A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Elevated Levels of Tenascin-C in Patients with Cryptogenic Organizing Pneumonia

Objective Idiopathic interstitial pneumonias (IIPs) comprises a group of diffuse parenchymal lung diseases of unknown etiology with varying degrees of inflammation and fibrosis including cryptogenic organizing pneumonia (COP), idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP). Tenascin-C is an extracellular matrix molecule that is expressed during wound healing in various tissues. The present study was aimed to investigate the role of tenascin-C in the pathogenesis of IIPs. Methods We used enzyme-linked immunosorbent assays to measure levels of tenascin-C in serum and bronchoalveolar lavage fluid (BALF) from 17 patients with IPF, 12 with NSIP, 15 with COP and from 23 healthy individuals. Results Serum levels of tenascin-C were significantly elevated in patients with COP compared with those in all other participants, whereas those in patients with IPF and NSIP were not significantly elevated compared with healthy individuals. The levels of tenascin-C in BALF from patients with COP and NSIP were significantly higher than those of healthy individuals. In addition, serum tenascin-C was significantly correlated with levels of serum C-reactive protein, which is a serum acute phase protein. Conclusion Systemic inflammation in the lung with IIPs might be associated with tenascin-C. These results suggest that tenascin-C is responsible for the pathogenesis of IIPs especially via inflammation, and that it might serve as a serum marker of COP