Identification and characterization of new genes involved in Drosophila heart development

Heart development is a crucial and conserved process that is related to the major type of human birth defects. Dorsal vessel, the Drosophila heart, has been regarded as an insightful system to identify new genes and study gene functions involved in heart development. Using heart-specific GFP transgenes, I did a genetic screen for cardiogenic genes on Drosophila chromosome II. Drosophila mutants that carry chromosome II deficiencies were tested for their phenotypes of heart development. Based on the screen results, chromosome regions containing genes required for heart development were identified. Fly strains with single gene mutations located within the defined deficiency regions were tested further. Seven genes have been identified to be involved in heart development. ^ The LIM homeodomain transcription factor gene tailup (tup) was further studied for its function in heart development. Based on this study, tup is expressed in cardioblasts and pericardial cells of the heart tube, as well as in associated lymph glands and alary muscles. In depth analysis of tup mutant phenotypes demonstrated tup is required for normal development of both heart and lymph glands. Tup was shown to bind to two DNA recognition sequences in the dorsal vessel enhancer of the Hand bHLH transcription factor gene, with one site proven essential for the expression of Hand in lymph glands, pericardial cells, and Svp/Doc cardioblasts. Together, these studies demonstrate that Tup is a critical new transcription factor in dorsal vessel morphogenesis and lymph gland formation, and strongly suggest Tup is a direct regulator of the expression of Hand in these developmental processes. ^

Determining associations and assessing methodological issues in a case-control study of hazardous air pollutants and neural tube defects

Recent studies have reported positive associations between maternal exposures to air pollutants and several adverse birth outcomes. However, there have been no assessments of the association between environmental hazardous air pollutants (HAPs) such as benzene, toluene, ethylbenzene, and xylene (BTEX) and neural tube defects (NTDs) a common and serious group of congenital malformations. Before examining this association, two important methodological questions must be addressed: (1) is maternal residential movement likely to result in exposure misclassification and (2) is it appropriate to lump defects of the neural tube, such as anencephaly and spina bifida, into a composite disease endpoint (i.e., NTDs). ^ Data from the National Birth Defects Prevention Study and Texas Birth Defects Registry were used to: (1) assess the extent to which change of residence may result in exposure misclassification when exposure is based on the address at delivery; (2) formally assess heterogeneity of the associations between known risk factors for NTDs, using polytomous logistic regression; and (3) conduct a case-control study assessing the association between ambient air levels of BTEX and the risk of NTDs among offspring. ^ Regarding maternal residential mobility, this study suggests address at delivery was not significantly different from using address at conception when assigning quartile of benzene exposure (OR 1.0, 95% CI 0.9, 1.3). On the question of effect heterogeneity among NTDs, the effect estimates for infant sex P = 0.017), maternal body mass index P = 0.016), and folate supplementation P = 0.050) were significantly different for anencephaly and spina bifida, suggesting it is often more appropriate to assess potential risk factors among subgroups of NTDs. For the main study question on the association between environmental HAPs and NTDs, mothers who have offspring with isolated spina bifida are 2.4 times likely to live in areas with the highest benzene levels (95% CI 1.1, 5.0). However, no other significant associations were observed.^ This project is the first to include not only an assessment of the relationship between environmental levels of BTEX and NTDs, but also two separate studies addressing important methodological issues associated with this question. Our results contribute to the growing body of evidence regarding air pollutant exposure and adverse birth outcomes. ^

Prevention of birth defects in a national study

The following analyses covered two main objectives focused on the prevention of and identification of risk factors for birth defects, the leading cause of infant mortality. All analyses utilized data from the National Birth Defects Prevention Study (NBDPS), an ongoing, population-based, case-control study of major structural birth defects. ^ The first objective was to identify predictors of folic acid supplementation among women of reproductive age. To meet this objective, a previous analysis of potential predictors of periconcecptional folic acid use in the NBDPS was repeated using data from more recent years (1997-2000 versus 2001-2005). The results of these analyses were consistent with the initial analyses, indicating that folic acid use is associated with maternal race/ethnicity, age, education, pregnancy awareness, smoking status, first prenatal care visit, previous live births, and fertility treatments). In addition, data from NBDPS controls were used to identify predictors of preconceptional folic acid use, since supplementation is optimally initiated prior to pregnancy (rather than after conception). These analyses indicated that maternal race/ethnicity, education, age, nativity, employment status, income, number of dependents, smoking, and birth control are significantly associated with preconceptional folic acid supplementation. Ultimately the results of these analyses can be used to guide the development of targeted interventions for preconceptional folic acid use. ^ The second objective was to investigate the association between parental Hispanic acculturation and the risk of gastroschisis, a congenital malformation of the abdominal wall, in offspring. Significant association were not observed for mothers < 20 years of age at conception. Among mothers ≥ 20 years of age, white parents were at a decreased risk of having a child with gastroschisis as compared to Hispanic parents who were born in the United States (US) [odd ratios (ORs) ranging from 0.60 to 0.55] and Hispanics parents who predominantly spoke English (ORs ranging from 0.65 to 0.58). Compared to Hispanic mothers born in the US, the risk of gastroschisis was lower among Hispanic mothers who had lived in the US < 5 years (OR=0.36, 95% CI: 0.42, 0.81) at the time of delivery and Hispanic mothers who migrated to the US at ≥ 20 years of age (OR=0.48, 95% CI: 0.26, 0.89). The results of these analyses provide further evidence that the risk of gastroschisis in offspring is associated with parent Hispanic ethnicity and, among Hispanics, with the degree of parental acculturation. Future studies should focus on characteristic differences between less and more acculturated parents to better understand the relationship between acculturation and gastroschisis.^

