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1.  Maternal Residential Atrazine Exposure and Risk for Choanal Atresia and Stenosis in Offspring 
The Journal of pediatrics  2012;162(3):581-586.
Objective
To assess the relationship between estimated residential maternal exposure to atrazine during pregnancy and risk for choanal atresia or stenosis in offspring.
Study Design
Data for 280 nonsyndromic cases and randomly selected, population-based controls delivered during 1999 to 2008 were obtained from the Texas Birth Defects Registry. County-level estimates of atrazine levels obtained from the United States Geological Survey were assigned to cases and controls based on maternal county of residence at delivery. Unconditional logistic regression was used to assess the relationship between maternal residential atrazine exposure and risk for choanal atresia or stenosis in offspring.
Results
Compared to offspring of mothers with low levels of estimated residential atrazine exposure, those with high levels had nearly a two-fold increase in risk for choanal atresia or stenosis (adjusted odds ratio: 1.79, 95% confidence interval: 1.17–2.74). A significant linear trend was also observed with increasing levels of atrazine exposure (adjusted P = 0.002).
Conclusions
A link between maternal exposure to endocrine disruptors, such as atrazine, and choanal atresia risk is plausible based on previous findings. Our results further support this hypothesis.
doi:10.1016/j.jpeds.2012.08.012
PMCID: PMC4105141  PMID: 23036484
Texas; epidemiology; maternal exposure; congenital malformations
3.  Allergies, atopy, immune-related factors and childhood rhabdomyosarcoma: a report from the Children’s Oncology Group 
Rhabdomyosarcoma (RMS) is a highly malignant tumor of developing muscle that can occur anywhere in the body. Due to its rarity, relatively little is known about the epidemiology of RMS. Atopic disease is hypothesized to be protective against several malignancies; however, to our knowledge, there have been no assessments of atopy and childhood RMS. Therefore, we explored this association in a case-control study of 322 childhood RMS cases and 322 pair-matched controls. Cases were enrolled in a trial run by the Intergroup Rhabdomyosarcoma Study Group. Controls were matched to cases on race, sex, and age. The following atopic conditions were assessed: allergies, asthma, eczema, and hives; in addition we examined other immune-related factors: birth order, day-care attendance, and breastfeeding. Conditional logistic-regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for age, race, sex, household income, and parental education. As the two most common histologic types of RMS are embryonal (n=215) and alveolar (n=66), we evaluated effect heterogeneity of these exposures. Allergies (OR=0.60, 95% CI: 0.41–0.87), hives (OR=0.61, 95% CI: 0.38–0.97), day-care attendance (OR=0.48, 95% CI: 0.32–0.71), and breastfeeding for ≥12 months (OR=0.36, 95% CI: 0.18–0.70) were inversely associated with childhood RMS. These exposures did not display significant effect heterogeneity between histologic types (p>0.52 for all exposures). This is the first study indicating that atopic exposures may be protective against childhood RMS, suggesting additional studies are needed to evaluate the immune system’s role in the development of this tumor.
doi:10.1002/ijc.28363
PMCID: PMC3869863  PMID: 23824786
Allergies; atopy; epidemiology; rhabdomyosarcoma; soft tissue sarcoma
4.  Evaluating the effects of maternal exposure to benzene, toluene, ethyl benzene, and xylene on oral clefts among offspring in Texas: 1999-2008 
BACKGROUND
There is evidence from previous studies that maternal occupational exposure to hazardous air pollutants is positively associated with oral clefts, however, studies evaluating the association between residential exposure to these toxicants and oral clefts are lacking. Therefore, our goal was to conduct a case-control study examining the association between estimated maternal residential exposure to benzene, toluene, ethyl benzene, and xylene (BTEX) and the risk of oral clefts among offspring.
METHODS
Data on 6,045 non-syndromic isolated oral cleft cases (3,915 cleft lip with or without cleft palate [CL±P] and 2,130 non-syndromic isolated cleft palate [CP] cases) delivered between 1999 and 2008 were obtained from the Texas Birth Defects Registry. The control group was a sample of unaffected live births, frequency matched to cases on year of birth. Census tract-level estimates of annual average exposures were obtained from the U.S. Environmental Protection Agency 2005 Hazardous Air Pollutant Exposure Model (HAPEM5) for each pollutant and assigned to each subject based on maternal residence during pregnancy. Logistic regression was used to assess the relationship between estimated maternal exposure to each pollutant (benzene, toluene, ethyl benzene, and xylene) separately and the risk of oral clefts in offspring.
RESULTS
High estimated maternal exposure to benzene was not associated with oral clefts, compared with low estimated exposure (CL±P adjusted OR=0.95; 95% CI=0.81-1.12; CP adjusted OR=0.85; 95% CI=0.67-1.09). Similar results were seen for the other pollutants.
