Genetic loci influencing kidney function and chronic kidney disease

Chambers, John C.; Zhang, Weihua; Lord, Graham M.; Harst, Pim van der; Lawlor, Debbie A.; Sehmi, Joban; Gale, Daniel P.; Wass, Mark N.; Ahmadi, Kourosh R.; Bakker, Stephan J. L.; Beckmann, Jacques S.; Bilo, Henk J. G.; Bochud, Murielle; Brown, Morris J.; Caulfield, Mark; Connell, John; Cook, H. Terence; Cotlarciuc, Ioana; Smith, George Davey; Silva, Ranil de; Deng, Guohong; Devuyst, Olivier; Dikkeschei, L. D.; Dimković, Nada; Dockrell, Mark E. C.; Dominiczak, Anna F.; Ebrahim, Shah; Eggermann, Thomas; Farrall, Martin; Ferrucci, Luigi; Floege, Jürgen; Forouhi, Nita G.; Gansevoort, Ron T.; Han, Xijin; Hedblad, Bo; Heide, Jaap J. Homan van der; Hepkema, Bouke; Hernandez-Fuentes, Maria P.; Hyppönen, Elina; Johnson, Toby; Jong, Paul E. de; Kleefstra, Nanne; Lagou, Vasiliki; Lapsley, Marta; Li, Yun; Loos, Ruth J.F.; Luan, Jian’an; Luttropp, Karin; Maréchal, Céline; Melander, Olle; Munroe, Patricia B.; Nordfors, Louise; Parsa, Afshin; Peltonen, Leena; Penninx, Brenda W. J. H.; Perucha, Esperanza; Pouta, Anneli; Prokopenko, Inga; Roderick, Paul; Ruokonen, Aimo; Samani, Nilesh J.; Sanna, Serena; Schalling, Martin; Schlessinger, David; Schlieper, Georg; Seelen, Marc A.; Shuldiner, Alan R.; Sjögren, Marketa; Smit, Johannes H.; Snieder, Harold; Soranzo, Nicole; Spector, Timothy D.; Stenvinkel, Peter; Sternberg, Michael J.E.; Swaminathan, R.; Tanaka, Toshiko; Ubink-Veltmaat, L. J.; Uda, Manuela; Vollenweider, Péter; Wallace, Chris; Waterworth, Dawn; Zerres, Klaus; Waeber, Gérard; Wareham, Nicholas J.; Maxwell, Patrick H.; McCarthy, Mark I.; Järvelin, Marjo‐Riitta; Mooser, Vincent; Abecasis, Gonçalo R.; Lightstone, Liz; Scott, James A.; Navis, Gerjan; Elliott, Paul; Kooner, Jaspal S.

doi:10.1038/ng.566

Cited by 246 publications

(228 citation statements)

References 16 publications

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“…We suspect that the greater genetic diversity of our study population has resulted in a breakdown of the linkage disequilibrium in the ALMS1/NAT8 region of the genome, which resulted in a sharper association peak. While the molecular function of ALMS1 is not known, genetic variations within ALMS1 have been implicated in a number of kidney health disorder phenotypes (Chambers et al 2010) including a rare genetic disease called Alström syndrome (Li et al 2007). We further confirmed the association (Nicholson et al 2011) observed for trimethylamine (TMA), thus confirming the strong impact of genetics on the metabolism of a precursor to the major cardiovascular risk factor TMAO (Wang et al 2011).…”

Section: Replication Of Gene-metabolism Associationssupporting

confidence: 68%

Current status on genome–metabolome-wide associations: an opportunity in nutrition research

et al. 2012

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Genome-wide association studies (GWASs) have become a very important tool to address the genetic origin of phenotypic variability, in particular associated with diseases. Nevertheless, these types of studies provide limited information about disease etiology and the molecular mechanisms involved. Recently, the incorporation of metabolomics into the analysis has offered novel opportunities for a better understanding of disease-related metabolic deregulation. The pattern emerging from this work is that gene-driven changes in metabolism are prevalent and that common genetic variations can have a profound impact on the homeostatic concentrations of specific metabolites. A particularly interesting aspect of this work takes into account interactions of environment and lifestyle with the genome and how this interaction translates into changes in the metabolome. For instance, the role of PY-ROXD2 in trimethylamine metabolism points to an interaction between host and microbiome genomes (host/ microbiota). Often, these findings reveal metabolic deregulations, which could eventually be tuned with a nutritional intervention. Here we review the development of gene-metabolism association studies from a single-gene/ single-metabolite to a genome-wide/metabolome-wide approach and highlight the conceptual changes associated with this ongoing transition. Moreover, we report some of our recent GWAS results on a cohort of 265 individuals from an ethnically diverse population that validate and refine previous findings on gene-urine metabolism interactions. Specifically, our results confirm the effect of PYROXD2 polymorphisms on trimethylamine metabolism and suggest that a previously reported association of N-acetylated compounds with the ALMS1/NAT8 locus is driven by SNPs in the ALMS1 gene.

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Section: Replication Of Gene-metabolism Associationssupporting

confidence: 68%

Current status on genome–metabolome-wide associations: an opportunity in nutrition research

et al. 2012

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“…70 In support, recent genome-wide association studies showed a link between the SLC22A2 gene and both serum creatinine and estimated glomerular filtration rate. 71,72 The SLC22A2 genotype was found to be associated with a net tubular creatinine secretion phenotype, indicating that using plasma creatinine levels to determine renal function in CKD is biased. 73 Remarkably, data obtained in animals are less conclusive and quite Figure 2.…”

Section: Octs In Uremiamentioning

confidence: 99%

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Masereeuw

Mutsaers

Toyohara³

et al. 2014

Seminars in Nephrology

130

118

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This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited.

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“…Systemic approaches identified novel players in renal fibrosis (157), such as the homeodomain interacting protein kinase 2 (HIPK2) in HIV transgenic mice (158). In patients with chronic kidney disease or glomerulosclerosis, genome-wide association studies (GWAS) identified several susceptibility loci (159)(160)(161), including in genes for myosin heavy chain 9 (MYH9) and uromodulin (Tamm-Horsfall protein, UMOD). Both proteins are expressed in TECs, the latter exclusively.…”

Section: The Role Of Glomerular Cellsmentioning

confidence: 99%

Renal Allograft Fibrosis: Biology and Therapeutic Targets

Floege

2015

American Journal of Transplantation

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Genetic loci influencing kidney function and chronic kidney disease

Cited by 246 publications

References 16 publications

Current status on genome–metabolome-wide associations: an opportunity in nutrition research

Current status on genome–metabolome-wide associations: an opportunity in nutrition research

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Renal Allograft Fibrosis: Biology and Therapeutic Targets

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