Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies.
Front Pharmacol. 2016;7:299
Authors: Thompson MD, Capra V, Clunes MT, Rovati GE, Stankova J, Maj MC, Duffy DL
Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions. Of the three enzymes involved in the formation of the leukotrienes, arachidonate 5 lipoxygenase 5 (ALOX5), leukotriene C4 synthase (LTC4S), and leukotriene hydrolase (LTA4H) are all polymorphic. These polymorphisms often result in variable production of the CysLTs (LTC4, LTD4, and LTE4) and LTB4. Variable number tandem repeat sequences located in the Sp1-binding motif within the promotor region of the ALOX5 gene are associated with leukotriene burden and bronchoconstriction independent of asthma risk. A 444A > C SNP polymorphism in the LTC4S gene, encoding an enzyme required for the formation of a glutathione adduct at the C-6 position of the arachidonic acid backbone, is associated with severe asthma and altered response to the CYSLTR1 receptor antagonist zafirlukast. Genetic variability in the CysLT pathway may contribute additively or synergistically to altered drug responses. The 601 A > G variant of the CYSLTR2 gene, encoding the Met201Val CYSLTR2 receptor variant, is associated with atopic asthma in the general European population, where it is present at a frequency of ?2.6%. The variant was originally found in the founder population of Tristan da Cunha, a remote island in the South Atlantic, in which the prevalence of atopy is approximately 45% and the prevalence of asthma is 36%. In vitro work showed that the atopy-associated Met201Val variant was inactivating with respect to ligand binding, Ca(2+) flux and inositol phosphate generation. In addition, the CYSLTR1 gene, located at Xq13-21.1, has been associated with atopic asthma. The activating Gly300Ser CYSLTR1 variant is discussed. In addition to genetic loci, risk for asthma may be influenced by environmental factors such as smoking. The contribution of CysLT pathway gene sequence variants to atopic asthma is discussed in the context of other genes and environmental influences known to influence asthma.
PMID: 27990118 [PubMed – in process]
View full post on pubmed: asthma
Determinants of longitudinal health-related quality of life change in children with asthma from low-income families: a report from the PROMIS(®) Pediatric Asthma Study.
Clin Exp Allergy. 2016 Sep 24;
Authors: Li Z, Leite W, Thompson L, Gross HE, Shenkman E, Reeve BB, DeWalt DA, Huang IC
BACKGROUND: How the longitudinal asthma control status and other socio-demographic factors influence the changes of health-related quality of life (HRQOL) among asthmatic children, especially from low-income families, has not been fully investigated.
OBJECTIVES: This study aimed to describe the trajectories of asthma-specific HRQOL over 15 months, and examine the effect of asthma control status on HRQOL by taking socio-demographic factors into consideration.
METHODS: 229 dyads of asthmatic children and their parents enrolled in public insurance programs were recruited for assessing asthma control status and HRQOL over 4 time points of assessment. Asthma control status was measured using the Asthma Control and Communication Instrument and asthma-specific HRQOL was assessed using the Patient-Reported Outcomes Measurement Information System’s Pediatric Asthma Impact Scale. Latent growth models (LGMs) were applied to examine the trajectory of HRQOL and the factors contributing to the changes of HRQOL.
RESULTS: Unconditional LGM revealed that HRQOL was improved over time. Conditional LGM suggested that accounting for asthma control and participants’ socio-demographic factors, the variation in the initial level of HRQOL was significant, yet the rate of change was not. Conditional LGM also revealed that poorly-controlled asthma status was associated with poor HRQOL at each time point (p’s<0.05). Lower parental education was associated with lower baseline HRQOL (p<0.05). Hispanic children had a larger increase in HRQOL over time (p<0.01) than non-Hispanic White children.
CONCLUSIONS: Vulnerable socio-demographic characteristics and poorly controlled asthma status affect HRQOL in children. This finding encourages interventions to improve asthma control status and HRQOL in minority children. This article is protected by copyright. All rights reserved.
PMID: 27664979 [PubMed – as supplied by publisher]
View full post on pubmed: asthma
Differential respiratory health effects from the 2008 northern California wildfires: A spatiotemporal approach.
Environ Res. 2016 Jun 15;150:227-235
Authors: Reid CE, Jerrett M, Tager IB, Petersen ML, Mann JK, Balmes JR
We investigated health effects associated with fine particulate matter during a long-lived, large wildfire complex in northern California in the summer of 2008. We estimated exposure to PM2.5 for each day using an exposure prediction model created through data-adaptive machine learning methods from a large set of spatiotemporal data sets. We then used Poisson generalized estimating equations to calculate the effect of exposure to 24-hour average PM2.5 on cardiovascular and respiratory hospitalizations and ED visits. We further assessed effect modification by sex, age, and area-level socioeconomic status (SES). We observed a linear increase in risk for asthma hospitalizations (RR=1.07, 95% CI=(1.05, 1.10) per 5µg/m(3) increase) and asthma ED visits (RR=1.06, 95% CI=(1.05, 1.07) per 5µg/m(3) increase) with increasing PM2.5 during the wildfires. ED visits for chronic obstructive pulmonary disease (COPD) were associated with PM2.5 during the fires (RR=1.02 (95% CI=(1.01, 1.04) per 5µg/m(3) increase) and this effect was significantly different from that found before the fires but not after. We did not find consistent effects of wildfire smoke on other health outcomes. The effect of PM2.5 during the wildfire period was more pronounced in women compared to men and in adults, ages 20-64, compared to children and adults 65 or older. We also found some effect modification by area-level median income for respiratory ED visits during the wildfires, with the highest effects observed in the ZIP codes with the lowest median income. Using a novel spatiotemporal exposure model, we found some evidence of differential susceptibility to exposure to wildfire smoke.
PMID: 27318255 [PubMed – as supplied by publisher]
View full post on pubmed: asthma
Sponsor: University of California, San Francisco
Not yet recruiting – verified June 2016
View full post on ClinicalTrials.gov: asthma | received in the last 14 days