Our research is supported by several national and international funding agencies. We are part of the Collaborative Research Center 1140 of the German Research Foundation at the University of Freiburg, Germany (http://www.sfb1140.uni-freiburg.de). This collaborative research center aims to understand mechanisms underlying genetic diseases of the kidney and provides optimal synergies with the Division of Genetic Epidemiology’s research interests.
German Research Foundation (KO 3598-4/1): “Renal Metabolite Handling: from Gene to Function to Disease”, 2014-2017
Summary: The risk for complex diseases such as chronic kidney disease (CKD) is influenced both by the environment and risk variants in many genes, as well as their interplay. Many complex diseases are common and thus represent a large public health burden. Recent breakthroughs using high-throughput –omics techniques have led to fundamental new insights recognizing the role of genetic and metabolic variation in the pathogenesis of many human complex diseases. Yet, the exact genes and metabolic changes contributing to complex disease susceptibility and their underlying pathophysiological mechanisms of action mostly remain unclear.
This project addresses these knowledge gaps: it tests the hypotheses that variation in metabolite handling contributes to the complex disease CKD and that underlying processes can be uncovered by the systematic integration of human genetic and metabolic variation, the modeling of organ-specific functions, and functional and epidemiological follow-up studies. This will be accomplished through four steps:
1. In the first step, genome-wide association studies of concentrations of a wide variety of metabolites in serum and urine of CKD patients participating in the German Chronic Kidney Disease Study will be conducted. Significant associations between genetic variants and metabolite concentrations will systematically allow for the identification of novel genes connected to the handling of the respective metabolite.
2. For significantly associated genetic variants, the modeling of kidney-specific functions from the metabolite data will help to prioritize genes for follow-up experiments addressing their putative function. For example, an association with the fractional excretion of the specific metabolite may suggest that the gene encodes for a transport protein of that metabolite.
3. Prioritized genes from steps 1 and 2 will be subjected to functional investigations in experimental models such as transport experiments in Xenopus oocytes.
4. Identified metabolites will be evaluated with respect to their role across different etiologies of CKD and for their potential to predict CKD progression as well as death among 5,217 participants of the German Chronic Kidney Disease Study, the largest prospective study of CKD worldwide.
The proposal extends beyond standard genome-wide association studies and has the potential to generate important novel insights. Feasibility is ensured because it builds on established resources, including a large prospective study with available biosamples and genome-wide marker genotypes. The innovative and multi-disciplinary approach addresses the fundamental question how individual genetic and metabolic variation can be systematically used to understand general pathophysiological mechanisms underlying CKD and other complex diseases in the population.
German Research Foundation (KO 3598-3/1): Heisenberg Professorship
Summary: Funds the Professorship of Dr. Anna Köttgen
German Research Foundation (CRC 1140 “KIDGEM: Kidney Disease – From Genes to Mechanisms”): Project A05 “Genetic risk variants for chronic kidney diseases in a prospective cohort of 5,217 patients”
Summary: Membranous nephropathy (MN) and focal-segmental glomerulosclerosis (FSGS) are the most common causes for nephrotic syndrome in adults, a hallmark of glomerular diseases. This project aims to address important knowledge gaps about their genetic architecture in a large, prospective study of 5217 patients with chronic kidney disease (CKD), the German Chronic Kidney Disease (GCKD) Study. As part of our work program, we will first conduct genome-wide association studies at unprecedented coverage examining >10 million common genome-wide SNP markers per person, to map risk genes and refine risk variant associations for MN, FSGS and all-cause CKD. Moreover, we will carry out the first examination of >250,000 rare missense, splice and stop mutations discovered through whole exome sequencing to identify potentially causal mutations for MN, FSGS and all-cause CKD. Validated risk variants will be examined for their combined effect and for interactions with each other and environmental exposures, capitalizing on the detailed information about medication intake and the in-depth clinical and biochemical profiles available in GCKD. Genome-wide searches for effect modifiers will also be carried out. Specificity of identified risk variants for MN or FSGS vs. their generalizability to other CKD etiologies will be assessed by examination of effects across the many CKD etiologies represented in the GCKD Study. Lastly, risk variants will be evaluated for their association with CKD progression (kidney function decline, incident ESRD) and complications (cardiovascular events, mortality) using methods for prospective data analysis. These studies will be complemented by genome-wide searches for variants that may be associated with disease progression rather than disease development. The prospective nature of the GCKD Study allows for the evaluation of the identified risk variants as diagnostic and especially prognostic markers. In addition to a better understanding of the genetic architecture of MN, FSGS and all-cause CKD, this work can generate novel insights about the physiology of glomerular kidney diseases. The generation of genome-wide association statistics from thousands of CKD patients will provide a valuable resource for the targeted investigation of human genes studied in other KIDGEM projects.
KfH Stiftung Präventivmedizin: The German Chronic Kidney Disease (GCKD) Study
Summary: The Stiftung Präventivmedizin of the Kuratorium für Heimdialyse supports the multi-centric observational prospective GCKD Study. This study enrolled 5,217 patients with chronic kidney disease across Germany and now follows the patients over 10 years to assess disease progression and renal and cardiovascular endpoints. Freiburg is one of nine study centers, in which team members of the Division of Genetic Epidemiology and the Department of Internal Medicine IV at the Medical Center of the University of Freiburg work together to carry out the study visits and follow-up. More information on the study can be found here: http://www.gckd.de/
Else Kröner Forschungskolleg NAKSYS (Nierenfunktionsstörungen als Komplikation von Systemerkrankungen): Project 08 Relationship of Thyroid Function and Chronic Kidney Disease
No summary, since only available in German
Subcontract to “Epigenetic Landscape of Chronic Kidney Disease”, NIDDK 5R01DK087635-07 (to Dr. Katalin Susztak, PI)
Summary by the PI: Genome wide association studies (GWAS) have been extremely powerful and successful identifying associations between genetic polymorphisms (SNP) and diabetic and chronic kidney disease (CKD) development. Our next big challenge is to translate this information to understand the mechanism of diabetic and CKD development. The major hurdle is that the majority of CKD associated polymorphisms lie outside the coding region of the genome. Therefore classic protein biochemistry and gene deletion studies of model organisms cannot yet be applied. Several recent pioneering studies have provided a novel framework for such experiments and indicate that the cell type specific epigenome can be used to understand and annotate the non-coding region of the genome. As there are hundreds of established SNPs for CKD, performing individual experiments for each SNP could be a daunting task, therefore there is a critical need for genome wide cell type specific mapping of non-coding regulatory regions and defining the correlation between SNP's and transcript levels. The proposal will use a combination of methods to dissect the association between diabetic and chronic kidney disease associated polymorphisms and disease.