CONCLUSION
In our study, there was no evidence that maternal exposure to environmental levels of BTEX was associated with oral clefts.
doi:10.1002/bdra.23139
PMCID: PMC3771492  PMID: 23893927
oral clefts; maternal exposure; hazardous air pollutants; benzene; epidemiology
5.  BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups 
BRAF-V600E expression is identified in hematopoietic progenitor and precursor myeloid dendritic cells in patients with high-risk LCH, and enforced expression of BRAF-V600E in CD11c+ cells recapitulates a high-risk LCH-like phenotype in mice.
Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207+ dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207+ DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c+ and CD14+ fractions and in bone marrow (BM) CD34+ hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207+ DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
doi:10.1084/jem.20130977
PMCID: PMC3978272  PMID: 24638167
6.  MATERNAL OCCUPATIONAL EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS AND RISK OF ORAL CLEFT-AFFECTED PREGNANCIES 
Objective
Evaluate whether there is an association between maternal occupational exposure to polycyclic aromatic hydrocarbons (PAHs) and oral cleftsin offspring. This is the first human study of PAHs and clefts of which the authors are aware.
Design
Case-control study.
Setting, Participants
Data for 1997–2002 from the National Birth Defects Prevention Study, a large population-based case-control study in the US, were analyzed. Maternal telephone interviews yielded information on jobs held in the month before through three months after conception. Two industrial hygienists independently assessed occupational exposure to PAHs ; all jobs rated as exposed or with rating difficulty were reviewed with a third industrial hygienist to reach consensus on all exposure parameters. Logistic regression estimated crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for cleft lip with or without cleft palate (CL±P) and cleft palate alone (CP).
Results
There were 2989 controls( 3.5% exposed), 805 cases of CL±P (5.8% exposed) and 439 cases of CP (4.6% exposed). The odds of maternal occupational exposure to PAH (any vs none) during pregnancy was increased for CL±P cases as compared with controls (OR 1.69, 95% CI 1.18–2.40); the OR was 1.47 (95% CI 1.02–2.12) adjusted for maternal education. There was a statistically significant adjusted exposure-response relationship for CL±P (ptrend = 0.02). ORs for CP were not statistically significant.
Conclusions
Maternal occupational exposure to PAHs was associated with increased risk of cleft lip with or without cleft palate in offspring.
doi:10.1597/12-104
PMCID: PMC4096036  PMID: 23136939
PAHs; polycyclic aromatic hydrocarbons; occupation; malformations; oral clefts
7.  Association of traffic-related hazardous air pollutants and cervical dysplasia in an urban multiethnic population: a cross-sectional study 
Environmental Health  2014;13:52.
Background
Human papillomavirus (HPV) infection is a necessary cause in the development of cervical cancer; however, not all women infected with HPV develop cervical cancer indicating that other risk factors are involved. Our objective was to determine the association between exposure to ambient levels of common traffic-related air toxics and cervical dysplasia, a precursor lesion for cervical cancer.
Methods
The study sample consisted of women enrolled in a Phase II clinical trial to evaluate diagnostic techniques for cervical disease in Houston, Texas. The current assessment is a secondary data analysis in which cases were defined as women diagnosed with cervical dysplasia, while those without cervical dysplasia served as controls. Residential census tract-level estimates of ambient benzene, diesel particulate matter (DPM), and polycyclic aromatic hydrocarbons (PAHs) were used to assess exposure. Census tract-level pollutant estimates were obtained from the United States Environmental Protection Agency. Multivariable logistic regression was used to estimate prevalence odds ratios (aOR) and 95% confidence intervals (CI) adjusted for age, race/ethnicity, education, smoking status, and HPV status.
Results
Women in the highest residential exposure categories for benzene and DPM had an increased prevalence of cervical dysplasia compared to the lowest exposure category (Benzene: aOR [95% CI] for high exposure = 1.97[1.07-3.62], very high exposure = 2.30[1.19-4.46]. DPM: aOR [95% CI] for high exposure = 2.83[1.55-5.16], very high exposure = 2.10[1.07-4.11]). Similarly, women with high residential exposure to PAHs had an increased prevalence of cervical dysplasia (aOR [95% CI] = 2.46[1.35-4.48]). The highest PAH exposure category was also positively associated with cervical dysplasia prevalence but was not statistically significant. Assessment of the combined effect of HAP exposure indicates that exposure to high levels of more than one HAP is positively associated with cervical dysplasia prevalence (p for trend = 0.004).
Conclusions
Traffic-related HAPs, such as benzene, DPM, and PAHs, are not as well-regulated and monitored as criteria air pollutants (e.g., ozone), underscoring the need for studies evaluating the role of these toxicants on disease risk. Our results suggest that exposure to traffic-related air toxics may increase cervical dysplasia prevalence.
doi:10.1186/1476-069X-13-52
PMCID: PMC4063240  PMID: 24924773
Benzene; Cervical dysplasia; Diesel particulate matter; Hazardous air pollutants; Polycyclic aromatic hydrocarbons
8.  Maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood acute lymphoblastic leukemia 
Leukemia research  2013;37(5):531-535.
Discovering genetic predictors of childhood acute lymphoblastic leukemia (ALL) necessitates the evaluation of novel factors including maternal genetic effects, which are a proxy for the intrauterine environment, and robust epidemiologic study designs. Therefore, we evaluated five maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood ALL among 120 case-parent triads. Two of the five haplotypes were significantly associated with risk: GSTM3/GSTM4 (P=0.01) and GSTP1 (P=0.02). The EPHX1 haplotype was marginally associated with risk (P=0.05), whereas haplotypes in CYP1B1 and GSTA4 were not. Our results suggest genetic variation in xenobiotic metabolism is important in childhood ALL etiology.
doi:10.1016/j.leukres.2013.01.020
PMCID: PMC3622777  PMID: 23433810
Acute lymphoblastic leukemia; case-parent triad; haplotypes; xenobiotic metabolism
9.  Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons: Effects on Gastroschisis among Offspring in the National Birth Defects Prevention Study 
Environmental Health Perspectives  2012;120(6):910-915.
Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) occurs in many occupational settings. There is evidence in animal models that maternal exposure to PAHs during pregnancy is associated with gastroschisis in offspring; however, to our knowledge, no human studies examining this association have been conducted.
Objective: Our goal was to conduct a case–control study assessing the association between estimated maternal occupational exposure to PAHs and gastroschisis in offspring.
Methods: Data from gastroschisis cases and control infants were obtained from the population-based National Birth Defects Prevention Study for the period 1997–2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to determine the association between estimated occupational PAH exposure and gastroschisis among children whose mothers were employed for at least 1 month during the month before conception through the third month of pregnancy.
Results: The prevalence of estimated occupational PAH exposure was 9.0% in case mothers (27 of 299) and 3.6% in control mothers (107 of 2,993). Logistic regression analyses indicated a significant association between occupational PAHs and gastroschisis among mothers ≥ 20 years of age [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.27, 5.04] after adjusting for maternal body mass index, education, gestational diabetes, and smoking. This association was not seen in mothers < 20 years (OR = 1.14; 95% CI: 0.55, 2.33), which is notable because although young maternal age is the strongest known risk factor for gastroschisis, most cases are born to mothers ≥ 20 years.
Conclusion: Our findings indicate an association between occupational exposure to PAHs among mothers who are ≥ 20 years and gastroschisis. These results contribute to a body of evidence that PAHs may be teratogenic.
doi:10.1289/ehp.1104305
PMCID: PMC3385431  PMID: 22330681
birth defects; gastroschisis; maternal exposure; occupation; PAHs
10.  Using a Bayesian Hierarchical Model for Identifying Single Nucleotide Polymorphisms Associated with Childhood Acute Lymphoblastic Leukemia Risk in Case-Parent Triads 
PLoS ONE  2013;8(12):e84658.
Childhood acute lymphoblastic leukemia (ALL) is a condition that arises from complex etiologies. The absence of consistent environmental risk factors and the presence of modest familial associations suggest ALL is a complex trait with an underlying genetic component. The identification of genetic factors associated with disease is complicated by complex genetic covariance structures and multiple testing issues. Both issues can be resolved with appropriate Bayesian variable selection methods. The present study was undertaken to extend our hierarchical Bayesian model for case-parent triads to incorporate single nucleotide polymorphisms (SNPs) and incorporate the biological grouping of SNPs within genes. Based on previous evidence that genetic variation in the folate metabolic pathway influences ALL risk, we evaluated 128 tagging SNPs in 16 folate metabolic genes among 118 ALL case-parent triads recruited from the Texas Children’s Cancer Center (Houston, TX) between 2003 and 2010. We used stochastic search gene suggestion (SSGS) in hierarchical Bayesian models to evaluate the association between folate metabolic SNPs and ALL. Using Bayes factors among these variants in childhood ALL case-parent triads, two SNPs were identified with a Bayes factor greater than 1. There was evidence that the minor alleles of NOS3 rs3918186 (OR = 2.16; 95% CI: 1.51-3.15) and SLC19A1 rs1051266 (OR = 2.07; 95% CI: 1.25-3.46) were positively associated with childhood ALL. Our findings are suggestive of the role of inherited genetic variation in the folate metabolic pathway on childhood ALL risk, and they also suggest the utility of Bayesian variable selection methods in the context of case-parent triads for evaluating the role of SNPs on disease risk.
doi:10.1371/journal.pone.0084658
PMCID: PMC3868670  PMID: 24367687
11.  Diabetes and Obesity-Related Genes and the Risk of Neural Tube Defects in the National Birth Defects Prevention Study 
American Journal of Epidemiology  2012;176(12):1101-1109.
