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Biomedical subjects

Gary M Shaw

Publications and source records attributed to Gary M Shaw.

At least 37 records · Page 2Linked to original sources
PubMed2005

Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes.

Investigating possible genetic polymorphisms and gene-environment interactions in the etiology of human conotruncal defects is a prudent research approach. In this study we explore gene-only and gene-environment effects of 32 single nucleotide polymorphisms (SNPs) on conotruncal defect risks. The genes bearing these SNPs participate in one of five pathogenetic processes, homocysteine metabolism, coagulation, cell-cell interaction, inflammatory response, and blood pressure regulation. We used DNA samples and data from a California population-based case-control interview study (1987-1988 birth cohort). We employed a multilocus allele-specific hybridization assay. Allelic variants were determined by genotyping 155 infants with conotruncal defects (cases) and 437 infants without malformations (controls). Among the 32 SNPs, four were associated with odds ratios of 2 or more, and two with odds ratios of 0.5 or less. The four SNPs were F2 G20210A (prothrombin) with an odds ratio of 2.5 (95% confidence interval; 0.9-7.0), F7 promoter (-323) 10-bp del/ins with an odds ratio of 2.3 (0.8-6.8), ITGB3 leu33pro (platelet glycoprotein IIIa) with an odds ratio of 2.2 (0.9-5.7), and NPPA T2238C (atrial natriuretic precursor peptide) with an odds ratio of 2.9 (0.8-10.1). Two SNPs were associated with decreased risks: TNF (tumor necrosis factor, G (-376A)) and ADD1 gly460trp (alpha adducin) with odds ratios of 0.5 (0.1-2.3) and 0.5 (0.2-1.9), respectively. Analyses that investigated a potential gene-nutrient interaction between maternal periconceptional vitamin use and MTHFR genotypes did not indicate that the CT or TT genotype contributed to conotruncal defect risk in infants even in the absence of maternal use of multivitamin supplements with folic acid. Analyses that investigated a potential interaction on risk between NOS3 genes and maternal cigarette smoking, revealed some evidence for higher risk of conotruncal defects in infants whose mothers smoked cigarettes periconceptionally and who had one of the variant alleles for NOS3 A(-922G) or NOS3 glu298asp compared to those infants whose mothers did not smoke and whose genotypes were wild-type. Our results provide some support for involvement of genetic variation of biologically relevant candidate genes for some birth defects whose pathogenesis may be related to altered vascular tone or integrity. In particular, NPPA appears to be a good candidate gene for conotruncal defects and warrants further investigation.

California↗
PubMed2005

Schizencephaly: heterogeneous etiologies in a population of 4 million California births.

Schizencephaly is a rare congenital brain defect characterized by gray matter lined clefts of the cerebral mantle, frequently accompanied by other defects of the CNS such as absence of the corpus callosum. This study in a California population of >4 million births from 1985-2001 found a population prevalence of 1.54/100,000. Among 63 cases, there was an association with young parental age in isolated schizencephaly (RR 3.9 mothers; 5.8 fathers), which was also seen in mothers but not fathers of non-isolated cases (RR 3.2). Monozygotic twins may also be at increased risk for schizencephaly (RR 2.1). One third of cases had a non-CNS abnormality, over half of which could be classified as secondary to vascular disruption, including gastroschisis, bowel atresias, and amniotic band disruption sequence. Other apparent rare causes included chromosomal aneuploidy, non-random associations, and unusual syndromes. Our observations suggest that schizencephaly has heterogeneous etiologies many of which are vascular disruptive in origin.

Adult↗
PubMed2005

Epidemiologic characteristics of anophthalmia and bilateral microphthalmia among 2.5 million births in California, 1989-1997.

