Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P <9.57x10(-8)). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57x10(-8) <

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Pathogenesis and treatment of chronic pulmonary disease

Endothelial ENaC-α Restrains Oxidative Stress in Lung Capillaries in Murine Pneumococcal Pneumonia-associated Acute Lung Injury.

Infection of lung endothelial cells with pneumococci activates the superoxide-generating enzyme NADPH oxidase 2 (NOX2), involving the pneumococcal virulence factor pneumolysin (PLY). Excessive NOX2 activity disturbs capillary barriers, but its global inhibition can impair bactericidal phagocyte activity during pneumococcal pneumonia. Depletion of the α subunit of the epithelial sodium channel (ENaC) in pulmonary endothelial cells increases expression and PMA-induced activity of NOX2. Direct ENaC activation by TIP peptide improves capillary barrier function -measured by electrical cell substrate impedance sensing in endothelial monolayers and by Evans Blue Dye incorporation in mouse lungs- following infection with pneumococci. PLY-induced hyperpermeability in HL-MVEC monolayers is abrogated by both NOX2 inhibitor gp91dstat and TIP peptide. Endothelial NOX2 expression is assessed by increased surface membrane presence of phosphorylated p47 &lt;sup&gt;phox&lt;/sup&gt; subunit (Western blotting) in vitro and by co-localization of CD31 and gp91 &lt;sup&gt;phox&lt;/sup&gt; in mouse lung slices using DuoLink, whereas NOX2-generated superoxide is measured by chemiluminescence. TIP peptide blunts PMA-induced NOX2 activity in cells expressing ENaC-α, but not in neutrophils, which lack ENaC. Conditional endothelial ENaC-α KO (enENaC-α KO) mice develop increased capillary leak upon i.t. instillation with PLY or pneumococci, compared to wild type (wt) animals. TIP peptide diminishes capillary leak in Sp-infected wt mice, without significantly increasing lung bacterial load. Lung slices from Sp-infected enENaC-α KO mice have a significantly increased endothelial NOX2 expression, as compared to infected CRE mice. In conclusion, endothelial ENaC may represent a novel therapeutic target to reduce NOX2-mediated oxidative stress and capillary leak in ARDS, without impairing host defense

Crescimento inicial e absorção de zinco pelo milho em função do modo de aplicação e fontes do nutriente

Corn grain yield is very responsive do Zn in Brazilian soils. A greenhouse experiment was conducted in the Crop Science Department of the Botucatu College of Agricultural Sciences to compare sources of Zn and their application to corn. Three plants were grown up to 45 days in 10 L pots filled with a Dark Red Latosol (Acrortox, 22% clay). The soil was limed to 70% of base saturation. Zinc was applied to corn seeds (90 g ha-1), in the seed furrow, blended with the basal fertilizers (5.3 kg ha-1) or incorporated to the soil (5.3 kg ha-1) as zinc oxide, zinc sulphate, EDTA-Zn and lignosulphonate-Zn. The seed treatment was effective in supplying Zn during early growth of corn. The incorporation, irrespective of Zn source, as well as the chelate sources led to higher Zn availability to the plants. The corn root system was decreased when Zn availability was too high. The 5.3 kg ha-1 rate of Zn as EDTA or lignosulphonate, when applied in the seed furrow, is phytotoxic to corn plants.Freqüentemente, têm-se obtido aumentos na produção de grãos de milho em resposta ao Zn, em solos brasileiros. O objetivo do presente trabalho foi comparar fontes e modos de aplicação de Zn à cultura do milho. O experimento foi desenvolvido em casa de vegetação, em vasos de polietileno com capacidade de 10 litros, utilizando-se amostras de um Latossolo Vermelho-Escuro de textura média. Aplicou-se calcário para se atingir 70% de saturação do solo por bases. Os tratamentos consistiram da aplicação de zinco como óxido, sulfato, EDTA e lignossulfonado, na semente (90 g ha-1), no sulco de semeadura (5,3 kg ha-1) e incorporado (5,3 kg ha-1). As plantas foram colhidas 45 dias após a emergência. A aplicação de zinco via semente é eficiente no fornecimento de Zn para o crescimento das plantas até os 45 dias. A incorporação, independentemente da fonte, e o zinco aplicado como EDTA e lignossulfonado proporcionam maior disponibilidade do nutriente ao milho. O crescimento do sistema radicular é prejudicado quando há muito Zn disponível na zona de crescimento. A dose de 5,3 kg ha-1 de zinco como EDTA ou lignossulfonado, quando aplicada no sulco de semeadura, é fitotóxica ao milho.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)UNESP Faculdade de Ciências Agronômicas Departamento de Agricultura e Melhoramento VegetalUNESP Faculdade de Ciências AgronômicasUNESP Faculdade de Ciências Agronômicas Departamento de Agricultura e Melhoramento VegetalUNESP Faculdade de Ciências Agronômica

Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility