Identification and Characterization of Genetic Risk Variants for Chronic Kidney Disease and Related Traits
Final Report Abstract
Chronic kidney disease (CKD) affects ~10% of the adult population in many countries. It can not only progress to kidney failure but also increases the risk for cardiovascular morbidity and mortality. The processes causing CKD and contributing to its progression are incompletely understood. The aim of the Emmy Noether Group "Identification and Characterization of Genetic Risk Variants for Chronic Kidney Disease and Related Traits" was to generate insights into the mechanisms underlying kidney function in health and disease through a combination of unbiased forward genetic screens in human populations identification of biomarkers of renal function and the functional and epidemiological characterization of identified genetic risk variants. Improved insights into the underlying genetic architecture of CKD can provide a starting point for improved detection, treatment and prevention of renal dysfunction. From 2010-2015, the Emmy Noether group has worked on three specific aims. In Aim 1, we used unbiased genome-wide association studies (GWAS) in population-based studies and patients with CKD to identify and characterize genetic variants associated with kidney function and damage, serum urate and gout as well as with the concentrations of additional metabolites. Our work on kidney function markers highlights a central role for the contribution of common variants that map into regulatory regions of DNA in or near genes that are preferentially expressed in the kidney. Our work on kidney damage highlights an important role of the tubular reabsorption of filtered albumin especially in individuals with diabetes. Through GWAS of serum urate, we identified a surprising new role for multiple players in the inhibins/activins pathway as potential new targets to lower serum urate concentrations. The examination of CKD from specific etiologies generated the insight that specific risk variants in the HLA region are shared across several kidney diseases. In Aim 2, targeted re-sequencing of the UMOD gene led to the insights that the association signal detected by GWAS could not be explained by rare protein-altering variants either alone or in combination consistent with a proposed causal role of common regulatory variants that influence the risk of CKD in adult life. We expanded the scope of our studies to patients with rare kidney diseases and to the whole exome and identified the first instance of a family in which the co-occurrence of three independent autosomal-recessive diseases gives rise to a complex clinical presentation. In Aim 3, we identified and replicated serum metabolites that can serve as novel kidney function markers. By examining hundreds of known and unknown metabolites in several thousands of study participants we identified metabolites that showed an equal or better correlation with kidney function than serum creatinine while showing additional advantages such as independence from muscle mass. These metabolites represent attractive novel markers to improve the estimation of kidney function in research and clinical practice. Our results have been published in high-impact peer-reviewed international journals such as Nature Genetics. The identification of novel gout genes has received substantial coverage in the media (e.g. http://www.spiegel.de/wissenschaft/medizin/gicht-forscher-entdecken-gene-der-stoffwechselkrankheit-a-874636.html). Our findings open up new research areas in both basic and population sciences which we hope will ultimately lead to the development of novel ways to diagnose treat and prevent CKD.
Publications
- Human metabolic individuality in biomedical and pharmaceutical research. Nature. 2011 Aug 31;477(7362):54-60
Suhre K, Shin SY, Petersen AK, Mohney RP, Meredith D, Wägele B, Altmaier E; CARDIoGRAM, Deloukas P, Erdmann J, Grundberg E, Hammond CJ, de Angelis MH, Kastenmüller G, Köttgen A, Kronenberg F, Mangino M, Meisinger C, Meitinger T, Mewes HW, Milburn MV, Prehn C, Raffler J, Ried JS, Römisch-Margl W, Samani NJ, Small KS, Wichmann HE, Zhai G, Illig T, Spector TD, Adamski J, Soranzo N, Gieger C
- Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. Hum Mol Genet. 2011 Oct 15;20(20):4056-68
Tin A, Woodward OM, Kao WH, Liu CT, Lu X, Nalls MA, Shriner D, Semmo M, Akylbekova EL, Wyatt SB, Hwang SJ, Yang Q, Zonderman AB, Adeyemo AA, Palmer C, Meng Y, Reilly M, Shlipak MG, Siscovick D, Evans MK, Rotimi CN, Flessner MF, Köttgen M, Cupples LA, Fox CS, Köttgen A
- Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. Hum Mol Genet. 2012 Dec 15;21(24):5329-5343
Chasman DI, ... Köttgen A
- Multiple Novel Loci Highlighting Metabolic Control of Urate Production and Excretion are Associated with Gout. Nat Genet. 2013 Feb;45(2):145-54
Köttgen A et al.
- A Metabolome-Wide Association Study of Kidney Function and Disease in the General Population. J Am Soc Nephrol. 2016 Apr;27(4):1175-88
Sekula P, Goek ON, Quaye L, Barrios C, Levey AS, Römisch-Margl W, Menni C, Yet I, Gieger C, Inker LA, Adamski J, Gronwald W, Illig T, Dettmer K, Krumsiek J, Oefner PJ, Valdes AM, Meisinger C, Coresh J, Spector TD, Mohney RP, Suhre K, Kastenmüller G, Köttgen A
(See online at https://doi.org/10.1681/ASN.2014111099) - Against all odds: blended phenotypes of three singlegene defects. Eur J Hum Genet. 2016 Jan 27 [Epub ahead of print]
Li Y, Salfelder A, Schwab KO, Grünert SC, Velten T, Lütjohann D, Villavicencio-Lorini P, Matysiak-Scholze U, Zabel B, Köttgen A, Lausch E
(See online at https://doi.org/10.1038/ejhg.2015.285) - Combination of mouse models and genomewide association studies highlights novel genes associated with human kidney function. Kidney Int. 2016 Jun 3
Jing J, Pattaro C, Hoppmann A, Okada Y; CKDGen Consortium, Fox CS, Köttgen A
(See online at https://doi.org/10.1016/j.kint.2016.04.004) - Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. Nat Commun. 2016 Jan 21;7:10023
Pattaro C, ... Köttgen A, Kao WH, Fox C
(See online at https://doi.org/10.1038/ncomms10023) - Genome-wide Association Studies Identify Genetic Loci Associated with Albuminuria in Diabetes. Diabetes. 2016 Mar;65(3):803-1
Teumer A, ... Fox CS, Pattaro C, Köttgen A
(See online at https://doi.org/10.2337/db15-1313) - Mendelian Randomization as an Approach to Assess Causality Using Observational Data. J Am Soc Nephrol. 2016 Aug 2 [Epub ahead of print]
Sekula P, Del Greco M F, Pattaro C, Köttgen A
(See online at https://doi.org/10.1681/ASN.2016010098)
