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Asthma is a chronic lung disease that has a high prevalence. The therapeutic intervention of this disease can be made more effective if genetic variability in patients' response to medications is implemented. However, a clear picture of the genetic architecture of asthma intervention response remains elusive. We conducted a genome-wide association study (GWAS) to identify drug response-associated genes for asthma, in which 909 622 SNPs were genotyped for 120 randomized participants who inhaled multiple doses of glucocorticoids. By integrating pharmacodynamic properties of drug reactions, we implemented a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention. Our pharmacodynamic model observed associations of genome-wide significance between dose-dependent response to inhaled glucocorticoids (measured as %FEV1) and five loci (P=5.315 × 10(-7) to 3.924 × 10(-9)), many of which map to metabolic genes related to lung function and asthma risk. All significant SNPs detected indicate a recessive effect, at which the homozygotes for the mutant alleles drive variability in %FEV1. Significant associations were well replicated in three additional independent GWAS studies. Pooled together over these three trials, two SNPs, chr6 rs6924808 and chr11 rs1353649, display an increased significance level (P=6.661 × 10(-16) and 5.670 × 10(-11)). Our study reveals a general picture of pharmacogenomic control for asthma intervention. The results obtained help to tailor an optimal dose for individual patients to treat asthma based on their genetic makeup.

Abstract: Multi‐species approaches provide valuable insight for conservation planning, yet most studies focus on only one species while generalizing across taxa. Here, we employed 5–14 microsatellite DNA loci to evaluate population genetic patterns and future vulnerability for a freshwater turtle assemblage distributed across north‐eastern Illinois. Focal species (Emydoidea blandingii, Clemmys guttata, Chrysemys picta and Chelydra serpentina) differ in conservation status as well as in ecological and life‐history traits, which modulate gene flow across heterogeneous landscapes. We hypothesized (1) common and more ubiquitous species (C. picta and C. serpentina) would exhibit higher levels of genetic connectivity compared to species more restricted in distributions and with an elevated conservation status (E. blandingii and C. guttata) and (2) endangered species exhibit a greater loss of future genetic diversity. We found that genetic patterns varied considerably among co‐distributed species. Endangered species had lower levels of genetic diversity and gene flow, more pronounced genetic structure and a higher risk of genetic drift compared to common species, thus supporting our hypotheses. The observed patterns are potentially attributable to life‐history and ecological traits and will affect the long‐term viability of the four species within a modified north‐eastern Illinois landscape. Our study is an important first step for understanding how landscape features and species‐specific traits interact to affect gene flow and population genetic structure within altered landscapes. It also underscores how multi‐species approaches can be informative for conservation actions. [ABSTRACT FROM AUTHOR]

Background: Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking.Methods: In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial.Results: Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events.Conclusions: Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.). [ABSTRACT FROM AUTHOR]

Rationale: To date, most studies aimed at discovering genetic factors influencing treatment response in asthma have focused on biologic candidate genes. Genome-wide association studies (GWAS) can rapidly identify novel pharmacogenetic loci.Objectives: To investigate if GWAS can identify novel pharmacogenetic loci in asthma.Methods: Using phenotypic and GWAS genotype data available through the NHLBI-funded Single-nucleotide polymorphism Health association-Asthma Resource Project, we analyzed differences in FEV(1) in response to inhaled corticosteroids in 418 white subjects with asthma. Of the 444,088 single nucleotide polymorphisms (SNPs) analyzed, the lowest 50 SNPs by P value were genotyped in an independent clinical trial population of 407 subjects with asthma.Measurements and Main Results: The lowest P value for the GWAS analysis was 2.09 × 10(-6). Of the 47 SNPs successfully genotyped in the replication population, three were associated under the same genetic model in the same direction, including two of the top four SNPs ranked by P value. Combined P values for these SNPs were 1.06 × 10(-5) for rs3127412 and 6.13 × 10(-6) for rs6456042. Although these two were not located within a gene, they were tightly correlated with three variants mapping to potentially functional regions within the T gene. After genotyping, each T gene variant was also associated with lung function response to inhaled corticosteroids in each of the trials associated with rs3127412 and rs6456042 in the initial GWAS analysis. On average, there was a twofold to threefold difference in FEV(1) response for those subjects homozygous for the wild-type versus mutant alleles for each T gene SNP.Conclusions: Genome-wide association has identified the T gene as a novel pharmacogenetic locus for inhaled corticosteroid response in asthma. [ABSTRACT FROM AUTHOR]

Current guidelines for asthma care categorize asthma severity based on the frequency of asthma symptoms, medication use, and lung function measures. The objective of this study was to determine whether lung function measures are consistent with levels of asthma severity as defined by the National Asthma Education and Prevention Program/Expert Panel Report 2 Guidelines. Parents of children aged 5-18 years with asthma seen in two outpatient subspecialty clinics completed questionnaires regarding asthma medication use and symptom frequency over the preceding 1 and 4 weeks, respectively. All children performed spirometry. When asthma severity was based on the higher severity of asthma symptom frequency or medication use, asthma was mild intermittent in 6.9% of participants, mild persistent in 27.9%, moderate persistent in 22.4%, and severe persistent in 42.9%. FEV(1) % predicted did not differ by level of asthma severity. FEV(1)/FVC decreased as asthma severity increased (p < 0.0001) and was abnormal in 33% of the participants, and a greater percentage of participants had an abnormal FEV(1)/FVC as asthma severity increased (p = 0.0001). In children, asthma severity classified by symptom frequency and medication usage does not correlate with FEV(1) categories defined by National Asthma Education and Prevention Program Guidelines. FEV(1) is generally normal, even in severe persistent childhood asthma, whereas FEV(1)/FVC declines as asthma severity increases. [ABSTRACT FROM AUTHOR]

Purpose: The Black Women's Health Study (BWHS) was designed to investigate determinants of health and disease in US black women. More than 64,000 women are enrolled in the BWHS cohort. This study assessed the relative validity of the 68-item food frequency questionnaire (FFQ) used in the BWHS baseline questionnaire.Methods: Four hundred and eight BWHS enrollees were asked to provide three telephone, 24-hour recalls and one written 3-day food diary over a one-year period. Means and Pearson correlations were computed to compare estimates for energy, total fat, saturated fat, protein, carbohydrate, dietary fiber, calcium, iron, vitamin C, folate, beta-carotene, and vitamin E from the FFQ, recalls, and diaries.Results: Mean energy intake (kcal) was higher for the diary (1716) than the FFQ (1601) or recalls (1510). Other nutrient estimates (% kcal or per 1000 kcal) were similar across methods, except beta-carotene (FFQ higher). Correlations (energy-adjusted, except for energy, and corrected for intraperson variation) between the FFQ and the recalls were higher than for the diary data and were between 0.5 and 0.8, except for energy and vitamin E (both <0.3).Conclusion: The BWHS FFQ will support meaningful analyses of diet-health associations for 10 of the 11 energy-adjusted nutrient intake variables analyzed. [ABSTRACT FROM AUTHOR]