The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Review: Surfactant protein D: A lung specific biomarker in COPD?

A major impediment in the development of novel drugs for chronic obstructive pulmonary disease (COPD) has been the scarcity of a well-validated, robust, and easily obtainable intermediate end point such as serum biomarkers. To date the best serum biomarkers in COPD have been non-speci“c pro-in”ammatory molecules synthesized largely by extra-pulmonary organs. In COPD, an ideal biomarker would be one that (1) was produced mostly in the lungs (and was reliably measurable in the peripheral circulation using commercially available kits), (2) changed with the clinical status of patients or with relevant exposures; and (3) had inherent functional attributes that suggested a possible causal role in the pathogenesis of the disease. In this paper, we review one promising systemic biomarker that ful“lls some of these criteria, surfactant protein D (SPD)

The airway epithelium: more than just a structural barrier

The mammalian airway is lined by a variety of specialized epithelial cells that not only serve as a physical barrier but also respond to environment-induced damage through the release of biologically active factors and constant cellular renewal. The lung epithelium responds to environmental insults such as pathogens, cigarette smoke and pollution by secreting inflammatory mediators and antimicrobial peptides, and by recruiting immune cells to the site of infection or damage. When the epithelium is severely damaged, basal cells and Clara cells that have stem-cell-like properties are capable of self-renewal and proliferation in the affected area, to repair the damage. In order to effectively fight off infections, the epithelium requires the assistance of neutrophils recruited from the peripheral circulation through transendothelial followed by transepithelial migration events. Activated neutrophils migrate across the epithelium through a series of ligand–receptor interactions to the site of injury, where they secrete proteolytic enzymes and oxidative radicals for pathogen destruction. However, chronic activation and recruitment of neutrophils in airway diseases such as chronic obstructive pulmonary disease and asthma has been associated with tissue damage and disease severity. In this paper, we review the current understanding of the airway epithelial response to injury and its interaction with inflammatory cells, in particular the neutrophil

Forced expiratory volume in 1 second and physical activity in the general population

Among patients with advanced lung disease, forced expiratory volume in 1 second (FEV1) correlates well with reduced exercise capacity and decreased health-related quality of life (1–5). There are, however, little data on the clinical effect of FEV1 on participation in physical activity in patients who may not have clinically apparent lung disease but who have reduced lung function. Moreover, even if such a relation exists, neither the shape of the relation nor the (threshold) value of FEV1 at which functional impairment occurs is known. We analyzed data from the Third National Health and Nutrition Examination Survey (NHANES III) to determine the relation between FEV1 and participation in common physical activities by adults living in the United States

The effects of inhaled and oral corticosteroids on serum inflammatory biomarkers in COPD: an exploratory study

Background: Several studies suggest that inhaled and oral corticosteroids repress systemic inflammation in chronic obstructive pulmonary disease (COPD). However, the cytokines that may respond to these medications are unclear. Method: We used data from 41 patients with a history of stable moderate COPD (average age 64 years) who were randomised to inhaled fluticasone (500 μg twice daily from a Diskus inhaler), oral prednisone (30 mg daily) or placebo for 2 weeks. Using a multiplexed array system, different serum cytokines that have been implicated in COPD pathogenesis were measured. Results: We found that compared with placebo, inhaled fluticasone significantly reduced levels of soluble tumour necrosis factor receptor-2 (sTNF-R2) by 24% (95% CI, 7—38%; p = 0.01), monocyte chemoattractant protein-1 by 20% (95% CI, 5—32%; p = 0.01), interferon gamma inducible CXCL10 (IP-10) by 43% (95% CI, 3—66%; p = 0.04), and soluble L-selectin levels by 15% (95% CI, 1—28%; p = 0.04). Compared with placebo, oral prednisone reduced levels of sTNF-R2 by 26% (95% CI, 15—36%; p < 0.001), L-selectin by 22% (95% CI, 8—34%; p = 0.004), intercellular adhesion molecule-1 by 31% (95% CI, 9—48%; p = 0.01), pulmonary and activation-regulated chemokine (PARC) by 18% (95% CI, 2—32%; p = 0.03) and IP-10 by 40% (95% CI, 0—64%; p = 0.05). sTNF-R2, L-selectin and IP-10 were significantly reduced by both oral and inhaled corticosteroids. The other cytokines were not significantly repressed by either oral or inhaled corticosteroids. Conclusions: In summary, inhaled and oral corticosteroids significantly repressed a selected number of systemic cytokines in patients with stable, moderate COPD; most of the steroid-responsive cytokines appear to be chemoattractants