👤 F Faiz

COPD is characterised by chronic airflow limitation and persistent inflammation. Inhaled corticosteroids (ICS) are often used to reduce airway inflammation in patients. However, the response to ICS treatment varies among patients, and blood eosinophils may not fully reflect treatment effectiveness. In this study, we aim to identify gene modules associated with ICS responsiveness and assess the underlying biological pathways. We included 55 patients from the GLUCOLD study with mild-moderate COPD treated with ICS for 6 months with available gene expression data from biopsies. Treatment response was defined as changes in post-bronchodilator forced expiratory volume in 1 s (FEV We identified four gene modules associated to ICS-induced improvement in FEV This study identified gene modules and pathways associated with ICS responsiveness in COPD, providing a potential mechanistic explanation for the variability in ICS treatment responsiveness in COPD. Show less

Primary chronic intestinal pseudo-obstruction (CIPO) is a rare, potentially life-threatening disorder characterized by severely impaired gastrointestinal motility. The objective of this study was to examine the contribution of ACTG2, LMOD1, MYH11, and MYLK mutations in an Australasian cohort of patients with a diagnosis of primary CIPO associated with visceral myopathy. Pediatric and adult patients with primary CIPO and suspected visceral myopathy were recruited from across Australia and New Zealand. Sanger sequencing of the genes encoding enteric gamma-actin (ACTG2) and smooth muscle leiomodin (LMOD1) was performed on DNA from patients, and their relatives, where available. MYH11 and MYLK were screened by next-generation sequencing. We identified heterozygous missense variants in ACTG2 in 7 of 17 families (~41%) diagnosed with CIPO and its associated conditions. We also identified a previously unpublished missense mutation (c.443C>T, p.Arg148Leu) in one family. One case presented with megacystis-microcolon-intestinal hypoperistalsis syndrome in utero with subsequent termination of pregnancy at 28 weeks' gestation. All of the substitutions identified occurred at arginine residues. No likely pathogenic variants in LMOD1, MYH11, or MYLK were identified within our cohort. ACTG2 mutations represent a significant underlying cause of primary CIPO with visceral myopathy and associated phenotypes in Australasian patients. Thus, ACTG2 sequencing should be considered in cases presenting with hypoperistalsis phenotypes with suspected visceral myopathy. It is likely that variants in other genes encoding enteric smooth muscle contractile proteins will contribute further to the genetic heterogeneity of hypoperistalsis phenotypes. Show less