Environmental and genetic risk factors and gene-environment interactions in the pathogenesis of chronic obstructive lung disease.

Current understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD), a source of substantial morbidity and mortality in the United States, suggests that chronic inflammation leads to the airways obstruction and parenchymal destruction that characterize this condition. Environmental factors, especially tobacco smoke exposure, are known to accelerate longitudinal decline of lung function, and there is substantial evidence that upregulation of inflammatory pathways plays a vital role in this process. Genetic regulation of both inflammatory responses and anti-inflammatory protective mechanisms likely underlies the heritability of COPD observed in family studies. In alpha-1 protease inhibitor deficiency, the only genetic disorder known to cause COPD, lack of inhibition of elastase activity, results in the parenchymal destruction of emphysema. Other genetic polymorphisms have been hypothesized to alter the risk of COPD but have not been established as causes of this condition. It is likely that multiple genetic factors interacting with each other and with a number of environmental agents will be found to result in the development of COPD

Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COPD

BACKGROUND: Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes. METHODS: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity). RESULTS: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV1 (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar. CONCLUSIONS: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis.

BACKGROUND: Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers. METHODS: We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation. RESULTS: From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies. CONCLUSIONS: Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR

A chromosome-level Amaranthus cruentus genome assembly highlights gene family evolution and biosynthetic gene clusters that may underpin the nutritional value of this traditional crop

Traditional crops historically provided accessible and affordable nutrition to millions of rural dwellers but have been neglected, with most modern agricultural systems over reliant on a small number of internationally-traded crops. Traditional crops are typically well-adapted to local agro-ecological conditions and many are nutrient-dense. They can play a vital role in local food systems through enhanced nutrition (especially where diets are dominated by starch crops), food security and livelihoods for smallholder farmers, and a climate-resilient and biodiverse agriculture. Using short-read, long-read and phased sequencing technologies we generated a high-quality chromosome-level genome assembly for Amaranthus cruentus, an under-researched crop with micronutrient- and protein-rich leaves and gluten-free seed, but lacking improved varieties, with respect to productivity and quality traits. The 370.9 MB genome demonstrates a shared whole genome duplication with a related species, Amaranthus hypochondriacus. Comparative genome analysis indicates chromosomal loss and fusion events following genome duplication that are common to both species, as well as fission of chromosome 2 in A. cruentus alone, giving rise to a haploid chromosome number of 17 (versus 16 in A. hypochondriacus). Genomic features potentially underlying the nutritional value of this crop include two A. cruentus-specific genes with a likely role in phytic acid synthesis (an anti-nutrient), expansion of ion transporter gene families, and identification of biosynthetic gene clusters conserved within the amaranth lineage. The A. cruentus genome assembly will underpin much-needed research and global breeding efforts to develop improved varieties for economically viable cultivation and realisation of the benefits to global nutrition security and agrobiodiversity