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It is believed that genetic factors play a large role in the development of many cognitive and neurological processes; however, epidemiological evidence for the genetic basis of childhood neurodevelopment is very limited. Identification of the genetic polymorphisms associated with early-stage neurodevelopment will help elucidate biological mechanisms involved in neuro-behavior and provide a better understanding of the developing brain. To search for such variants, we performed a genome-wide association study (GWAS) for infant mental and motor ability at two years of age with mothers and children recruited from cohorts in Bangladesh and Mexico. Infant ability was assessed using mental and motor composite scores calculated with country-specific versions of the Bayley Scales of Infant Development. A missense variant (rs1055153) located in the gene WWTR1 reached genome-wide significance in association with mental composite score (meta-analysis effect size of minor allele ßmeta = -6.04; 95% CI: -8.13 to -3.94; P = 1.56×10-8). Infants carrying the minor allele reported substantially lower cognitive scores in both cohorts, and this variant is predicted to be in the top 0.3% of most deleterious substitutions in the human genome. Fine mapping and region-based association testing provided additional suggestive evidence that both WWTR1 and a second gene, LRP1B, were associated with infant cognitive ability. Comparisons with recently conducted GWAS in intelligence and educational attainment indicate that our phenotypes do not possess a high genetic correlation with either adolescent or adult cognitive traits, suggesting that infant neurological assessments should be treated as an independent outcome of interest. Additional functional studies and replication efforts in other cohorts may help uncover new biological pathways and genetic architectures that are crucial to the developing brain.

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Several homeobox-related gene (HOX) transcription factors such as mesenchyme HOX-2 (MEOX2) have previously been associated with cancer drug resistance, malignant progression and/or clinical prognostic responses in lung cancer patients; however, the mechanisms involved in these responses have yet to be elucidated. Here, an epigenomic strategy was implemented to identify novel MEOX2 gene promoter transcription targets and propose a new molecular mechanism underlying lung cancer drug resistance and poor clinical prognosis. Chromatin immunoprecipitation (ChIP) assays derived from non-small cell lung carcinomas (NSCLC) hybridized on gene promoter tiling arrays and bioinformatics analyses were performed, and quantitative, functional and clinical validation were also carried out. We statistically identified a common profile consisting of 78 gene promoter targets, including Hedgehog-GLI1 gene promoter sequences (FDR≤0.1 and FDR≤0.2). The GLI-1 gene promoter region from -2,192 to -109 was occupied by MEOX2, accompanied by transcriptionally active RNA Pol II and was epigenetically linked to the active histones H3K27Ac and H3K4me3; these associations were quantitatively validated. Moreover, siRNA genetic silencing assays identified a MEOX2-GLI1 axis involved in cellular cytotoxic resistance to cisplatinum in a dose-dependent manner, as well as cellular migration and proliferation. Finally, Kaplan-Maier survival analyses identified significant MEOX2-dependent GLI-1 protein expression associated with clinical progression and poorer overall survival using an independent cohort of NSCLC patients undergoing platinum-based oncological therapy with both epidermal growth factor receptor (EGFR)-non-mutated and EGFR-mutated status. In conclusion, this is the first study to investigate epigenome-wide MEOX2-transcription factor occupation identifying a novel overexpressed MEOX2-GLI1 axis and its clinical association with platinum-based cancer drug resistance and EGFR-tyrosine kinase inhibitor (TKI)-based therapy responses in NSCLC patients.

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BACKGROUND: Neurodevelopment is a complex process involving both genetic and environmental factors. Prenatal exposure to lead (Pb) has been associated with lower performance on neurodevelopmental tests. Adverse neurodevelopmental outcomes are more frequent and/or more severe when toxic exposures interact with genetic susceptibility. METHODS: To explore possible loci associated with increased susceptibility to prenatal Pb exposure, we performed a genome-wide gene-environment interaction study (GWIS) in young children from Mexico (n = 390) and Bangladesh (n = 497). Prenatal Pb exposure was estimated by cord blood Pb concentration. Neurodevelopment was assessed using the Bayley Scales of Infant Development. RESULTS: We identified a locus on chromosome 8, containing UNC5D, and demonstrated evidence of its genome-wide significance with mental composite scores (rs9642758, p meta = 4.35 × 10-6). Within this locus, the joint effects of two independent single nucleotide polymorphisms (SNPs, rs9642758 and rs10503970) had a p-value of 4.38 × 10-9 for mental composite scores. Correlating GWIS results with in vitro transcriptomic profiles identified one common gene, SLC1A5, which is involved in synaptic function, neuronal development, and excitotoxicity. Further analysis revealed interconnected interactions that formed a large network of 52 genes enriched with oxidative stress genes and neurodevelopmental genes. CONCLUSIONS: Our findings suggest that certain genetic polymorphisms within/near genes relevant to neurodevelopment might modify the toxic effects of Pb exposure via oxidative stress.

