Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

Bridging the Gaps between Design and Use: Developing Tools to Support Environmental Management and Policy

Sound decisions in environmental policy and management usually require the examination of alternative solutions, and may require the consideration of alternative problem fornlulations prior to option assessment. Constructing and considering the consequences of alternative problems (variables and relations) and policy options (norms and standards) is fundamental for processes of policy fornlulation (Vickers, 1965)

Chapter three Bridging the gaps between design and use: Developing tools to support environmental management and policy

Integrated assessment models, decision support systems (DSS) and Geographic Information Systems (GIS) are examples of a growing number of computer-based tools designed to provide decision and information support to people engaged in formulating and implementing environmental policy and management. It is recognised that environmental policy and management users are often not as receptive to using such tools as desired but that little research has been done to uncover and understand the reasons. There is a diverse range of environmental decision and information support tools (DISTs) with uses including organisational and participatory decision support, and scientific research. The different uses and users of DISTs each present particular needs and challenges to the tool developers. The lack of appreciation of the needs of end-users by developers has contributed to the lack of success of many DISTs. Therefore it is important to engage users and other stakeholders in the tool development process to help bridge the gap between design and use. Good practice recommendations for developers to involve users include being clear about the purpose of the tool, working collaboratively with other developers and stakeholders, and building social and scientific credibilit

Exclusion and inclusion of parents of hospitalized children in Norway in the period 1877–2017

Abstract Background Today, Norwegian parents have the right to stay with their children when they are in hospital. This right is relatively new. The purpose of this article is to examine the nursing profession’s ideas on how parents should be included/excluded when their children are in hospital, and to examine the social and ideological conditions that made the nursing profession’s ideas on inclusion/exclusion practices possible. Methods The analyses are done in the tradition of the French philosopher Michel Foucault’s writings on how different kinds of knowledge have been used to discipline citizens. Such studies include analyses of descriptive and normative material and analyses of the ideological and social conditions that made the practices possible. The analyses are based on Norwegian textbooks on nursing. Results Parents are rarely mentioned in Norwegian nursing textbooks from the period 1877–1940, and they are not present in photos from hospitals. The exclusion of parents may be due to the absence of welfare services and the fear of parents transmitting diseases from the hospitals to the general population. The first Norwegian nursing textbook that argued for the importance of letting parents visit their children in hospital was published in 1941. In 1968, nursing textbooks started to argue for parents’ participation in the care. Since 1987, nursing textbooks have advocated full parental participation. The inclusion of parents was in accordance with humanistic ideology. The inclusion of parents occurred in a period of great nursing shortage. In this situation, it would have been of interest to entrust as much as possible of the nurse’s work to the family. Conclusions Our conclusion is that ideas break through when they are in line with social conditions. From 1877 to 1940 social and economic conditions made it difficult for parents to be with their children in hospital, and hygiene ideology/theory contributed to legitimization of the exclusion of the parents in the care. During the period 1941–2017 it has been economically advantageous for the hospitals that parents care for their children. Ideas on the vulnerable child and self-help ideology have contributed to legitimization of the inclusion of the parents

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n(DM) = 178,691, n(noDM) = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM