk for isolated and nonisolated CDH. Infant mortality was slightly decreased over the study period. CDH cases with additional anomalies had higher mortality rates than isolated cases. CONCLUSION: Our observations add to the relatively few population-based descriptive epidemiologic studies of the prevalence and mortality, and maternal and infant characteristics of CDH.

Abnormalities, Multiple↗
PubMed2006

Selected gene polymorphisms and their interaction with maternal smoking, as risk factors for gastroschisis.

BACKGROUND: Gastroschisis is a severe birth defect in which the infant is born with a portion of the intestines extruding through a small tear in the abdominal wall, usually to the right of the umbilical cord. Its etiology is unknown, but the prevailing hypothesis is that it results from a vascular accident at the time of involution of the right umbilical vein or of the development of the superior mesenteric artery. METHODS: In a case-control study of 57 cases of gastroschisis and 506 controls, we tested DNA for polymorphisms of 32 genes representing enzymes involved in angiogenesis, blood vessel integrity, inflammation, wound repair, and dermal or epidermal strength. RESULTS: In logistic regression, controlling for maternal ethnicity, and using the homozygote wild-type as referent, the following gene polymorphisms were associated with an increased risk for a gastroschisis for heterozygotes: ICAM1 gly241arg (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1 -3.4); NOS3 glu298asp (OR, 1.9; 95% CI, 1.1-3.4); NPPA 2238T > C (OR, 1.9; 95% CI, 1.0-3.4); and ADD1 gly460trp (OR, 1.5; 95% CI, 0.8-2.8). Additionally, for the NPPA and ADD1 single-nucleotide polymorphisms (SNPs), the homozygote variants had a significantly higher risk than the heterozygotes (OR, 7.5; 95% CI, 1.7-33.5 and OR, 4.9; 95% CI, 1.9-12.9, respectively). Three SNPs showed a strong interaction with maternal smoking. The risk for smokers with 1 or 2 variant alleles compared to nonsmokers with the wild-type allele were: NOS3 (OR, 5.2; 95% CI, 2.4-11.4); ICAM1 (OR, 5.2; 95% CI, 2.1-12.7); and NPPA (OR, 6.4; 95% CI, 2.8-14.6). CONCLUSIONS: These results support the hypothesis of a vascular compromise as part of a multifactorial etiology of gastroschisis involving both genes and environmental factors.

Female↗
PubMed2006

Neural tube defects and folate: case far from closed.

Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents approximately 50-75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.

Animals↗
PubMed2006

Validation of self-reported proximity to agricultural crops in a case-control study of neural tube defects.

Self-reported perinatal exposures to chemicals or pollutant sources in case-control studies of birth defects may be inaccurate due to misreporting among mothers. In a case-control study of neural tube defects delivered in California in 1987-1988, mothers of case and control infants were asked whether they lived within 0.25 mile (400 m) of agricultural crops. Responses were compared against a gold standard derived from historical agricultural land-use survey maps. The odds ratio for self-reported proximity to any crops (1.62, 95% confidence interval: 1.08, 2.43) appeared to be positively biased compared with the estimate for map-based proximity (1.17, 95% confidence interval: 0.79, 1.71). This pattern was also observed for proximity to specific crops such as nonpermanent and orchard crops. For vineyards, however, we observed an increased risk associated with map-based proximity (odds ratio=2.45, 95% confidence interval: 1.08, 5.58) but not with self-reported proximity (1.09, 95% confidence interval: 0.51, 2.34). The sensitivity of self-reported proximity to any crops was greater for case (65.7%) than control mothers (50.0%) while specificity was about the same for case and control mothers (87.5 vs. 89.3%), suggesting that control mothers under-reported proximity to crops. Differential reporting was also observed between geographic regions, urban and rural residents, and across levels of maternal employment and education. These results suggest differential reporting between case and control mothers as well as an influence from maternal demographic characteristics on reporting accuracy.

Adolescent↗
PubMed2006

Recovery of genomic DNA from residual frozen archival blood clots suitable for amplification and use in genotyping assays.

A greatly neglected source of DNA potentially useful for genetic or forensic studies is the clot remaining from blood samples collected for serum chemistry measurements. We have investigated the utility of residual clots remaining from venipunctures collected for California's Expanded Maternal Serum Alpha-Fetoprotein Screening Program. We report a protocol based on the salting out method for the extraction of DNA from samples which have been archived and frozen for up to 2.5 years. As much as 57 microg of high-quality DNA can be obtained from a 2-ml clot as determined by PicoGreen (Molecular Probes, Inc., Eugene, OR) fluorescence measurements. Quality of the purified DNA was evaluated by its ability to serve as template in polymerase chain reaction (PCR) amplifications, using primers that flank the polymorphic regions of six genes of pharmacogenetic interest distributed throughout the human genome. Sizes of the gene regions successfully amplified range from 215 bp to 2064 bp, using as little as 10 ng of template DNA. Because many genotyping protocols routinely recommend the design of amplicons in the 100-200 bp range, and 10-50 ng of template, we conclude that the clot remaining after serum has been removed from blood collected for serum chemistry measurements can serve as a reliable source of DNA for genotyping studies.

Biological Specimen Banks↗
PubMed2006

Maternal nutrient intakes and risk of orofacial clefts.

BACKGROUND: Information about nutritional factors as potential risks of orofacial clefts is limited. METHODS: In this population-based case-control study, we investigated whether periconceptional intakes of supplemental folic acid, dietary folate, and several other nutrients were associated with orofacial clefts. We included data on deliveries from 1997 through 2000 in the National Birth Defects Prevention Study. Orofacial cleft cases were infants or fetuses born with cleft palate (CP) or with cleft lip with or without cleft palate (CLP). Infants without malformations were eligible as controls. Interview participation was 71% among case mothers and 68% among control mothers. Interviews were completed for 704 CLP cases, 404 CP cases, and 2594 controls. RESULTS: The odds ratio (OR) for CLP associated with use of vitamin supplements containing folic acid was 0.88 (95% confidence interval = 0.73-1.07) and for CP was 1.09 (0.84-1.40). Adjusting for maternal race/ethnicity, age, and education produced an OR of 1.01 (0.82-1.24) for CLP and 1.02 (0.77-1.34) for CP. We found some evidence for decreased CLP risks (>or=30% reduction in risk) with increasing intakes of total protein, choline, and methionine. Decreased CP risk was associated with increased intake of cysteine. Intakes of only 2 micronutrients, iron and riboflavin, were found to reduce CLP risk when adjusted for other nutrients. CONCLUSION: Our observations contribute to the limited body of evidence suggesting a woman's periconceptional diet may influence clefting risks in her offspring. Our finding of no reduction in clefting risk with periconceptional use of supplements containing folic acid is inconsistent with many previous observations but not all.

Adult↗
PubMed2006

Understanding the increased risk of neural tube defect-affected pregnancies among Mexico-born women in California: immigration and anthropometric factors.

Mexico-born women in the United States have an unexplained twofold increased risk of neural tube defect (NTD)-affected pregnancies. We examined whether immigration characteristics were associated with the NTD risk and whether anthropometric factors contributed to the increased risk among Mexico-born women. Data were derived from a large population-based case-control study in California. In-person interviews were conducted with mothers of 538 (88% of eligible) NTD-affected fetuses/infants and mothers of 539 (88%) randomly selected non-malformed control infants. The crude odds ratio (OR) for NTDs among all Mexico-born women, women residing <2 years in the US, and women >16 years old at immigration compared with non-Hispanic white women was 2.4 [95% confidence interval (CI) = 1.8, 3.3], 7.2 [95% CI = 3.7, 14.0] and 3.0 [95% CI = 2.0, 4.4], respectively. Risk for second- or third-generation Mexican-Americans was similar to that of white women. The crude OR for all Mexico-born women was reduced from 2.4 to 2.0 [95% CI = 1.3, 3.0] and for those residing <2 years in the US from 8.4 to 7.1 [95% CI = 3.2, 15.3] after adjustment for maternal body mass index (BMI), height, compromised diet, diabetes, and other known risk factors. In term pregnancies, additional adjustment for pregnancy weight gain reduced the OR in all Mexico-born women and recent immigrants by 16% and 25%, respectively. Low pregnancy weight gain (<10 vs. 10-14 kg) was particularly associated with increased NTD risk among Mexico-born women (OR(ADJ) = 5.8; 95% CI = 2.1, 15.8). Findings indicate that recent Mexican immigrants have a sevenfold increased risk for NTDs. Maternal BMI and height contributed very little, and inadequate weight gain contributed modestly to the NTD risk disparity for Mexican immigrants.

Adolescent↗
PubMed2005

Endothelial nitric oxide synthase (NOS3) genetic variants, maternal smoking, vitamin use, and risk of human orofacial clefts.

Orofacial clefts have been associated with maternal cigarette smoking and lack of folic acid supplementation (which results in higher plasma homocysteine concentrations). Because endothelial nitric oxide synthase (NOS3) activity influences homocysteine concentration and because smoking compromises NOS3 activity, genetic variation in NOS3 might interact with smoking and folic acid use in clefting risk. The authors genotyped 244 infants with isolated cleft lip with or without cleft palate (CL/P), 99 with isolated cleft palate, and 588 controls from a California population-based case-control study (1987-1989 birth cohort) for two NOS3 polymorphisms: A(-922)G and G894T. Analyses of gene-only effects for each polymorphism revealed a 60% increased risk of CL/P among NOS3 A(-922)G homozygotes (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.6). There was some evidence for higher risk of CL/P with maternal periconceptional smoking in infants with an NOS3 -922G allele (for homozygotes, OR = 2.5, 95% CI: 1.2, 5.6) but not in those with an 894T allele. For CL/P risk, odds ratios were over 4 among mothers who smoked, who did not use vitamins, and whose infants had at least one variant allele for each NOS3 polymorphism (for A(-922)G, OR = 4.6, 95% CI: 2.1, 10.2; for 894T, OR = 4.4, 95% CI: 1.8, 10.7). No similar patterns were observed for risk of cleft palate.

Adult↗
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↗