Hospital Universitario Virgen Macarena. Sevilla

Dr. Agustín Valido

[ERS] FKBP5 a candidate for corticosteroid insensitivity in COPD

Faiz A, Postma DS, Koppelman GH, Hiemstra PS, Sterk PJ, Timens W, et al.

Mesa 4

Introduction.-

- The Groningen and Leiden Universities study of Corticosteroids in Obstructive Lung Disease (GLUCOLD) has identified a subset of COPD patients who respond favourably to inhaled corticosteroid (ICS) treatment and were distinguishable by their gene-expression profiles.

- The availability of longitudinal gene expression data and genetic information in GLUCOLD, pre- and post-treatment, allows to identify inducible eQTLs (eQTLs), i.e. genetic variants that regulate gene expression changes in response to treatment with ICS.

Objetive.-

The aim of this study was to perform an inducible eQTL analysis in the GLUCOLD study to better understand the genetic factors related to steroid responsiveness in COPD.

Methods.-- GWAS was performed using the Illumina HumanCytoSNP-12

array. - Gene expression profiling was performed in bronchial biopsies

obtained before and after 6-month treatment with ICS using Affymetrix-HuGene_ST1.0 arrays in patients with COPD (n = 42).

- Genetic variants acting in Cis (50,000 kb flanking the gene) were associated to the 278 previously identified corticosteroid sensitive genes in GLUCOLD.

Results.- - We identified 13 inducible eQTLs in 12 different genes. Notably,

FK506 binding protein 5 (FKBP5), which in the GLUCOLD study was the most highly upregulated gene by ICS was found to be regulated by rs2766545 (Beta = 0.87, FDR<0.05).

- FKBP5 is a known negative regulator of the glucocorticoid receptor which directly regulates corticosteroid anti-inflammatory function.

Conclusions.-

- Our results suggest that genetic factors contribute to ICS treatment responsiveness. Furthermore, FKBP5 provides an important candidate which may contribute to corticosteroid insensitivity in COPD.

[ERS] High density lipoprotein cholesterol (HDL-C) and longitudinal lung function in six United

States (US) cohorts Oelsner E, Balte P, Schwartz JE, Burkart KM, Cassano P, Jacobs DR, et al.

Mesa 4

Introduction.-COPD is a major cause of morbidity and mortality, yet risk factors in the general population beyond smoking are poorly defined. HDL particles contain ceramides that cause emphysema in mice; higher HDL-C and HDL-related genes are associated with radiographic emphysema and lower lung function.

Objetive.-To test associations of HDL-C with decline in lung function in the general population.

Methods.-- Six US population-based cohorts of adults were harmonized and

pooled. - Pre-bronchodilator spirometry was measured repeatedly

following ATS/ERS guidelines. - HDL-C was measured by enzymatic methods. - Mixed models with cohort-specific covariance structure were

adjusted for baseline age, sex, race/ethnicity, pack-years, hypertension, LDL and total cholesterol, cohort, and time-varying height, weight, and smoking status.

Results.- (I) - Among 32,350 adults with longitudinal spirometry measures

(mean age 49±19 years, 45% never smokers, 25% obese, 14% with airflow limitation, median 2 measures), mean HDL-C was 1.4±0.4 mmol/L.

- The mean rate of FEV1 decline was 29.2±0.1 mL/year.

- In adjusted models, higher HDL-C was associated with a greater rate of decline in FEV1 (P<.0001) and FEV1/FVC (P<.0001).

Results.- (II)- Over 7 years median follow-up, compared to the lowest HDL-C

quartile, the highest HDL-C quartile showed a 9 mL greater decline in FEV1 (P<.0001), an effect size similar to a 10-year

increment in pack-years. - In stratified analyses, findings were similar in men and

women, in never-smokers, in non-obese participants, and in those without airflow limitation.

Conclusions.-

- Higher levels of HDL-C were associated with more rapid decline in lung function in a large US population-based sample of adults.

[ERS] Single-dose safety, tolerability, PD & PK of AZD8999, a bi-functional muscarinic

antagonist/β2-agonist (MABA), in patients with COPD

Singh D, Mant T, Pujol H, Massana E, Falques M, Gonzalez M, et al.

Mesa 4

Introduction.-AZD8999 (formerly LAS190792) is a novel MABA bronchodilator in development for COPD treatment.

Objetive.-Phase I safety, tolerability, PD & PK study of single doses of AZD8999, in patients with COPD. This investigation formed Part 2 of a First-in-Man study

Methods.-- Randomised, double-blind, placebo-controlled, single-dose, 5-

way complete crossover investigating safety/tolerability, PD of AZD8999 100μg & 400μg, v indacaterol (IND) 150μg & tiotropium (TIO) 18μg in subjects with moderate to severe COPD (N = 38). PK of AZD8999 was assessed in a subset of at least 10 evaluable patients.

Results.- (I) - Both AZD8999 doses were safe and well tolerated.- PD

Statistically significant, clinically meaningful, sustained improvements in change from baseline in trough FEV1 were seen

for all treatments v placebo (178mL and 104mL with AZD8999 400μg and 100μg, respectively). Improvement was statistically significantly greater with AZD8999 400μg than AZD8999 100μg & IND 150μg, and with TIO 18μg than AZD8999 100μg (Fig).

Results.- (II) - PK

AZD8999 plasma levels detected up to 2h (100μg) and 6h (400μg) post-dose. AZD8999 parameters: Cmax 15.4 pg/mL

(100μg) & 56.2 pg/mL (400μg); Tmax: 0.5 hrs; AUC(0-t)

20.5pg*h/mL (100μg) & 127pg*h/mL (400μg).

Conclusions.-

- Both AZD8999 doses were safe and well tolerated. A good efficacy profile was observed over 24 hours.