Latent variable models for gene-environment interactions in longitudinal studies with multiple correlated exposures.

Many existing cohort studies designed to investigate health effects of environmental exposures also collect data on genetic markers. The Early Life Exposures in Mexico to Environmental Toxicants project, for instance, has been genotyping single nucleotide polymorphisms on candidate genes involved in mental and nutrient metabolism and also in potentially shared metabolic pathways with the environmental exposures. Given the longitudinal nature of these cohort studies, rich exposure and outcome data are available to address novel questions regarding gene-environment interaction (G × E). Latent variable (LV) models have been effectively used for dimension reduction, helping with multiple testing and multicollinearity issues in the presence of correlated multivariate exposures and outcomes. In this paper, we first propose a modeling strategy, based on LV models, to examine the association between repeated outcome measures (e.g., child weight) and a set of correlated exposure biomarkers (e.g., prenatal lead exposure). We then construct novel tests for G × E effects within the LV framework to examine effect modification of outcome-exposure association by genetic factors (e.g., the hemochromatosis gene). We consider two scenarios: one allowing dependence of the LV models on genes and the other assuming independence between the LV models and genes. We combine the two sets of estimates by shrinkage estimation to trade off bias and efficiency in a data-adaptive way. Using simulations, we evaluate the properties of the shrinkage estimates, and in particular, we demonstrate the need for this data-adaptive shrinkage given repeated outcome measures, exposure measures possibly repeated and time-varying gene-environment association.

Maternal MTHFR genotype and haplotype predict deficits in early cognitive development in a lead-exposed birth cohort in Mexico City.

BACKGROUND: Maternal folate nutritional status and prenatal lead exposure can influence fetal development and subsequent health. The methylenetetrahydrofolate reductase (MTHFR) gene is important for folate metabolism, and 2 common polymorphisms, C677T and A1298C, reduce enzymatic activity; C677T is present at high penetrance in Mexican populations. OBJECTIVE: The objective of this study was to examine potential links between maternal and child MTHFR polymorphisms and child neurodevelopment in a lead-exposed population. DESIGN: Data regarding MTHFR polymorphisms C677T and A1298C, peri- and postnatal lead measures, and Bayley Mental Development Index at 24 mo of age (MDI-24) scores were available for 255 mother-child pairs who participated in the ELEMENT (Early Life Exposures in Mexico to Environmental Toxicants) study during 1994-1995. RESULTS: In covariate-adjusted regression models, maternal MTHFR 677 genotype predicted MDI-24 scores, in which each copy of the maternal MTHFR 677T variant allele was associated with lower MDI-24 scores (beta = -3.52; 95% CI: -6.12, -0.93; P = 0.004). Maternal MTHFR haplotype also predicted MDI-24 scores (mean +/- SE: 93.3 +/- 1.2 for 677C-1298A compared with 89.9 +/- 0.8 for 677T-1298A; P < 0.05). MDI-24 scores were not associated with maternal MTHFR 1298 genotype or child MTHFR genotypes. We did not observe significant MTHFR genotype x lead interactions with respect to any of the subject biomarkers of lead exposure. CONCLUSIONS: The maternal MTHFR 677T allele is an independent predictor of poorer child neurodevelopment at 24 mo. These results suggest that maternal genetic variations in folate metabolism during pregnancy may program offspring neurodevelopment trajectories. Further research is warranted to determine the generalizability of these results across other populations.

A polymorphism in the delta-aminolevulinic acid dehydratase gene modifies plasma/whole blood lead ratio.

Delta aminolevulinic acid dehydratase (ALAD) plays an important role in lead poisoning. This study was carried out to examine the effects of ALAD gene polymorphism (G177C) on %Pb-P(plasma lead)/Pb-B(whole blood) ratio in 142 subjects environmentally exposed to lead. Genotypes for the ALAD G177C polymorphism were determined by PCR and restriction fragment length digestion. Pb-P and Pb-B were determined by inductively coupled plasma mass spectrometry and by graphite furnace atomic absorption spectrometry, respectively. The allele frequencies for ALAD1 and ALAD2 alleles were 0.897 and 0.103, respectively. We combined both ALAD 1-2 and ALAD 2-2 genotypes together (ALAD 1-2/2-2 group) and compared with the ALAD 1-1 genotype group. While no significant differences were found in Pb-B, subjects from the ALAD 1-2/2-2 genotype group presented significantly higher Pb-P concentrations and %Pb-P/Pb-B ratios (0.89+/-0.07 microg/l, and 1.45+/-0.10%, respectively) when compared with subjects from the ALAD 1-1 genotype group (0.44+/-0.05 microg/l, and 0.48+/-0.02, respectively; both P<0.0001). The higher %Pb-P/Pb-B ratios in carriers of the ALAD-2 allele compared with noncarriers indicate that ALAD 1-2/2-2 subjects are probably at increased health risks associated with lead exposure.

