Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma

Investing in Threatened Species Conservation: Does Corruption Outweigh Purchasing Power?

In many sectors, freedom in capital flow has allowed optimization of investment returns through choosing sites that provide the best value for money. These returns, however, can be compromised in countries where corruption is prevalent. We assessed where the best value for money might be obtained for investment in threatened species that occur at a single site, when taking into account corruption. We found that the influence of corruption on potential investment decisions was outweighed by the likely value for money in terms of pricing parity. Nevertheless global conservation is likely to get best returns in terms of threatened species security by investing in “honest” countries than in corrupt ones, particularly those with a high cost of living

Inducible expression quantitative trait locus analysis of the MUC5AC gene in asthma in urban populations of children

BACKGROUND: Mucus plugging can worsen asthma control, lead to reduced lung function and fatal exacerbations. MUC5AC is the secretory mucin implicated in mucus plugging, and MUC5AC gene expression has been associated with development of airway obstruction and asthma exacerbations in urban children with asthma. However, the genetic determinants of MUC5AC expression are not established. OBJECTIVE: To assess single-nucleotide polymorphisms (SNPs) that influence MUC5AC expression and relate to pulmonary functions in childhood asthma. METHODS: We used RNA-sequencing data from upper airway samples and performed cis-expression quantitative trait loci (eQTL) and allele specific expression (ASE) analyses in two cohorts of predominantly Black and Hispanic urban children, a high asthma-risk birth cohort and an exacerbation-prone asthma cohort. We further investigated inducible MUC5AC eQTLs during incipient asthma exacerbations. We tested significant eQTLs SNPs for associations with lung function measurements and investigated their functional consequences in DNA regulatory databases. RESULTS: We identified two independent groups of SNPs in the MUC5AC gene that were significantly associated with MUC5AC expression. Moreover, these SNPs showed stronger eQTL associations with MUC5AC expression during asthma exacerbations, consistent with inducible expression. SNPs in one group also showed significant association with decreased pulmonary functions. These SNPs included multiple EGR1 transcription factor binding sites suggesting a mechanism of effect. CONCLUSIONS: These findings demonstrate the applicability of organ specific RNA-sequencing data to determine genetic factors contributing to a key disease pathway. Specifically, they suggest important genetic variations that may underlie propensity to mucus plugging in asthma and could be important in targeted asthma phenotyping and disease management strategies

Angiotensin II for the Treatment of Vasodilatory Shock

BACKGROUND Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. METHODS We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 mu g of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. RESULTS A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P = 0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P = 0.12). CONCLUSIONS Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT02338843.)Peer reviewe

African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

BACKGROUND: Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. METHODS: We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American-specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. RESULTS: Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. CONCLUSIONS: Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases

The Urban Environment and Childhood Asthma (URECA) birth cohort study: design, methods, and study population

<p>Abstract</p> <p>Background</p> <p>The incidence and morbidity of wheezing illnesses and childhood asthma is especially high in poor urban areas. This paper describes the study design, methods, and population of the Urban Environment and Childhood Asthma (URECA) study, which was established to investigate the immunologic causes of asthma among inner-city children.</p> <p>Methods and Results</p> <p>URECA is an observational prospective study that enrolled pregnant women in central urban areas of Baltimore, Boston, New York City, and St. Louis and is following their offspring from birth through age 7 years. The birth cohort consists of 560 inner-city children who have at least one parent with an allergic disease or asthma, and all families live in areas in which at least 20% of the population has incomes below the poverty line. In addition, 49 inner-city children with no parental history of allergies or asthma were enrolled. The primary hypothesis is that specific urban exposures in early life promote a unique pattern of immune development (impaired antiviral and increased Th2 responses) that increases the risk of recurrent wheezing and allergic sensitization in early childhood, and of asthma by age 7 years. To track immune development, cytokine responses of blood mononuclear cells stimulated <it>ex vivo </it>are measured at birth and then annually. Environmental assessments include allergen and endotoxin levels in house dust, pre- and postnatal maternal stress, and indoor air nicotine and nitrogen dioxide. Nasal mucous samples are collected from the children during respiratory illnesses and analyzed for respiratory viruses. The complex interactions between environmental exposures and immune development will be assessed with respect to recurrent wheeze at age 3 years and asthma at age 7 years.</p> <p>Conclusion</p> <p>The overall goal of the URECA study is to develop a better understanding of how specific urban exposures affect immune development to promote wheezing illnesses and asthma.</p