Few studies have evaluated genetic susceptibility related to diabetes and obesity as a risk factor for neural tube defects (NTDs). The authors investigated 23 single nucleotide polymorphisms among 9 genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, SLC2A2, TCF7L2, and UCP2) associated with type 2 diabetes or obesity. Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study during 1999–2007. Log-linear models were used to evaluate maternal and offspring genetic effects. After application of the false discovery rate, there were 5 significant maternal genetic effects. The less common alleles at the 4 FTO single nucleotide polymorphisms showed a reduction of NTD risk (for rs1421085, relative risk (RR) = 0.73 (95% confidence interval (CI): 0.62, 0.87); for rs8050136, RR = 0.79 (95% CI: 0.67, 0.93); for rs9939609, RR = 0.79 (95% CI: 0.67, 0.94); and for rs17187449, RR = 0.80 (95% CI: 0.68, 0.95)). Additionally, maternal LEP rs2071045 (RR = 1.31, 95% CI: 1.08, 1.60) and offspring UCP2 rs660339 (RR = 1.32, 95% CI: 1.06, 1.64) were associated with NTD risk. Furthermore, the maternal genotype for TCF7L2 rs3814573 suggested an increased NTD risk among obese women. These findings indicate that maternal genetic variants associated with glucose homeostasis may modify the risk of having an NTD-affected pregnancy.
doi:10.1093/aje/kws190
PMCID: PMC3571234  PMID: 23132673
case-parent triads; diabetes; genetics; neural tube defects; obesity
12.  Maternal Variation in EPHX1, a Xenobiotic Metabolism Gene, Is Associated with Childhood Medulloblastoma: An Exploratory Case-Parent Triad Study 
Pediatric hematology and oncology  2012;29(8):10.3109/08880018.2012.722747.
Common epidemiologic study designs used for evaluating germline genetic determinants of childhood medulloblastoma are often subject to population stratification bias and do not account for maternal genetic effects, a proxy for the intrauterine environment, which may be important in determining etiologic factors for this outcome. The case-parent triad design overcomes these limitations. Therefore, we conducted an exploratory study among 27 childhood medulloblastoma case-parent triads recruited from the Childhood Cancer Epidemiology and Prevention Center at Texas Children’s Hospital (Houston, TX) between 2003 and 2010. We assessed 13 single nucleotide polymorphisms (SNPs) in nine xenobiotic detoxification genes, as deficiencies in this pathway may induce brain tumorigenesis. Log-linear modeling was used to assess the association between medulloblastoma and both the offspring (i.e., case) and maternal genotypes of each SNP. In our population, there were no offspring genotypes that were significantly associated with disease risk. However, the maternal EPHX1 rs1051740 genotype (RR=3.26, P=0.01) was associated with medulloblastoma risk. This exploratory study highlights the utility of the case-parent triad design, but these results should be interpreted cautiously due to the limited sample size.
doi:10.3109/08880018.2012.722747
PMCID: PMC3855527  PMID: 22994552
Case-parent triad; epidemiology; genetic polymorphisms; medulloblastoma; xenobiotic detoxification
13.  A case-parent triad assessment of folate metabolic genes and the risk of childhood acute lymphoblastic leukemia 
Cancer causes & control : CCC  2012;23(11):1797-1803.
Purpose
We conducted a case-parent triad study evaluating the role of maternal and offspring genotypes in the folate metabolic pathway on childhood acute lymphoblastic leukemia (ALL) risk.
Methods
Childhood ALL case-parent triads (N = 120) were recruited from Texas Children’s Hospital. DNA samples were genotyped using the Sequenom iPLEX MassARRAY for 68 tagSNPs in six folate metabolic pathway genes (MTHFR, MTRR, MTR, DHFR, BHMT, and TYMS). Log-linear modeling was used to examine the associations between maternal and offspring genotypes and ALL.
Results
After controlling for the false discovery rate (<0.1), there were 20 significant maternal effects in the following genes: BHMT (N = 3), MTR (N = 12), and TYMS (N = 5). For instance, maternal genotypes for BHMT rs558133 (relative risk [RR] = 0.51, 95% confidence interval [CI]: 0.30–0.87, P = 0.008, Q = 0.08) and MTR rs2282369 (RR = 0.46, 95% CI: 0.27–0.80, P = 0.004, Q = 0.08) were associated with ALL. There were no significant offspring effects after controlling for the false discovery rate.
Conclusions
This is one of the few studies conducted to evaluate maternal genetic effects in the context of childhood ALL risk. Furthermore, we employed a family-based design that is less susceptible to population stratification bias in the estimation of maternal genetic effects. Our findings suggest that maternal genetic variation in the folate metabolic pathway is relevant in the etiology of childhood ALL. The observed maternal genetic effects support the need for continued research of how the uterine environment may influence risk of ALL.
doi:10.1007/s10552-012-0058-z
PMCID: PMC3472623  PMID: 22941668
Acute lymphoblastic leukemia; case-parent triad; folate; genetic epidemiology; pediatric cancer
14.  A GCH1 Haplotype and Risk of Neural Tube Defects in the National Birth Defects Prevention Study 
Molecular genetics and metabolism  2012;107(3):592-595.
