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

Investigating Multiple Candidate Genes and Nutrients in the Folate Metabolism Pathway to Detect Genetic and Nutritional Risk Factors for Lung Cancer

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

Estimated Maternal Pesticide Exposure from Drinking Water and Heart Defects in Offspring

Our objective was to examine the relationship between estimated maternal exposure to pesticides in public drinking water and the risk of congenital heart defects (CHD). We used mixed-effects logistic regression to analyze data from 18,291 nonsyndromic cases with heart defects from the Texas Birth Defects Registry and 4414 randomly-selected controls delivered in Texas from 1999 through 2005. Water district-level pesticide exposure was estimated by linking each maternal residential address to the corresponding public water supply district’s measured atrazine levels. We repeated analyses among independent subjects from the National Birth Defects Prevention Study (NBDPS) (1620 nonsyndromic cases with heart defects and 1335 controls delivered from 1999 through 2005). No positive associations were observed between high versus low atrazine level and eight CHD subtypes or all included heart defects combined. These findings should be interpreted with caution, in light of potential misclassification and relatively large proportions of subjects with missing atrazine data. Thus, more consistent and complete monitoring and reporting of drinking water contaminants will aid in better understanding the relationships between pesticide water contaminants and birth defects

Maternal–fetal metabolic gene–gene interactions and risk of neural tube defects

Single-gene analyses indicate that maternal genes associated with metabolic conditions (e.g., obesity) may influence the risk of neural tube defects (NTDs). However, to our knowledge, there have been no assessments of maternal-fetal metabolic gene-gene interactions and NTDs. We investigated 23 single nucleotide polymorphisms among 7 maternal metabolic genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, and TCF7L2) and 2 fetal metabolic genes (SLC2A2 and UCP2). Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study for birth years 1999–2007. We used a 2-step approach to evaluate maternal-fetal gene-gene interactions. First, a case-only approach was applied to screen all potential maternal and fetal interactions (n=76), as this design provides greater power in the assessment of gene-gene interactions compared to other approaches. Specifically, ordinal logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for each maternal-fetal gene-gene interaction, assuming a log-additive model of inheritance. Due to the number of comparisons, we calculated a corrected p-value (q-value) using the false discovery rate. Second, we confirmed all statistically significant interactions (q<0.05) using a log-linear approach among case-parent triads. In step 1, there were 5 maternal-fetal gene-gene interactions with q<0.05. The “top hit” was an interaction between maternal ENPP1 rs1044498 and fetal SLC2A2 rs6785233 (interaction OR=3.65, 95% CI: 2.32–5.74, p=2.09×10−8, q=0.001), which was confirmed in step 2 (p=0.00004). Our findings suggest that maternal metabolic genes associated with hyperglycemia and insulin resistance and fetal metabolic genes involved in glucose homeostasis may interact to increase the risk of NTDs

a report from the Children's Oncology Group and the Utah Population Database

Relatively little is known about the epidemiology and factors underlying susceptibility to childhood rhabdomyosarcoma (RMS). To better characterize genetic susceptibility to childhood RMS, we evaluated the role of family history of cancer using data from the largest case–control study of RMS and the Utah Population Database (UPDB). RMS cases (n = 322) were obtained from the Children's Oncology Group (COG). Population-based controls (n = 322) were pair-matched to cases on race, sex, and age. Conditional logistic regression was used to evaluate the association between family history of cancer and childhood RMS. The results were validated using the UPDB, from which 130 RMS cases were identified and matched to controls (n = 1300) on sex and year of birth. The results were combined to generate summary odds ratios (ORs) and 95% confidence intervals (CI). Having a first-degree relative with a cancer history was more common in RMS cases than controls (ORs = 1.39, 95% CI: 0.97–1.98). Notably, this association was stronger among those with embryonal RMS (ORs = 2.44, 95% CI: 1.54–3.86). Moreover, having a first-degree relative who was younger at diagnosis of cancer (<30 years) was associated with a greater risk of RMS (ORs = 2.37, 95% CI: 1.34–4.18). In the largest analysis of its kind, we found that most children diagnosed with RMS did not have a family history of cancer. However, our results indicate an increased risk of RMS (particularly embryonal RMS) in children who have a first-degree relative with cancer, and among those whose relatives were diagnosed with cancer at <30 years of age

Association between maternal occupational exposure to organic solvents and congenital heart defects, National Birth Defects Prevention Study, 1997–2002

To examine the relation between congenital heart defects (CHDs) in offspring and estimated maternal occupational exposure to chlorinated solvents, aromatic solvents, and Stoddard solvent during the period from one month before conception through the first trimester

Maternal occupational exposure to polycyclic aromatic hydrocarbons and risk of neural tube defect-affected pregnancies

This study evaluated whether there is an association between maternal occupational exposure to polycyclic aromatic hydrocarbons (PAHs) and neural tube defects (NTDs) in offspring. This is the first such study of which the authors are aware

Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Risk of Oral Cleft-Affected Pregnancies

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