Genotoxicity induced in CD-1 mice by inhaled lead: differential organ response.

Lead is perhaps the longest used and best recognized toxic environmental chemical and it is still being used recklessly. Lead (Pb) has been found to be capable of eliciting a positive response in an extraordinarily wide range of biological and biochemical tests; among them tests for enzyme inhibition, fidelity of DNA synthesis, mutation, chromosomal aberrations, cancer and birth defects. Since inhalation is one of the most important routes of environmental Pb exposure, in the present study a lead inhalation model in mice was implemented in order to detect the induction of genotoxic damage as single-strand breaks and alkali-labile sites in several mouse organs (nasal epithelial cells, lung, whole blood, liver, kidney, bone marrow, brain and testes), assessed by single cell gel electrophoresis (SCGE) or Comet assay. We found differences among the organs studied after a single and subsequent inhalations: in the organs analyzed we observed a positive induction of DNA damage after a single inhalation only in the liver and the lung. In subsequent inhalations the response was positive in all organs except the testicle, however, DNA damage induction over time was different for each organ. A correlation between length of exposure, DNA damage and metal tissue concentration was observed for lung, liver and kidney. Differences in DNA damage occurred in organs when lead acetate was administered acutely or sub-chronically. These results show that lead acetate inhalation induces systemic DNA damage but that some organs are special targets of this metal, such as lung and liver, depending in part on length of exposure, suggesting alternative organ processes to handle lead intoxication.

El saturnismo, una porfiria tóxica aguda, es una enfermedad toxogenética / The saturnism, a toxic acute porphyria, is a toxogenetic disease

Se ha determinado actividad de ALA-D eritrocitaria en familias y pacientes no vinculados con distintas porfirias, que han estado expuestos al Pb. Se ha observado que los valores de ALA-D fueron menores que los que corresponderían a la plumbemia medida. En algunos pacientes I-Pb, se encontró además una significativa disminución en la actividad de la Deaminasa, observándose una mayor predisposición a manifestaciones clínicas agudas, aun a bajos niveles de Pb. En base a estos resultados se postula que los pacientes porfíricos, en los cuales existe una deficiencia primaria específica de algunas de las enzimas del camino biosintético del hemo( con un factor de toxogeneticidad k = 5 ñ 0,5, para un k = 10 ñ 1 en individuos no porfíricos intoxicados con plomo), son mucho más sensibles a una I-Pb. En estos casos, el saturnismo podría considerarse como una enfermedad toxogenética

El saturnismo, una porfiria tóxica aguda, es una enfermedad toxogenética / The saturnism, a toxic acute porphyria, is a toxogenetic disease

Se ha determinado actividad de ALA-D eritrocitaria en familias y pacientes no vinculados con distintas porfirias, que han estado expuestos al Pb. Se ha observado que los valores de ALA-D fueron menores que los que corresponderían a la plumbemia medida. En algunos pacientes I-Pb, se encontró además una significativa disminución en la actividad de la Deaminasa, observándose una mayor predisposición a manifestaciones clínicas agudas, aun a bajos niveles de Pb. En base a estos resultados se postula que los pacientes porfíricos, en los cuales existe una deficiencia primaria específica de algunas de las enzimas del camino biosintético del hemo( con un factor de toxogeneticidad k = 5 ñ 0,5, para un k = 10 ñ 1 en individuos no porfíricos intoxicados con plomo), son mucho más sensibles a una I-Pb. En estos casos, el saturnismo podría considerarse como una enfermedad toxogenética (AU)

Population genetics in the state of Nuevo León, Mexico. II. Genetic markers, frequencies and their possible association with chromosome damage in workers exposed to lead.

In order to find out genetic variability and its possible association with chromosomic damage, we studied the ABO, Rh and MN blood groups as well as the ability to taste PTC, ear lobe type and mid-digital hair, in 77 workers exposed to lead oxides. 23 people who worked near the source of lead (internal control) and 20 people not exposed to lead (external control). From each person a blood sample was taken for chromosome analysis in cultured lymphocytes and for lead determination, at the same time an urine sample was taken for delta-aminolevulinic acid (ALA) determinations; at the same time an urine sample increased chromosome damage, blood lead levels and urinary ALA, were found as compared with both controls. Differences were statistically significant. As for genetic marker frequencies differences were found only for the Rh factor, between the internal control and both the external control and exposed workers. No significant association was found between genetic markers and chromosome damage. Association was observed between blood lead levels, and urinary ALA with some genetic markers like ABO and MN blood groups and ear lobe type.