The association between parity and selected structural birth defects

BACKGROUND: Parity is a risk factor in neonatal morbidity and mortality. This dissertation examined the association between first births and selected birth defects. The first aim was to assess the risk of 66 birth defects among first births and third or greater births. The second aim was to determine if maternal race, maternal age, infant sex or infant birth weight modify the association between first births and selected birth defects. METHODS: The Texas Birth Defects Registry provided data for 1999-2009. For the first aim, odds ratios were calculated for each birth defect. For the second aim, analysis was restricted to the ten birth defects significantly associated with first births. Stratified analyses were conducted and interaction terms were added to logistic regression models to assess whether differences in the odds ratios for the effect of first birth were statistically significant across strata. RESULTS: Findings for the first aim showed that first births had significantly increased odds of having an infant with 24 of the 66 birth defects. Third or greater births had significantly increased odds of having four of the 66 birth defects. For the second aim, a number of significant effect modifiers were observed. For patent ductus arteriosis, obstructive urinary defects and gastroschisis, the effect of first births was significantly modified by black or U.S.-born Hispanic mothers. The effect of first birth was also significantly modified among mothers ≥30 years for mitral valve insufficiency, atrial septal defect and congenital hip dislocation. The effect of first births was significantly modified among infants with low birth weight for hypospadias, congenital hip dislocation and gastroschisis. CONCLUSIONS: First births were associated with an elevated risk of 24 categories of birth defects. For some of the birth defects studied, the effect of first birth is modified by maternal age, maternal race and low birth weight. Knowledge of the increased risk for birth defects among women having their first birth allows physicians and midwives to provide better patient care and spur further research into the etiology of associated birth defects. This knowledge may bring about interventions prior to conception in populations most likely to conceive.^

First -year mortality and survival among infants with selected congenital anomalies in Texas, 1995 to 1997

Congenital anomalies have been a leading cause of infant mortality for the past twenty years in the United States. Few registry-based studies have investigated the mortality experience of infants with congenital anomalies. Therefore, a registry-based mortality study was conducted of 2776 infants from the Texas Birth Defects Registry who were born January 1, 1995 to December 31, 1997, with selected congenital anomalies. Infants were matched to linked birth-infant death files from the Texas Department of Health, Bureau of Vital Statistics. One year Kaplan-Meier survival curves, and mortality estimates were generated for each of the 23 anomalies by maternal race/ethnicity, infant sex, birth weight, gestational age, number of life-threatening anomalies, prenatal diagnosis, hospital of birth and other variables. ^ There were 523 deaths within the first year of life (mortality rate = 191.0 per 1,000 infants). Infants with gastroschisis, trisomy 21, and cleft lip ± palate had the highest first year survival (92.91%, 92.32%, and 87.59%, respectively). Anomalies with the lowest survival were anencephaly (5.13%), trisomy 13 (7.41%), and trisomy 18 (10.29%). ^ Infants born to White, Non-Hispanic women had the highest first year survival (83.57%; 95% CI: 80.91, 85.88), followed by African-Americans (82.43%; 95% CI: 76.98, 86.70) and Hispanics (79.28%; 95% CI: 77.19, 81.21). Infants with birth weights ≥2500 grams and gestational ages ≥37 weeks also had the highest first year survival. First year mortality drastically increased as the number of life-threatening anomalies increased. Mortality was also higher for infants with anomalies that were prenatally diagnosed. Slight differences existed in survival based on infant's place of delivery. ^ In logistic regression analysis, birth weight (<1500 grams: OR = 7.48; 95% CI: 5.42, 10.33; 1500–2499 grams: OR = 3.48; 95% CI: 2.74, 4.42), prenatal diagnosis (OR = 1.92; 95% CI: 1.43, 2.58) and number of life-threatening anomalies (≥3: OR = 22.45; 95% CI: 11.67, 43.18) were the strongest predictors of death within the first year of life for all infants with selected congenital anomalies. To achieve further reduction in the infant mortality rate in the United States, additional research is needed to identify ways to reduce mortality among infants with congenital anomalies. ^