Tetrahydrobiopterin (BH4) is an essential cofactor and an important cellular antioxidant. BH4 deficiency has been associated with diseases whose etiologies stem from excessive oxidative stress. GTP cyclohydrolase I (GCH1) catalyzes the first and rate-limiting step of de novo BH4 synthesis. A 3-SNP haplotype in GCH1 (rs8007267, rs3783641, and rs10483639) is known to modulate GCH1 gene expression levels and has been suggested as a major determinant of plasma BH4 bioavailability. As plasma BH4 bioavailability has been suggested as a mechanism of neural tube defect (NTD) teratogenesis, we evaluated the association between this GCH1 haplotype and the risk of NTDs. Samples were obtained from 760 NTD case-parent triads included in the National Birth Defects Prevention Study (NBDPS). The three SNPs were genotyped using TaqMan® SNP assays. An extension of the log-linear model was used to assess the association between NTDs and both offspring and maternal haplotypes. Offspring carrying two copies of haplotype C-T-C had a significantly increased NTD risk (risk ratio [RR] = 3.40, 95% confidence interval [CI]: 1.02–11.50), after adjusting for the effect of the maternal haplotype. Additionally, mothers carrying two copies of haplotype C-T-C had a significantly increased risk of having an NTD-affected offspring (RR = 3.46, 95% CI: 1.05–11.00), after adjusting for the effect of the offspring haplotype. These results suggest offspring and maternal variation in the GCH1 gene and altered BH4 biosynthesis may contribute to NTD risk.
doi:10.1016/j.ymgme.2012.09.020
PMCID: PMC3704723  PMID: 23059057
GCH1 gene; GTP cyclohydrolase I; haplotype; neural tube defects; tetrahydrobiopterin (BH4)
15.  A case–control study of maternal bathing habits and risk for birth defects in offspring 
Environmental Health  2013;12:88.
Background
Nearly all women shower or take baths during early pregnancy; however, bathing habits (i.e., shower and bath length and frequency) may be related to the risk of maternal hyperthermia and exposure to water disinfection byproducts, both of which are suspected to increase risk for multiple types of birth defects. Thus, we assessed the relationships between bathing habits during pregnancy and the risk for several nonsyndromic birth defects in offspring.
Methods
Data for cases with one of 13 types of birth defects and controls from the National Birth Defects Prevention Study delivered during 2000–2007 were evaluated. Logistic regression analyses were conducted separately for each type of birth defect.
Results
There were few associations between shower frequency or bath frequency or length and risk for birth defects in offspring. The risk for gastroschisis in offspring was increased among women who reported showers lasting ≥15 compared to <15 minutes (adjusted odds ratio: 1.43, 95% confidence interval: 1.18-1.72). In addition, we observed modest increases in the risk for spina bifida, cleft lip with or without cleft palate, and limb reduction defects in offspring of women who showered ≥15 compared to <15 minutes. The results of comparisons among more specific categories of shower length (i.e., <15 minutes versus 15–19, 20–29, and ≥ 30 minutes) were similar.
Conclusions
Our findings suggest that shower length may be associated with gastroschisis, but the modest associations with other birth defects were not supported by analyses of bath length or bath or shower frequency. Given that showering for ≥15 minutes during pregnancy is very common, further evaluation of the relationship between maternal showering habits and birth defects in offspring is worthwhile.
doi:10.1186/1476-069X-12-88
PMCID: PMC4015781  PMID: 24131571
Congenital abnormalities; Gastroschisis; Baths; Water; Hyperthermia
16.  An Exploratory Case-Only Analysis of Gene-Hazardous Air Pollutant Interactions and the Risk of Childhood Medulloblastoma 
Pediatric blood & cancer  2012;59(4):605-610.
Background
There is evidence that exposure to chlorinated solvents may be associated with childhood medulloblastoma and primitive neuroectodermal tumor (M/PNET) risk. Animal models suggest genes related to detoxification and DNA repair are important in the carcinogenicity of these pollutants, however, there have been no human studies assessing the modifying effects of these genotypes on the association between chlorinated solvents and childhood M/PNET risk.
Procedure
We conducted a case-only study to evaluate census tract-level exposure to chlorinated solvents and the risk of childhood M/PNET in the context of detoxification and DNA repair genotypes. Cases (n = 98) were obtained from Texas Children’s Hospital and MD Anderson Cancer Center. Key genotypes (n = 22) were selected from the Illumina Human 1M Quad SNP Chip. Exposure to chlorinated solvents (methylene chloride, perchloroethylene, trichloroethylene, and vinyl chloride) was estimated from the U.S. EPA’s 1999 Assessment System for Population Exposure Nationwide (ASPEN). Logistic regression was used to estimate the case-only odds ratios and 95% confidence intervals (CIs).
Results
There were 11 significant gene-environment interactions associated with childhood M/PNET risk. However, after correcting for multiple comparisons, only the interaction between high trichloroethylene levels and OGG1 rs293795 significantly increased the risk of childhood M/PNET risk (OR = 9.24, 95% CI: 2.24, 38.24, Q = 0.04).