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BACKGROUND: Tobacco workers are exposed to several respiratory occupational sensitizers. METHODS: A representative cross-sectional study was carried out on 2469 tobacco family farming growers. Gender-stratified multivariate analyses evaluated the association between wheezing and socio-demographic, behavioral, and occupational variables. RESULTS: Wheezing prevalence was 11.0% with no difference between genders. Among men, age, smoking, strenuous work, pesticide use, contact with vegetable dust and dried tobacco dust, lifting sticks with tobacco leaves to the curing barns, and green tobacco sickness (GTS) were risk factors for wheezing. Among women, family history of asthma, tying hands of tobacco, strenuous work, contact with chemical disinfectants, and GTS were positively associated with wheezing. Harvesting lower tobacco leaves was a protective factor for the outcome in both genders. CONCLUSIONS: Pesticides, dusts exposure, and GTS were risk factors for wheezing. The synergic effect of these factors needs to be better evaluated to improve prevention.

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Two central challenges in the field of occupational and environmental epidemiology include accurately measuring biologic responses to exposure and preventing subsequent disease. As exposure-related lung diseases continue to be identified, advances in exposure biology have introduced toxicogenomic approaches that detect biomarkers of exposure at the gene, protein, and metabolite levels. Moreover, genetic epidemiology research has focused more recently on common, low-penetrant (ie, low-relative-risk) genetic variants that may interact with commonly encountered exposures. A number of such gene by environment interactions have been identified for airways and interstitial lung diseases, with the goal of preventing disease among susceptible populations that may not otherwise have been identified. Exhaled breath condensate analysis has provided another noninvasive means of assessing toxicant exposures and systemic effects. As these technologies become more refined, clinicians and public health practitioners will need to appreciate the social implications of the individual- and population-level risks conferred by certain genetic polymorphisms or by biomarker evidence of exposure. At present, the primary approach to occupational and environmental lung disease prevention remains elimination or reduction of known hazardous exposures and requires continued application of local and international resources toward exposure control.

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BACKGROUND: Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism. METHODS: Archived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: HFE [hemochromatosis], TF [transferrin], and ALAD [δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data. RESULTS: Percentage of participants carrying at least one copy of HFE C282Y, HFE H63D, TF P570S, and ALAD K59N variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either C282Y or H63D allele in HFE gene was 19.6%. Geometric mean (geometric standard deviation) manganese concentrations were 17.0 (1.5) µg/l. Women with any HFE variant allele had 12% lower blood manganese concentrations than women with no variant alleles (ß = -0.12 [95% CI = -0.23 to -0.01]). TF and ALAD variants were not significant predictors of blood manganese. In animal models, Hfe(-/-) mice displayed a significant reduction in blood manganese compared with Hfe(+/+) mice, replicating the altered manganese metabolism found in our human research. CONCLUSIONS: Our study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements.

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OBJECTIVES: [corrected] This article describes the prevalence of musculoskeletal pain in several anatomic sites in children and teens, and investigates, while adjusting for potential confounders, the association between musculoskeletal pain and back pain and the following: age, gender, sports practice, use of computer/video games/television, school attendance, intensity of involvement in household domestic activities, care of other children, care of sick/elderly family members, work activities, and workloads. METHODS: We conducted a cross-sectional study interviewing 3,269 children aged 10-17 years in the low-income areas of Pelotas, Brazil. RESULTS: The prevalence of pain in the neck, knee, wrist or hands, and upper back exceeded 15%. Workers in manufacturing had a significantly increased risk for musculoskeletal pain (prevalence ratio [PR]=1.31) and for back pain (PR=1.69), while workers in domestic service had 17% more musculoskeletal pain and 23% more back pain than nonworkers. Awkward posture (PR=1.15) and heavy physical work (PR=1.07) were associated with musculoskeletal pain, while monotonous work (PR=1.34), awkward posture (PR=1.31), and noise (PR=1.25) were associated with back pain. CONCLUSIONS: Musculoskeletal pain is common among working children and teens. Knowledge of occupational risk factors can support actions to restructure work conditions to reduce or eliminate childhood exposure to hazardous conditions. Our results suggest that strategies to prevent musculoskeletal disorders in child workers should be developed.

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