There is a paucity of epidemiologic information about the eye malformations anophthalmia and microphthalmia. Using data from a large population-based registry, we explored prevalences and maternal/infant characteristics associated with anophthalmia and bilateral microphthalmia. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 2.5 million births (liveborn and stillborn) occurred during the ascertainment period, 1989-1997. Information on maternal and infant/fetal characteristics was obtained from California birth certificate and fetal death files. The prevalence per 10,000 livebirths and stillbirths for anophthalmia was 0.18 and for bilateral microphthalmia was 0.22. These estimates reflect prevalences among births without chromosomal anomalies. Relative risks of anophthalmia were modestly higher among women aged 40 or more (relative risk = 2.0, 95% confidence interval 0.5-8.6). Risks were substantially lower for those mothers with >12 years of education, even after adjusting for other study factors, relative risk = 0.6 (0.2-1.7). The risk of anophthalmia was approximately twofold among multiple births compared to singletons. Similar to results for anophthalmia, decreased risks for bilateral microphthalmia were observed for maternal education of 12 years or more and increased risks observed for multiple births. These data show descriptive epidemiologic features of anophthalmia and bilateral microphthalmia.

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

Risks for severe mental retardation occurring in isolation and with other developmental disabilities.

Individual and maternal characteristics as potential risk factors for having severe mental retardation (SMR) occurring with and without cerebral palsy (CP), epilepsy, or a pervasive developmental disorder (PDD) were explored among a cohort of 119,404 children without Down syndrome born in the California Central Valley in 1992 and 1993. Unadjusted and adjusted relative risks (RRs) and their 95% confidence intervals (CIs) based on the Poisson distribution were used to estimate the risks associated with each individual and maternal factor studied for each SMR diagnostic category. The most notable increased risks for SMR occurring in isolation or with CP or epilepsy was for children born low-birth-weight or preterm who were at a substantially increased risk (RRs 2.6-9.9). In contrast, the risk of SMR occurring with a PDD was the greatest among males compared to females (RR = 3.4, 95% CI 1.5, 7.9), Blacks compared to Whites (RR = 5.1, 95% CI 1.7, 15.5), and Asians compared to Whites (RR = 3.9, 95% CI 1.3, 12.0). Etiologic heterogeneity when SMR occurs with a PDD was suggested.

California↗
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

Maternal progestin intake and risk of hypospadias.

BACKGROUND: Previous studies have suggested that maternal intake of progestins during early pregnancy may be associated with an increased risk of hypospadias. Progesterone and its derivatives are commonly prescribed during early pregnancy, for example, in cases of luteal phase dysfunction and in conjunction with ovulation stimulation drugs. OBJECTIVE: To examine whether risk of hypospadias was associated with periconceptional progestin intake. DESIGN AND SETTING: The National Birth Defects Prevention Study, a population-based, multistate, case-control study including deliveries that had estimated due dates from October, 1997 to December, 2000. PARTICIPANTS: Participation in the study was 71% among case mothers and 68% among control mothers. This analysis included 502 subjects diagnosed with second- or third-degree hypospadias (ie, the urethra opened at the penile shaft, scrotum, or perineum) and 1286 male, live-born, nonmalformed control subjects. RESULTS: Forty-two case mothers (8.4%) and 31 control mothers (2.4%) reported any pregnancy-related progestin intake from 4 weeks before through 14 weeks after conception, resulting in an odds ratio of 3.7 (95% confidence interval [CI], 2.3-6.0). Analyses stratified by several potential covariates also suggested elevated risks. For example, among the 10 cases and 13 controls who did not report any fertility-related procedures or treatments other than progestins, the odds ratio was 2.2 (95% CI, 1.0-5.0). Progestin intake for the purpose of contraception was not associated with increased risk. CONCLUSION: This study found that pregnancy-related intake of progestins was associated with increased hypospadias risk.

Abnormalities, Drug-Induced↗
PubMed2005

Periconceptional dietary intake of myo-inositol and neural tube defects in offspring.