Conclusions
This study provides an initial assessment of the interaction between ambient levels of chlorinated solvents and potentially relevant genotypes on childhood M/PNET risk. Our results are exploratory and must be validated in animal models, as well as additional human studies.
doi:10.1002/pbc.24105
PMCID: PMC3371277  PMID: 22389292
Hazardous air pollutants; chlorinated solvents; DNA repair genes; detoxification genes; childhood medulloblastoma and primitive neuroectodermal tumor
17.  Gene-Gene Interactions in the Folate Metabolic Pathway and the Risk of Conotruncal Heart Defects 
Conotruncal and related heart defects (CTRD) are common, complex malformations. Although there are few established risk factors, there is evidence that genetic variation in the folate metabolic pathway influences CTRD risk. This study was undertaken to assess the association between inherited (i.e., case) and maternal gene-gene interactions in this pathway and the risk of CTRD. Case-parent triads (n = 727), ascertained from the Children's Hospital of Philadelphia, were genotyped for ten functional variants of nine folate metabolic genes. Analyses of inherited genotypes were consistent with the previously reported association between MTHFR A1298C and CTRD (adjusted P = .02), but provided no evidence that CTRD was associated with inherited gene-gene interactions. Analyses of the maternal genotypes provided evidence of a MTHFR C677T/CBS 844ins68 interaction and CTRD risk (unadjusted P = .02). This association is consistent with the effects of this genotype combination on folate-homocysteine biochemistry but remains to be confirmed in independent study populations.
doi:10.1155/2010/630940
PMCID: PMC2810479  PMID: 20111745
18.  Investigating Multiple Candidate Genes and Nutrients in the Folate Metabolism Pathway to Detect Genetic and Nutritional Risk Factors for Lung Cancer 
PLoS ONE  2013;8(1):e53475.
Purpose
Folate metabolism, with its importance to DNA repair, provides a promising region for genetic investigation of lung cancer risk. This project investigates genes (MTHFR, MTR, MTRR, CBS, SHMT1, TYMS), folate metabolism related nutrients (B vitamins, methionine, choline, and betaine) and their gene-nutrient interactions.
Methods
We analyzed 115 tag single nucleotide polymorphisms (SNPs) and 15 nutrients from 1239 and 1692 non-Hispanic white, histologically-confirmed lung cancer cases and controls, respectively, using stochastic search variable selection (a Bayesian model averaging approach). Analyses were stratified by current, former, and never smoking status.
Results
Rs6893114 in MTRR (odds ratio [OR] = 2.10; 95% credible interval [CI]: 1.20–3.48) and alcohol (drinkers vs. non-drinkers, OR = 0.48; 95% CI: 0.26–0.84) were associated with lung cancer risk in current smokers. Rs13170530 in MTRR (OR = 1.70; 95% CI: 1.10–2.87) and two SNP*nutrient interactions [betaine*rs2658161 (OR = 0.42; 95% CI: 0.19–0.88) and betaine*rs16948305 (OR = 0.54; 95% CI: 0.30–0.91)] were associated with lung cancer risk in former smokers. SNPs in MTRR (rs13162612; OR = 0.25; 95% CI: 0.11–0.58; rs10512948; OR = 0.61; 95% CI: 0.41–0.90; rs2924471; OR = 3.31; 95% CI: 1.66–6.59), and MTHFR (rs9651118; OR = 0.63; 95% CI: 0.43–0.95) and three SNP*nutrient interactions (choline*rs10475407; OR = 1.62; 95% CI: 1.11–2.42; choline*rs11134290; OR = 0.51; 95% CI: 0.27–0.92; and riboflavin*rs8767412; OR = 0.40; 95% CI: 0.15–0.95) were associated with lung cancer risk in never smokers.
Conclusions
This study identified possible nutrient and genetic factors related to folate metabolism associated with lung cancer risk, which could potentially lead to nutritional interventions tailored by smoking status to reduce lung cancer risk.
doi:10.1371/journal.pone.0053475
PMCID: PMC3553105  PMID: 23372658
19.  Evaluation of Heterogeneity in the Association between Congenital Heart Defects and Variants of Folate Metabolism Genes: Conotruncal and Left-Sided Cardiac Defects 
PURPOSE
Genetic variation in the folate metabolic pathway may influence the risk of congenital heart defects. This study was undertaken to assess the associations between the inherited and maternal genotypes for variants in folate-related genes and the risk of a composite heart phenotype that included two component phenotypes: conotruncal heart defects (CTDs) and left-sided cardiac lesions (LSLs).
METHODS
Nine folate-related gene variants were evaluated using data from 692 case-parent triads (CTD, n=419; LSL, n=273). Log-linear analyses were used to test for heterogeneity of the genotype-phenotype association across the two component phenotypes (i.e. CTD and LSLS) and, when there was no evidence of heterogeneity, to assess the associations of the maternal and inherited genotypes with the composite phenotype.
RESULTS
There was little evidence of heterogeneity of the genotype-phenotype association across the two component phenotypes or of an association between the genotypes and the composite phenotype. There was evidence of heterogeneity in the association of the maternal MTR A2756G genotype (p = 0.01) with CTDs and LSLs. However, further analyses suggested that the observed associations with the maternal MTR A2756G genotype might be confounded by parental imprinting effects.
