Analyses of association between PPAR gamma and EPHX1 polymorphisms and susceptibility to COPD in a Hungarian cohort, a case-control study

<p>Abstract</p> <p>Background</p> <p>In addition to smoking, genetic predisposition is believed to play a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Genetic association studies of new candidate genes in COPD may lead to improved understanding of the pathogenesis of the disease.</p> <p>Methods</p> <p>Two proposed casual single nucleotide polymorphisms (SNP) <it>(rs1051740, rs2234922) </it>in microsomal epoxide hydrolase (<it>EPHX1</it>) and three SNPs <it>(rs1801282, rs1800571, rs3856806) </it>in peroxisome proliferator-activated receptor gamma (<it>PPARG</it>), a new candidate gene, were genotyped in a case-control study (272 COPD patients and 301 controls subjects) in Hungary. Allele frequencies and genotype distributions were compared between the two cohorts and trend test was also used to evaluate association between SNPs and COPD. To estimate the strength of association, odds ratios (OR) (with 95% CI) were calculated and potential confounding variables were tested in logistic regression analysis. Association between haplotypes and COPD outcome was also assessed.</p> <p>Results</p> <p>The distribution of imputed <it>EPHX1 </it>phenotypes was significantly different between the COPD and the control group (P = 0.041), OR for the slow activity phenotype was 1.639 (95% CI = 1.08- 2.49; P = 0.021) in our study. In logistic regression analysis adjusted for both variants, also age and pack-year, the rare allele of His447His of <it>PPARG </it>showed significant association with COPD outcome (OR = 1.853, 95% CI = 1.09-3.14, P = 0.0218). In haplotype analysis the GC haplotype of <it>PPARG </it>(OR = 0.512, 95% CI = 0.27-0.96, P = 0.035) conferred reduced risk for COPD.</p> <p>Conclusions</p> <p>The "slow" activity-associated genotypes of <it>EPHX1 </it>were associated with increased risk of COPD. The minor His447His allele of <it>PPARG </it>significantly increased; and the haplotype containing the minor Pro12Ala and the major His447His polymorphisms of <it>PPARG </it>decreased the risk of COPD.</p

Ages for exoplanet host stars

Age is an important characteristic of a planetary system, but also one that is difficult to determine. Assuming that the host star and the planets are formed at the same time, the challenge is to determine the stellar age. Asteroseismology provides precise age determination, but in many cases the required detailed pulsation observations are not available. Here we concentrate on other techniques, which may have broader applicability but also serious limitations. Further development of this area requires improvements in our understanding of the evolution of stars and their age-dependent characteristics, combined with observations that allow reliable calibration of the various techniques.Comment: To appear in "Handbook of Exoplanets", eds. Deeg, H.J. & Belmonte, J.A, Springer (2018

Parental Smoking Modifies the Relation between Genetic Variation in Tumor Necrosis Factor-α (TNF) and Childhood Asthma

BACKGROUND: Polymorphisms in the proinflammatory cytokine genes tumor necrosis factor-α (TNF) and lymphotoxin-α (LTA, also called TNF-β) have been associated with asthma and atopy in some studies. Parental smoking is a consistent risk factor for childhood asthma. Secondhand smoke and ozone both stimulate TNF production. OBJECTIVES: Our goal was to investigate whether genetic variation in TNF and LTA is associated with asthma and atopy and whether the association is modified by parental smoking in a Mexican population with high ozone exposure. METHODS: We genotyped six tagging single nucleotide polymorphisms (SNPs) in TNF and LTA, including functional variants, in 596 nuclear families consisting of asthmatics 4–17 years of age and their parents in Mexico City. Atopy was determined by skin prick tests. RESULTS: The A allele of the TNF-308 SNP was associated with increased risk of asthma [relative risk (RR) = 1.54; 95% confidence interval (CI), 1.04–2.28], especially among children of non-smoking parents (RR = 2.06; 95% CI, 1.19–3.55; p for interaction = 0.09). Similarly, the A allele of the TNF-238 SNP was associated with increased asthma risk among children of nonsmoking parents (RR = 2.21; 95% CI, 1.14–4.30; p for interaction = 0.01). LTA SNPs were not associated with asthma. Haplotype analyses reflected the single SNP findings in magnitude and direction. TNF and LTA SNPs were not associated with the degree of atopy. CONCLUSIONS: Our results suggest that genetic variation in TNF may contribute to childhood asthma and that associations may be modified by parental smoking

