Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD

Diabetic nephropathy in a sibling and albuminuria predict early GFR decline: a prospective cohort study

Abstract Background Diabetic nephropathy is a growing clinical problem, and the cause for &gt;40% of incident ESRD cases. Unfortunately, few modifiable risk factors are known. The objective is to examine if albuminuria and history of diabetic nephropathy (DN) in a sibling are associated with early DN progression or mortality. Methods In this longitudinal study of adults &gt;18 yrs with diabetes monitored for up to 9 yrs (mean 4.6 ± 1.7 yrs), 435 subjects at high risk (DN family history) and 400 at low risk (diabetes &gt;10 yrs, normoalbuminuria, no DN family history) for DN progression were evaluated for rate of eGFR change using the linear mixed effects model and progression to ESRD. All-cause mortality was evaluated by Kaplan-Meier analyses while controlling for baseline covariates in a Cox proportional hazards model. Covariates included baseline eGFR, age, gender, race, diabetes duration, blood pressure, hemoglobin A1c and urine albumin:creatinine ratio. Propensity score matching was used to identify high and low risk group pairs with balanced covariates. Sensitivity analyses were employed to test for residual confounding. Results Mean baseline eGFR was 74 ml/min/1.73 m2 (86% of cohort &gt;60 ml/min/1.73 m2). Thirty high risk and no low risk subjects developed ESRD. eGFR decline was significantly greater in high compared to low risk subjects. After controlling for confounders, change in eGFR remained significantly different between groups, suggesting that DN family history independently regulates GFR progression. Mortality was also significantly greater in high versus low risk subjects, but after controlling for baseline covariates, no significant difference was observed between groups, indicating that factors other than DN family history more strongly affect mortality. Analyses of the matched pairs confirmed change in eGFR and mortality findings. Sensitivity analyses demonstrated that the eGFR results were not due to residual confounding by unmeasured covariates of a moderate effect size in the propensity matching. Conclusions Diabetic subjects with albuminuria and family history of DN are vulnerable for early GFR decline, whereas subjects with diabetes for longer than 10 years, normoalbuminuria and negative family history, experience slower eGFR decline, and are extremely unlikely to require dialysis. Although we would not recommend that patients with low risk characteristics be neglected, scarce resources would be more sensibly devoted to vulnerable patients, such as the high risk cases in our study, and preferably prior to the onset of albuminuria or GFR decline. </jats:sec

Deterrence in Cyberspace: An Interdisciplinary Review of the Empirical Literature

The popularity of the deterrence perspective across multiple scientific disciplines has sparked a lively debate regarding its relevance in influencing both offenders and targets in cyberspace. Unfortunately, due to the invisible borders between academic disciplines, most of the published literature on deterrence in cyberspace is confined within unique scientific disciplines. This chapter therefore provides an interdisciplinary review of the issue of deterrence in cyberspace. It begins with a short overview of the deterrence perspective, presenting the ongoing debates concerning the relevance of deterrence pillars in influencing cybercriminals’ and cyberattackers’ operations in cyberspace. It then reviews the existing scientific evidence assessing various aspects of deterrence in the context of several disciplines: criminology, law, information systems, and political science. This chapter ends with a few policy implications and proposed directions for future interdisciplinary academic research

Reasons for (prior) belief in Bayesian epistemology

Bayesian epistemology tells us with great precision how we should move from prior to posterior beliefs in light of new evidence or information, but says little about where our prior beliefs come from. It o¤ers few resources to describe some prior beliefs as rational or well-justified, and others as irrational or unreasonable. A di¤erent strand of epistemology takes the central epistemological question to be not how to change one's beliefs in light of new evidence, but what reasons justify a given set of beliefs in the first place. We o¤er an account of rational belief formation that closes some of the gap between Bayesianism and its reason-based alternative, formalizing the idea that an agent can have reasons for his or her (prior) beliefs, in addition to evidence or information in the ordinary Bayesian sense. Our analysis of reasons for belief is part of a larger programme of research on the role of reasons in rational agency

Tissue transglutaminase inhibition as treatment for diabetic glomerular scarring: it's good to be glueless

Diabetic nephropathy is characterized by enhanced glomerular and tubulointerstitial deposition of extracellular matrix proteins, which are bound together by tissue transglutaminase (TG2). Huang et al. demonstrate that infusion of a novel TG2 inhibitor in diabetic rats prevented renal scarring and albuminuria and preserved glomerular filtration rate. These studies confirm the role of TG2 in the pathogenesis of diabetic nephropathy and add to an emerging literature that demonstrates that TG2 is an attractive therapeutic target for sclerosing kidney diseases

The Contribution of Lipotoxicity to Diabetic Kidney Disease

Lipotoxicity is a fundamental pathophysiologic mechanism in diabetes and non-alcoholic fatty liver disease and is now increasingly recognized in diabetic kidney disease (DKD) pathogenesis. This review highlights lipotoxicity pathways in the podocyte and proximal tubule cell, which are arguably the two most critical sites in the nephron for DKD. The discussion focuses on membrane transporters and lipid droplets, which represent potential therapeutic targets, as well as current and developing pharmacologic approaches to reduce renal lipotoxicity