Populations are often divided categorically into distinct racial/ethnic groups based on social rather than biological constructs. Genetic ancestry has been suggested as an alternative to this categorization. Herein, we typed over 450,000 CpG sites in whole blood of 573 individuals of diverse Hispanic origin who also had high-density genotype data. We found that both self-identified ethnicity and genetically determined ancestry were each significantly associated with methylation levels at 916 and 194 CpGs, respectively, and that shared genomic ancestry accounted for a median of 75.7% (IQR 45.8% to 92%) of the variance in methylation associated with ethnicity. There was a significant enrichment (p=4.2×10-64) of ethnicity-associated sites amongst loci previously associated environmental exposures, particularly maternal smoking during pregnancy. We conclude that differential methylation between ethnic groups is partially explained by the shared genetic ancestry but that environmental factors not captured by ancestry significantly contribute to variation in methylation.DOI: http://dx.doi.org/10.7554/eLife.20532.001

Populations are often divided categorically into distinct racial/ethnic groups based on social rather than biological constructs. Genetic ancestry has been suggested as an alternative to this categorization. Herein, we typed over 450,000 CpG sites in whole blood of 573 individuals of diverse Hispanic origin who also had high-density genotype data. We found that both selfidentified ethnicity and genetically determined ancestry were each significantly associated with methylation levels at 916 and 194 CpGs, respectively, and that shared genomic ancestry accounted for a median of 75.7% (IQR 45.8% to 92%) of the variance in methylation associated with ethnicity. There was a significant enrichment (p=4.2Â10 -64 ) of ethnicity-associated sites amongst loci previously associated environmental exposures, particularly maternal smoking during pregnancy. We conclude that differential methylation between ethnic groups is partially explained by the shared genetic ancestry but that environmental factors not captured by ancestry significantly contribute to variation in methylation.

BackgroundPlasminogen activator inhibitor-1 (PAI-1) is induced in airways by virus and may mediate asthmatic airway remodeling. We sought to evaluate if genetic variants and early life lower respiratory infections jointly affect asthma risk.MethodsWe included Latino children, adolescents, and young adults aged 8–21 years (1736 subjects with physician-diagnosed asthma and 1747 healthy controls) from five U.S. centers and Puerto Rico after excluding subjects with incomplete clinical or genetic data. We evaluated the independent and joint effects of a PAI-1 gain of function polymorphism and bronchiolitis / Respiratory Syncytial Virus (RSV) or other lower respiratory infections (LRI) within the first 2 years of life on asthma risk, asthma exacerbations and lung function.ResultsRSV infection (OR 9.9, 95%CI 4.9–20.2) and other LRI (OR 9.1, 95%CI 7.2–11.5) were independently associated with asthma, but PAI-1 genotype was not. There were joint effects on asthma risk for both genotype-RSV (OR 17.7, 95% CI 6.3–50.2) and genotype-LRI (OR 11.7, 95% CI 8.8–16.4). A joint effect of genotype-RSV resulted in a 3.1-fold increased risk for recurrent asthma hospitalizations. In genotype-respiratory infection joint effect analysis, FEV1% predicted and FEV1/FVC % predicted were further reduced in the genotype-LRI group (β -2.1, 95% CI -4.0 to -0.2; β -2.0, 95% CI -3.1 to -0.8 respectively). Similarly, lower FEV1% predicted was noted in genotype-RSV group (β -3.1, 95% CI -6.1 to -0.2) with a trend for lower FEV1/FVC % predicted.ConclusionsA genetic variant of PAI-1 together with early life LRI such as RSV bronchiolitis is associated with an increased risk of asthma, morbidity, and reduced lung function in this Latino population.

BACKGROUND:The pathogenesis of BPD includes inflammation and oxidative stress in the immature lung. Corticosteroids improve respiratory status and outcome, but the optimal treatment regimen for benefit with low systemic effects is uncertain. METHODS: In a pilot dose escalation trial, we administered ≤5 daily doses of budesonide in surfactant to 24 intubated premature infants (Steroid And Surfactant in ELGANs (SASSIE)). Untargeted metabolomics was performed on dried blood spots using UPLC-MS/MS. Tracheal aspirate IL-8 concentration was determined as a measure of lung inflammation. RESULTS: Metabolomics data for 829 biochemicals were obtained on 121 blood samples over 96 h from 23 infants receiving 0.025, 0.05, or 0.1 mg budesonide/kg. Ninety metabolites were increased or decreased in a time-and dose-dependent manner at q ≤ 0.1 with overrepresentation in lipid and amino acid super pathways. Different dose response patterns occurred, with negative regulation associated with highest sensitivity to budesonide. Baseline levels of 22 regulated biochemicals correlated with lung inflammation (IL-8), with highest significance for sphingosine and thiamin. CONCLUSIONS: Numerous metabolic pathways are regulated in a dose-dependent manner by glucocorticoids, which apparently act via distinct mechanisms that impact dose sensitivity. The findings identify candidate blood biochemicals as biomarkers of lung inflammation and systemic responses to corticosteroids.

RATIONALE: Group 2 innate lymphoid cells (ILC2), a major source of type 2 cytokines (IL-5 and IL-13), facilitate eosinophilic inflammatory responses in murine asthma models in the absence of CD4+ T lymphocytes. Localized activation of ILC2 is associated with uncontrolled airway eosinophilia in prednisone-dependent severe asthmatics. This study investigated the role of ILC2 in the development of eosinophilia in allergic asthma. METHODS: In a diluent-controlled allergen (Ag)-challenge cross-over study, ILC2s (lin-FcεRI-CD45+CD127+ST2+CRTH2+), CD4+ T lymphocytes, and levels of intracellular IL-5 and IL-13 expression were enumerated by flow cytometry in steroid-naive mild atopic asthmatics. All subjects (n57) developed Ag-induced dual bronchoconstriction, airway eosinophilia and increased methacholine airway responsiveness. Bone marrow, blood and sputum samples were collected pre-, 24 and 48h postchallenge and immediately fixed in 1% paraformaldehyde prior to immunofluorescence staining. RESULTS: Compared to pre-Ag levels, there was a significant increase in sputum ILC2 at 24h (P<0.01) which decreased to baseline levels 48h post-Ag. This was co-incident with a significant decrease in blood and bone marrow ILC2 at 24h post-Ag compared to pre-Ag levels. Activated ILC2 (IL5+ or IL13+) in sputum increased significantly at 24 h post-Ag only. In contrast, although total CD4+ T lymphocytes and IL-13+CD4+ T cells increased at 24h post-Ag (P<0.01), IL-5+CD4+ T cells only showed a trend for an increase at 48h post-Ag. No effect of diluent was observed. CONCLUSIONS: Our findings suggest that post-allergen exposure in mild atopic asthmatics, ILC2 may initiate the development of eosinophilic inflammation while CD4+ T lymphocytes may be involved in the persistence of the asthmatic response.