CONCLUSIONS
Our analyses of these data provide little evidence that the folate-related gene variants evaluated in this study influence the risk of this composite congenital heart defect phenotype. However, larger and more comprehensive studies that evaluate parent-of-origin effects, as well as additional folate-related genes, are required to more fully explore the relation between folate and congenital heart defects.
doi:10.1002/bdra.22849
PMCID: PMC3257803  PMID: 21987465
Phenotypic heterogeneity; congenital heart defects; folate; case-parent triads; maternal genetic effects
20.  Optimal Therapy for Adults with Langerhans Cell Histiocytosis Bone Lesions 
PLoS ONE  2012;7(8):e43257.
Background
There is little data on treatment of Langerhans cell histiocytosis (LCH) in adults. Available data is on small numbers of patients with short follow-up times and no comparison of results from different treatment regimens. We analyzed the responses of adult LCH patients with bone lesions to three primary chemotherapy treatments to define the optimal one.
Methods and Findings
Fifty-eight adult patients with bone lesions, either as a solitary site or as a component of multisystem disease, were analyzed for disease location and response to surgery, curettage, steroids, radiation, vinblastine/prednisone, 2-Chlorodeoxyadenosine (2-CdA), or cytosine arabinoside (ARA-C). The mean age of patients was 32 years, with equal gender distribution. Twenty-nine patients had 1 lesion; 16, 2 lesions; 5, 3 lesions; and 8 had 4 or more. Most bone lesions were in the skull, spine, or jaw. Chemotherapy, surgery, curettage, or radiation, but not steroids alone, achieved improvement or resolution of lesions in a majority of patients. Comparison of the three chemotherapy regimens revealed 84% of patients treated with vinblastine/prednisone either did not respond or relapsed within a year, whereas 59% of patients treated with 2-CdA and 21% treated with ARA-C failed. Toxicity was worse with the vinblastine/prednisone group as 75% had grade 3–4 neuropathy. Grade 3–4 cytopenias occurred in 37% of the 2-CdA -treated patients and 20% of the ARA-C-treated patients. The major limitation of this study is it is retrospective and not a clinical trial.
Conclusions
ARA-C is an effective and minimally toxic treatment for LCH bone lesions in adults. In contrast, vinblastine/prednisone results in poor overall responses and excessive toxicity.
doi:10.1371/journal.pone.0043257
PMCID: PMC3419729  PMID: 22916233
21.  Staging Dementia Using Clinical Dementia Rating Scale Sum of Boxes Scores 
Archives of neurology  2008;65(8):1091-1095.
Background
The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score is commonly used, although the utility regarding this score in staging dementia severity is not well established.
Obiective
To investigate the effectiveness of CDRSOB scores in staging dementia severity compared with the global CDR score.
Design
Retrospective study.
Setting
Texas Alzheimer's Research Consortium minimum data set cohort.
Participants
A total of 1577 participants (110 controls, 202 patients with mild cognitive impairment, and 1265 patients with probable Alzheimer disease) were available for analysis.
Main Outcome Measures
Receiver operating characteristic curves were generated from a derivation sample to determine optimal cutoff scores and ranges, which were then applied to the validation sample.
Results
Optimal ranges of CDR-SOB scores corresponding to the global CDR scores were 0.5 to 4.0 for a global score of 0.5, 4.5 to 9.0 for a global score of 1.O, 9.5 to 15.5 for a global score of 2.0, and 16.0 to 18.0 for a global score of 3.0. When applied to the validation sample, κ scores ranged from 0.86 to 0.94 (P <.001 for all), with 93.0% of the participants falling within the new staging categories.
Conclusions
The CDR-SOB score compares well with the global CDR score for dementia staging. Owing to the increased range of values, the CDR-SOB score offers several advantages over the global score, including increased utility in tracking changes within and between stages of dementia severity. Interpretive guidelines for CDR-SOB scores are provided.
doi:10.1001/archneur.65.8.1091
PMCID: PMC3409562  PMID: 18695059
22.  Maternal Exposure to Ambient Levels of Benzene and Neural Tube Defects among Offspring: Texas, 1999–2004 
Environmental Health Perspectives  2010;119(3):397-402.
Background
Previous studies have reported positive associations between maternal exposure to air pollutants and several adverse birth outcomes. However, there have been no studies assessing the association between environmental levels of hazardous air pollutants, such as benzene, and neural tube defects (NTDs), a common and serious group of congenital malformations.
Objective
Our goal was to conduct a case–control study assessing the association between ambient air levels of benzene, toluene, ethylbenzene, and xylene (BTEX) and the prevalence of NTDs among offspring.
Methods
The Texas Birth Defects Registry provided data on NTD cases (spina bifida and anencephaly) delivered between 1999 and 2004. The control group was a random sample of unaffected live births, frequency matched to cases on year of birth. Census tract–level estimates of annual BTEX levels were obtained from the U.S. Environmental Protection Agency 1999 Assessment System for Population Exposure Nationwide. Restricted cubic splines were used in mixed-effects logistic regression models to determine associations between each pollutant and NTD phenotype.
