Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies.

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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

Abstract
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]

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Phase 2a, AMP Challenge, Dose Escalation Study to Assess the Dose Response for Topical Efficacy and Systemic Activity in Asthmatic Subjects

Condition:   Asthma
Interventions:   Drug: Fluticasone furoate (FF) Dry Powder Inhaler;   Drug: Fluticasone propionate (FP) Dry Powder Inhaler;   Drug: Budesonide (BUD) Turbuhaler;   Drug: Placebo (ELLIPTA or DISKUS)
Sponsor:   GlaxoSmithKline
Not yet recruiting – verified December 2016

View full post on ClinicalTrials.gov: asthma | Studies received in the last 14 days

Adherence to Omalizumab Does Not Correlate with Better Response for Asthma – MD Magazine


MD Magazine

Adherence to Omalizumab Does Not Correlate with Better Response for Asthma
MD Magazine
While clinicians should always encourage their patients to follow their medication schedules, it proved not to be a significant factor in the outcomes in patients with asthma taking omalizumab, according to a poster session at the 2015 American College

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FoxP3 Tregs Response to Sublingual Allergen Specific Immunotherapy in Children Depends on the Manifestation of Allergy.

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FoxP3 Tregs Response to Sublingual Allergen Specific Immunotherapy in Children Depends on the Manifestation of Allergy.

J Immunol Res. 2015;2015:731381

Authors: Stelmaszczyk-Emmel A, Zawadzka-Krajewska A, G?odkowska-Mrówka E, Demkow U

Abstract
Over the last decades allergic diseases has become a major health problem worldwide. The only specific treatment to date is allergen specific immunotherapy (ASIT). Although it was shown that ASIT generates allergen-tolerant T cells, detailed mechanism underlying its activity is still unclear and there is no reliable method to monitor its effectiveness. The aim of our study was to evaluate ASIT influence on the frequency of forkhead box P3 (FoxP3) Tregs in allergic children with various clinical manifestations. The relative number of FoxP3 Tregs in 32 blood samples from allergic children at baseline and/or after 1 year of ASIT was assessed by flow cytometry. In the entire studied group, the percentage of FoxP3 Tregs did not increase 1 year after ASIT. Nevertheless, the percentage of FoxP3 Tregs after ASIT significantly increased in children with respiratory allergy (conjunctivitis, asthma, and rhinitis) coexisting with nonrespiratory manifestations (food allergy and/or atopic dermatitis), whereas, in patients with respiratory allergy only, the percentage of FoxP3 Tregs decreased. To the best of our knowledge, this is the first report showing various differential FoxP3 Tregs response to ASIT in allergic children. FoxP3 Tregs number could be useful in treatment monitoring. Further studies are warranted to confirm these observations.

PMID: 26457309 [PubMed – in process]

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VNN1 Gene Could Serve As a Biomarker for Response to Corticosteroids in … – Lung Disease News


Lung Disease News

VNN1 Gene Could Serve As a Biomarker for Response to Corticosteroids in
Lung Disease News
According to study investigator Gurjit Khurana Hershey, MD, PhD, director of Asthma Research at Cincinnati Children's Hospital Medical Center, “Genome-wide analysis allowed us to identify a gene, whose expression discriminated between good and poor …

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Effect of different helminth extracts on the development of asthma in mice: the influence of early-life exposure and the role of IL-10 response.

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Effect of different helminth extracts on the development of asthma in mice: the influence of early-life exposure and the role of IL-10 response.

Exp Parasitol. 2015 Jun 17;

Authors: Pitrez PM, Gualdi LP, Barbosa GL, Sudbrack S, Ponzi D, Cao RG, Silva AC, Machado DC, Jones MH, Stein RT, Graeff-Teixeira C

Abstract
It is not currently clear whether different parasites have distinct effects on the airway inflammatory response in asthma and whether exposure in early life to helminths have a stronger impact in a potential inhibitory effect on asthma. The aim of this study is to evaluate the effect of exposure to different helminth extracts on the development of allergic pulmonary response in mice, including early-life exposure. Different helminth extracts (Angiostrongylus costaricensis, Angiostrongylus cantonensis and Ascaris lumbricoides) were studied in female adult BALB/c and C57BL/6 IL-10-deficient mice in a protocol of murine asthma, injected intraperitoneally in different periods of exposure (early, pre-sensitization and post-sensitization). Cell counts in bronchoalveolar lavage (BAL), eosinophil peroxidase (EPO) from lung tissue, cytokine levels from BAL/spleen cell cultures, and lung histology were analyzed. Airway cellular influx induced by OVA was significantly inhibited by extracts of A. cantonensis and A. lumbricoides. Extracts of A. lumbricoides and A. costaricensis led to a significant reduction of IL-5 in BAL (p<0.001). Only the exposure to A. lumbricoides led to an increased production of IL-10 in the lungs (p<0.001). In IL-10-deficient mice exposed to A. costaricensis pre-sensitization, eosinophil counts and IL-5 levels in BAL and EPO in lung tissue were significantly reduced. In the early exposure to A. cantonensis, lung inflammation was clearly inhibited. In conclusion, different helminth extracts inhibit allergic lung inflammation in mice. IL-10 may not play a central role in some helminth-host interactions. Early exposure to helminth extracts could be a potential strategy to explore primary prevention in asthma.

PMID: 26093162 [PubMed – as supplied by publisher]

View full post on pubmed: asthma