Limits of effective nutrient management in dairy farming: analyses of experimental farm De Marke

Key words: nutrient management, dairy, prototyping, organic matter, soil fertility, nitrogen, phosphor. Intensive dairy production in the Netherlands is associated with high farm nutrient (N and P) inputs and high losses to the environment. The Dutch government and the dairy sector stimulate farmers to reduce losses through more efficient use of N and P inputs on their farms. This study explores for a dairy farm on dry sandy soil with average Dutch production intensity (12,000 kg milk per ha) the possibilities to meet strict environmental standards related to N and P by maximizing N and P use efficiency at the level of the farm and of the soil. Moreover, the study addresses the effects of efficient nutrient management on soil fertility. The research was conducted on experimental dairy farm De Marke, that is designed to meet strict environmental standards, implemented in practice in 1989 and modified continuously to meet its targets by prototyping, i.e. a cyclic procedure of designing, implementing, testing and evaluating measures. The thesis evaluates system development since 2000, while results from 1993-1999 were used to analyse long-term developments. After implementation of the farming system in 1989, the nitrate concentration in groundwater ‘stabilized’ at a level exceeding the environmental standard: 55 mg l-1. Causes of excessive nitrate leaching were examined by relating measured nitrate concentrations to management. Grazing was associated with higher leaching in spite of careful management with rotational grazing. Leaching under permanent grassland was similar to the overall leaching in crop rotations in which grass was alternated with maize and grains. Spatial and temporal patterns of soil N mineralization were explored to improve the synchronization of N application and crop N requirements. This study indicated that fertilizing a 1st year maize crop, following grassland, is not necessary. Measures implemented since 2000 to improve nutrient efficiency, included reduced grazing, adoption of anaerobic digestion, application of manure in the rows of maize, growing spring barley as the last crop in the arable phase, and, since 2004, the abolishment of fertilizer N. These measures contributed to an increase in the manure-N utilization and to an increase in the farm-N use efficiency up to 2008 to values exceeding the value of 33% that was realized in the period 1993-1999. Farm-N use efficiency was 35% in 2000-2003, 43% in 2004-2008 and 37% in 2009-2010. Farm-P use efficiency also increased as compared to the 87% that was realized in 1993-1999, i.e., it was 103% in 2000-2003 and 91% in 2004-2008. In 2009-2010, however, the farm-P use efficiency decreased to 69%, lower than the value realized in 1993-1999. The lower N and P use efficiency in 2009-2010 can be attributed to the lower N and P yields in grassland as a delayed effect of N limitation resulting from the abolishment of fertilizer N in grassland since 2004. Hence, despite the increase in manure-N utilization, mineral-N use is not yet completely redundant. P-equilibrium fertilization seems to be compatible with highly efficient crop production, in the short and in the long term. Soil organic matter (SOM) percentage in the upper topsoil decreased by 0.03 yr-1 (average across all land uses) at a constant rate over the last 20 years. The possibilities to stop this decline by higher organic matter inputs to the soil seem conflicting with efficient nutrient use. Hence, the long term dynamics of SOM may become critical for future farm performance. It was concluded that N and P use efficiency can be enhanced substantially by on-farm nutrient management, but that efficient nutrient management may conflict with maintenance of SOM.</p

Prolastin, a pharmaceutical preparation of purified human α1-antitrypsin, blocks endotoxin-mediated cytokine release

BACKGROUND: α1-antitrypsin (AAT) serves primarily as an inhibitor of the elastin degrading proteases, neutrophil elastase and proteinase 3. There is ample clinical evidence that inherited severe AAT deficiency predisposes to chronic obstructive pulmonary disease. Augmentation therapy for AAT deficiency has been available for many years, but to date no sufficient data exist to demonstrate its efficacy. There is increasing evidence that AAT is able to exert effects other than protease inhibition. We investigated whether Prolastin, a preparation of purified pooled human AAT used for augmentation therapy, exhibits anti-bacterial effects. METHODS: Human monocytes and neutrophils were isolated from buffy coats or whole peripheral blood by the Ficoll-Hypaque procedure. Cells were stimulated with lipopolysaccharide (LPS) or zymosan, either alone or in combination with Prolastin, native AAT or polymerised AAT for 18 h, and analysed to determine the release of TNFα, IL-1β and IL-8. At 2-week intervals, seven subjects were submitted to a nasal challenge with sterile saline, LPS (25 μg) and LPS-Prolastin combination. The concentration of IL-8 was analysed in nasal lavages performed before, and 2, 6 and 24 h after the challenge. RESULTS: In vitro, Prolastin showed a concentration-dependent (0.5 to 16 mg/ml) inhibition of endotoxin-stimulated TNFα and IL-1β release from monocytes and IL-8 release from neutrophils. At 8 and 16 mg/ml the inhibitory effects of Prolastin appeared to be maximal for neutrophil IL-8 release (5.3-fold, p < 0.001 compared to zymosan treated cells) and monocyte TNFα and IL-1β release (10.7- and 7.3-fold, p < 0.001, respectively, compared to LPS treated cells). Furthermore, Prolastin (2.5 mg per nostril) significantly inhibited nasal IL-8 release in response to pure LPS challenge. CONCLUSION: Our data demonstrate for the first time that Prolastin inhibits bacterial endotoxin-induced pro-inflammatory responses in vitro and in vivo, and provide scientific bases to explore new Prolastin-based therapies for individuals with inherited AAT deficiency, but also for other clinical conditions

Inadequate glucose control in type 2 diabetes is associated with impaired lung function and systemic inflammation: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Inadequate glucose control may be simultaneously associated with inflammation and decreased lung function in type 2 diabetes. We evaluated if lung function is worse in patients with inadequate glucose control, and if inflammatory markers are simultaneously increased in these subjects.</p> <p>Methods</p> <p>Subjects were selected at the Colombian Diabetes Association Center in Bogotá. Pulmonary function tests were performed and mean residual values were obtained for forced expiratory volume (FEV₁₎, forced vital capacity (FVC) and FEV₁/FVC, with predicted values based on those derived by Hankinson et al. for Mexican-Americans. Multiple least-squares regression was used to adjust for differences in known determinants of lung function. We measured blood levels of glycosylated hemoglobin (HBA_1c), interleukin 6 (IL-6), tumor necrosis factor (TNF-α), fibrinogen, ferritin, and C-reactive protein (C-RP).</p> <p>Results</p> <p>495 diabetic patients were studied, out of which 352 had inadequate control (HBA_1c> 7%). After adjusting for known determinants of lung function, those with inadequate control had lower FEV₁(-75.4 mL, IC95%: -92, -59; P < 0.0001) and FVC (-121 mL, IC95%: -134, -108; P < 0,0001) mean residuals, and higher FEV₁/FVC (0.013%, IC95%: 0.009, 0.018, P < 0.0001) residuals than those with adequate control, as well as increased levels of all inflammatory markers (P < 0.05), with the exception of IL-6.</p> <p>Conclusions</p> <p>Subjects with type 2 diabetes and inadequate control had lower FVC and FEV₁than predicted and than those of subjects with adequate control. It is postulated that poorer pulmonary function may be associated with increased levels of inflammatory mediators.</p

Differences in Candidate Gene Association between European Ancestry and African American Asthmatic Children

Candidate gene case-control studies have identified several single nucleotide polymorphisms (SNPs) that are associated with asthma susceptibility. Most of these studies have been restricted to evaluations of specific SNPs within a single gene and within populations from European ancestry. Recently, there is increasing interest in understanding racial differences in genetic risk associated with childhood asthma. Our aim was to compare association patterns of asthma candidate genes between children of European and African ancestry.Using a custom-designed Illumina SNP array, we genotyped 1,485 children within the Greater Cincinnati Pediatric Clinic Repository and Cincinnati Genomic Control Cohort for 259 SNPs in 28 genes and evaluated their associations with asthma. We identified 14 SNPs located in 6 genes that were significantly associated (p-values <0.05) with childhood asthma in African Americans. Among Caucasians, 13 SNPs in 5 genes were associated with childhood asthma. Two SNPs in IL4 were associated with asthma in both races (p-values <0.05). Gene-gene interaction studies identified race specific sets of genes that best discriminate between asthmatic children and non-allergic controls.We identified IL4 as having a role in asthma susceptibility in both African American and Caucasian children. However, while IL4 SNPs were associated with asthma in asthmatic children with European and African ancestry, the relative contributions of the most replicated asthma-associated SNPs varied by ancestry. These data provides valuable insights into the pathways that may predispose to asthma in individuals with European vs. African ancestry

Association of the TLR4 Asp299Gly polymorphism with lung function in relation to body mass index

<p>Abstract</p> <p>Background</p> <p>Previous studies have shown conflicting results for the association between TLR4 polymorphism (Asp299Gly) and lung function. We investigated the influence of TLR4 Asp299Gly, a polymorphism, on lung function in a community population.</p> <p>Methods</p> <p>In 2003, a cross-sectional survey was conducted to assess the respiratory health of residents living in and around the town of Humboldt, Saskatchewan, Canada. There were 2090 adults age 18-79 years who completed a questionnaire that included a medical and smoking history, as well as socio-economic and lifestyle variables. Genetic information and lung function test measurements were available on 1725 subjects (754 males and 971 females) of the 2090 respondents. These subjects were selected for further analysis to investigate the association between TLR4 Asp299Gly genotype and forced expiratory volume in the first second in liters (FEV₁), forced vital capacity in liters (FVC), FEV₁/FVC ratio, and forced expiratory flow rate in liters/second (FEF_25-75). Multivariable linear regression analysis was used to investigate associations.</p> <p>Results</p> <p><b>A</b>djusted mean values of FEV₁and FVC were significantly different between TLR4 wild type and TLR4 variant groups [Mean ± S.E.: (TLR4 wild type - FEV₁: 3.18 ± 0.02, FVC: 3.95 ± 0.03; TLR4 variant - FEV₁: 3.31 ± 0.06, FVC: 4.14 ± 0.07)]. Based on multivariable regression analysis, we observed that body mass index (BMI) was associated with decreased FEV₁/FVC ratio and FEF_25-75in TLR4 variant group but not in wild type group.</p> <p>Conclusion</p> <p>BMI may modify the associations of TLR4 Asp299Gly polymorphism with FEV₁/FVC ratio and FEF_25-75.</p

Xenobiotic metabolizing enzyme gene polymorphisms predict response to lung volume reduction surgery

<p>Abstract</p> <p>Background</p> <p>In the National Emphysema Treatment Trial (NETT), marked variability in response to lung volume reduction surgery (LVRS) was observed. We sought to identify genetic differences which may explain some of this variability.</p> <p>Methods</p> <p>In 203 subjects from the NETT Genetics Ancillary Study, four outcome measures were used to define response to LVRS at six months: modified BODE index, post-bronchodilator FEV₁, maximum work achieved on a cardiopulmonary exercise test, and University of California, San Diego shortness of breath questionnaire. Sixty-four single nucleotide polymorphisms (SNPs) were genotyped in five genes previously shown to be associated with chronic obstructive pulmonary disease susceptibility, exercise capacity, or emphysema distribution.</p> <p>Results</p> <p>A SNP upstream from glutathione S-transferase pi (<it>GSTP1</it>; p = 0.003) and a coding SNP in microsomal epoxide hydrolase (<it>EPHX1</it>; p = 0.02) were each associated with change in BODE score. These effects appeared to be strongest in patients in the non-upper lobe predominant, low exercise subgroup. A promoter SNP in <it>EPHX1 </it>was associated with change in BODE score (p = 0.008), with the strongest effects in patients with upper lobe predominant emphysema and low exercise capacity. One additional SNP in <it>GSTP1 </it>and three additional SNPs in <it>EPHX1 </it>were associated (p < 0.05) with additional LVRS outcomes. None of these SNP effects were seen in 166 patients randomized to medical therapy.</p> <p>Conclusion</p> <p>Genetic variants in <it>GSTP1 </it>and <it>EPHX1</it>, two genes encoding xenobiotic metabolizing enzymes, were predictive of response to LVRS. These polymorphisms may identify patients most likely to benefit from LVRS.</p

Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up. © 2012 Nature America, Inc. All rights reserved