BACKGROUND: Periconceptional intake of nutrients in addition to folic acid may contribute to neural tube defect (NTD) etiologies; a likely candidate is myo-inositol. We investigated whether maternal periconceptional dietary intake of myo-inositol influenced NTD risk. METHODS: 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 454 NTD cases and with mothers of 462 nonmalformed controls. A standard 100-item food frequency questionnaire was used to assess nutrient intake. RESULTS: We observed small increases in risk, with increases slightly more evident for anencephaly, associated with intakes of myo-inositol less than the highest intake quartile, e.g., risk of anencephaly was 1.3 (0.7-2.4) among fetuses whose mothers consumed lowest versus highest intakes of myo-inositol. These small increases, however, were imprecise, and also did not indicate increasing risk with decreasing level of myo-inositol intake. Adjusted risk estimates did not differ considerably from their unadjusted counterparts. CONCLUSIONS: Our results do not indicate that myo-inositol intake, as measured in this study, is strongly associated with risk of human NTDs.

Female↗
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↗
PubMed2005

Gene-environment interactions in rare diseases that include common birth defects.

Rare syndromes often feature specific types of birth defects that frequently are major diagnostic clues to the presence of a given disorder. Despite this specificity, not everyone with the same syndrome is equally or comparably affected, and not everyone with a specific birth defect manifests the same syndrome or is affected with all the features of a particular syndrome. A symposium sponsored by the National Institutes of Health Office of Rare Diseases, and the National Toxicology Program Center for the Evaluation of Risks to Human Reproduction attempted to explore how much of this variability is due to genetic factors and how much is due to environmental factors. The specific types of birth defects examined included cardiovascular defects, holoprosencephaly, clefts of the lip and/or palate, neural tube defects, and diaphragmatic hernias.

Abnormalities, Drug-Induced↗
PubMed2005

Maternal obesity, gestational diabetes, and central nervous system birth defects.

BACKGROUND: Maternal obesity and diabetes are both associated with increased risk of congenital central nervous system (CNS) malformations in the offspring and may share a common underlying mechanism. Our objective was to evaluate whether gestational diabetes influenced the association of prepregnancy maternal obesity and risks for CNS birth defects. METHODS: This Texas population-based case-control study evaluated births occurring January 1997 through June 2001. Data came from structured telephone interviews. Cases (n=477) were mothers of offspring with anencephaly (n=120), spina bifida (n=184), holoprosencephaly (n=49), or isolated hydrocephaly (n=124). Controls (n=497) were mothers of live infants without abnormalities randomly selected from the same hospitals as cases. Response rates were approximately 60% for both cases and controls. We evaluated maternal obesity (body mass index > or =30.0 kg/m) and risks for CNS birth defects, as well as whether gestational diabetes influenced the risks. RESULTS: After adjusting for maternal ethnicity, age, education, smoking, alcohol use, and periconceptional vitamin use, obese women had substantially increased risks of delivering offspring with anencephaly (odds ratio=2.3; 95% confidence interval=1.2-4.3), spina bifida (2.8; 1.7-4.5), or isolated hydrocephaly (2.7; 1.5-5.0), but not holoprosencephaly (1.4; 0.5-3.8). Odds ratios were higher for the joint effects of maternal obesity and gestational diabetes, with evidence for interaction on a multiplicative scale. CONCLUSIONS: Maternal obesity and gestational diabetes may increase the risk of CNS birth defects through shared causal mechanisms.

Central Nervous System Diseases↗
PubMed2005

Maternal smoking, genetic variation of glutathione s-transferases, and risk for orofacial clefts.