Results
Mothers living in census tracts with the highest benzene levels were more likely to have offspring with spina bifida than were women living in census tracts with the lowest levels (odds ratio = 2.30; 95% confidence interval, 1.22–4.33). No significant associations were observed between anencephaly and benzene or between any of the NTD phenotypes and toluene, ethylbenzene, or xylene.
Conclusion
In the first study to assess the relationship between environmental levels of BTEX and NTDs, we found an association between benzene and spina bifida. Our results contribute to the growing body of evidence regarding air pollutant exposure and adverse birth outcomes.
doi:10.1289/ehp.1002212
PMCID: PMC3060005  PMID: 20923742
air pollution; benzene; birth defects; BTEX; epidemiology; hazardous air pollutants; maternal exposure; neural tube defects
23.  Variants of Folate Metabolism Genes and the Risk of Conotruncal Cardiac Defects 
Background
Although congenital heart defects (CHD) are the most common, serious group of birth defects, relatively little is known about the causes of these conditions and there are no established prevention strategies. There is evidence suggesting that the risk of CHD in general, and conotruncal and ventricular septal defects in particular, may be related to maternal folate status as well as genetic variants in folate-related genes. However, efforts to establish the relationships between these factors and CHD risk have been hampered by a number of factors including small study sample sizes and phenotypic heterogeneity.
Methods and Results
The present study examined the relationships between variation in nine folate-related genes and a subset of CHD phenotypes (i.e. conotruncal defects, perimembranous and malalignment type ventricular septal defects, and isolated aortic arch anomalies) in a cohort of over 700 case-parent triads. Further, both maternal and embryonic genetic effects were considered. Analyses of the study data confirmed a previously reported association between embryonic genotype for MTHFR A1298C and disease risk (unadjusted p=0.002).
Conclusions
These results represent the most comprehensive and powerful analysis of the relationship between CHD and folate-related genes reported to date, and provide additional evidence that, similar to neural tube defects, this subset of CHD is folate-related.
doi:10.1161/CIRCGENETICS.108.796342
PMCID: PMC3035562  PMID: 20031554
pediatrics; heart defects; congenital; genetics
24.  Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly 
Molecular genetics and metabolism  2009;98(1-2):225-234.
The cyclopic and laterality phenotypes in model organisms linked to disturbances in the generation or propagation of Nodal-like signals are potential examples of similar impairments resulting in birth defects in humans. However, the types of gene mutation(s) and their pathogenetic combinations in humans are poorly understood. Here we describe a mutational analysis of the human NODAL gene in a large panel of patients with phenotypes compatible with diminished NODAL ligand function. Significant reductions in the biological activity of NODAL alleles are detected among patients with congenital heart defects (CHD), laterality anomalies (e.g. left-right mis-specification phenotypes), and only rarely holoprosencephaly (HPE). While many of these NODAL variants are typical for family-specific mutations, we also report the presence of alleles with significantly reduced activity among common population variants. We propose that some of these common variants act as modifiers and contribute to the ultimate phenotypic outcome in these patients; furthermore, we draw parallels with strain-specific modifiers in model organisms to bolster this interpretation.
doi:10.1016/j.ymgme.2009.05.005
PMCID: PMC2774839  PMID: 19553149
NODAL; GDF1; TOF; TGA; DORV; cardiac defects; laterality; HPE
25.  Comparative Assessment of Air Pollution–Related Health Risks in Houston 
Environmental Health Perspectives  2007;115(10):1388-1393.
Background
Airborne emissions from numerous point, area, and mobile sources, along with stagnant meteorologic conditions, contribute to frequent episodes of elevated air pollution in Houston, Texas. To address this problem, decision makers must set priorities among thousands of individual air pollutants as they formulate effective and efficient mitigation strategies.
Objectives
Our aim was to compare and rank relative health risks of 179 air pollutants in Houston using an evidence-based approach supplemented by the expert judgment of a panel of academic scientists.
Methods
Annual-average ambient concentrations by census tract were estimated from the U.S. Environmental Protection Agency’s National-scale Air Toxics Assessment and augmented with measured levels from the Houston monitoring network. Each substance was assigned to one of five risk categories (definite, probable, possible, unlikely, uncertain) based on how measured or monitored concentrations translated into comparative risk estimates. We used established unit risk estimates for carcinogens and/or chronic reference values for noncarcinogens to set thresholds for each category. Assignment to an initial risk category was adjusted, as necessary, based on expert judgment about the quality and quantity of information available.
Results
Of the 179 substances examined, 12 (6.7%) were deemed definite risks, 9 (5.0%) probable risks, 24 (13.4%) possible risks, 16 (8.9%) unlikely risks, and 118 (65.9%) uncertain risks.
Conclusions
Risk-based priority setting is an important step in the development of cost-effective solutions to Houston’s air pollution problem.
doi:10.1289/ehp.10043
PMCID: PMC2022677  PMID: 17938725
air pollution; air toxics; comparative risk; diesel particles; hazardous pollutants; particulate matter; risk assessment

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