BACKGROUND: Maternal smoking is a known risk factor for orofacial clefts. We investigated whether risk is greater among offspring who lack the genetic capacity to produce glutathione S-transferase enzymes relevant to detoxification of chemicals in cigarette smoke. METHODS: Using a population-based case-control design, we genotyped 423 California infants with an isolated cleft and 294 nonmalformed controls for null variants of the glutathione S-transferases GSTT1 and GSTM1. RESULTS: If a mother smoked during pregnancy and her fetus was homozygous null for GSTT1, the risk of isolated cleft lip with or without cleft palate was tripled (odds ratio = 2.9; 95% confidence interval = 1.2-7.2). For fetuses who were homozygous null for GSTM1 and whose mothers smoked >/=20 cigarettes per day, we found nearly a 7-fold increased risk (6.8; 0.82-57). Combined absence of GSTM1 and GSTT1 enzymes among the offspring of smoking mothers was associated with a nearly 6-fold increased risk for cleft lip (6.3; 1.3-42). A similar increased risk for cleft palate was associated with absence of GSTM1, but not for absence of GSTT1. CONCLUSIONS: Maternal smoking during pregnancy increases risks for clefts among fetuses lacking enzymes involved in the detoxification of tobacco-derived chemicals.

Adult↗
PubMed2005

Hypospadias and maternal exposures to cigarette smoke.

The few previous studies of hypospadias and smoking have suggested either no association or a reduced risk. This study, which uses data from the National Birth Defects Prevention Study, a multi-state, population-based case-control study, includes data on males born with severe hypospadias (i.e. the urethra opens at the penile shaft, scrotum or perineum) from 1997 to 2000. Non-malformed, liveborn male controls were selected randomly from birth certificates or from birth hospitals. Maternal interviews were completed by telephone with 453 case mothers and 1267 control mothers. Maternal smoking was not associated with hypospadias risk. For example, during the third month of pregnancy, smoking < 0.5 pack/day had an odds ratio (OR) of 1.1 [95% CI 0.6, 1.9]; 0.5 pack/day, 0.6 [0.4, 1.1]; and > or = 1 pack/day, 0.8 [0.4, 1.6]. Exposure to any secondhand smoke at home during the third month of pregnancy showed an OR of 0.6 [95% CI 0.4, 1.0], and exposure at work or school, an OR of 0.7 [0.5, 1.1]. Similar risks were observed for other months during the periconceptional period, and adjustment for several potential confounders did not substantially alter results. This analysis does not confirm a recent report suggesting that maternal smoking is associated with a reduced risk of having offspring with hypospadias.

Adult↗
PubMed2004

Gene-nutrient interactions: importance of folates and retinoids during early embryogenesis.

The role that nutritional factors play in mammalian development has received renewed attention over the past two decades, as the scientific literature exploded with reports of retinoid compounds disrupting craniofacial development, and with other reports that folic acid supplementation in the periconceptional period can protect embryos from highly significant malformations. As was often the case, the situation became far more complicated, as the interaction between nutritional factors with selected genes was recognized. In this review, we attempt to summarize a complex clinical and experimental literature of nutritional factors, their biological transport mechanisms, and the impact that they have during early embryogenesis. Although not exhaustive, our goal was to provide an overview of important gene-nutrient interactions and a framework for their investigation.

Abnormalities, Drug-Induced↗
PubMed2004

Periconceptional dietary intake of choline and betaine and neural tube defects in offspring.

Periconceptional intake of folic acid prevents some neural tube defects (NTDs). Other nutrients may also contribute to NTD etiologies; a likely candidate is choline. Similar to folic acid, choline is involved in one-carbon metabolism for methylation of homocysteine to methionine. The authors investigated whether maternal periconceptional dietary intakes of choline and its metabolite betaine influence NTD risk. Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. In-person interviews were conducted with mothers of 424 NTD cases and with mothers of 440 nonmalformed controls. A standard 100-item food frequency questionnaire was used to assess nutrient intake. Dietary intakes of choline were associated with reduced NTD risks. Controlling for intake of supplemental folic acid, dietary folate, dietary methionine, and other covariates did not substantially influence risk estimates for choline. NTD risk estimates were lowest for women whose diets were rich in choline, betaine, and methionine. That is, for women whose intake was above the 75th percentile compared with below the 25th percentile for all three nutrients, the odds ratio was 0.17 (95% confidence interval: 0.04, 0.76). Study findings for dietary components other than folic acid offer additional clues about the complex etiologies of NTDs.

Betaine↗