CUBN Is a Gene Locus for Albuminuria

Böger, Carsten A.; Chen, Ming-Huei; Tin, Adrienne; Olden, Matthias; Köttgen, Anna; Boer, Ian H. de; Fuchsberger, Christian; O’Seaghdha, Conall M.; Pattaro, Cristian; Teumer, Alexander; Liu, Ching‐Ti; Glazer, Nicole L.; Li, Man; O’Connell, Jeffrey R.; Tanaka, Toshiko; Peralta, Carmen A.; Kutalik, Zoltán; Luan, Jian’an; Zhao, Jing Hua; Hwang, Shih Jen; Akylbekova, Ermeg L.; Kramer, Holly; Harst, Pim van der; Smith, Albert V.; Lohman, Kurt; Andrade, Mariza de; Hayward, Caroline; Kollerits, Barbara; Tönjes, Anke; Aspelund, Thor; Ingelsson, Erik; Eiríksdóttir, Guðný; Launer, Lenore J.; Harris, Tamara B.; Shuldiner, Alan R.; Mitchell, Braxton D.; Arking, Dan E.; Franceschini, Nora; Boerwinkle, Eric; Egan, Josephine M.; Hernandez, Dena G.; Reilly, Muredach P.; Townsend, Raymond R.; Lumley, Thomas; Siscovick, David S.; Psaty, Bruce M.; Kestenbaum, Bryan; Haritunians, Talin; Bergmann, Sven; Vollenweider, Péter; Waeber, Gérard; Mooser, Vincent; Waterworth, Dawn; Johnson, Andrew D.; Florez, José C.; Meigs, James B.; Lu, Xiaoning; Turner, Stephen T.; Atkinson, Elizabeth J.; Leak, Tennille S.; Aasarød, Knut; Skorpen, Frank; Syvänen, Ann Christine; Illig, Thomas; Baumert, Jens; Köenig, Wolfgang; Krämer, Bernhard K.; Devuyst, Olivier; Mychaleckyj, Josyf C.; Minelli, Cosetta; Bakker, Stephan J. L.; Kedenko, Lyudmyla; Paulweber, Bernhard; Coassin, Stefan; Endlich, Karlhans; Kroemer, Heyo K.; Biffar, Reiner; Stracke, Sylvia; Völzke, Henry; Stümvoll, Michael; Mägi, Reedik; Campbell, Harry; Vitart, Véronique; Hastie, Nicholas D.; Gudnason, Vilmundur; Kardia, Sharon L.R.; Liu, Yongmei; Polašek, Ozren; Curhan, Gary C.; Kronenberg, Florian; Prokopenko, Inga; Rudan, Igor; Ärnlöv, Johan; Hallan, Stein; Navis, Gerjan; Parsa, Afshin; Ferrucci, Luigi; Coresh, Josef; Shlipak, Michael G.; Bull, Shelley B.; Paterson, Andrew D.; Wichmann, H‐Erich; Wareham, Nicholas J.; Loos, Ruth J.F.; Rotter, Jerome I.; Pramstaller, Peter P.; Cupples, L. Adrienne; Beckmann, Jacques S.; Yang, Qiong; Heid, Iris M.; Rettig, Rainer; Dreisbach, Albert W.; Bochud, Murielle; Fox, Caroline S.; Kao, W. H. Linda

doi:10.1681/asn.2010060598

Cited by 211 publications

(227 citation statements)

References 76 publications

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“…39 Furthermore, a missense cubilin variant is associated with albuminuria in both the general population and individuals with diabetes. 40 Decreased renal cubilin-mediated salvage may affect HDL homeostasis in diabetes. In mouse models of diabetes, levels of renal cubilin are decreased.…”

Section: Discussionmentioning

confidence: 99%

Cubilin Maintains Blood Levels of HDL and Albumin

Aseem

Smith

Cooley

et al. 2014

Journal of the American Society of Nephrology

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Cubilin is an endocytic receptor highly expressed in renal proximal tubules, where it mediates uptake of albumin and filtered forms of apoA-I/HDL. Cubilin deficiency leads to urinary loss of albumin and apoA-I; however, the consequences of cubilin loss on the homeostasis of blood albumin and apoA-I/HDL have not been studied. Using mice heterozygous for cubilin gene deletion (cubilin HT mice), we show that cubilin haploinsufficiency leads to reduced renal proximal tubular uptake of albumin and apoA-I and significantly increased urinary loss of albumin and apoA-I. Moreover, cubilin HT mice displayed significantly decreased blood levels of albumin, apoA-I, and HDL. The levels of albumin and apoA-I protein or mRNA expressed in the liver, kidney, or intestine of cubilin HT mice did not change significantly. The clearance rate of small HDL 3 particles (density.1.13 g/ml) from the blood increased significantly in cubilin HT mice. In contrast, the rate of clearance of larger HDL 2 particles from the blood did not change significantly, indicating a decreased half-life for HDL particles capable of filtering through the glomerulus. On the basis of these findings, we conclude that cubilin deficiency reduces renal salvage and delivery back to the blood of albumin and apoA-I, which decreases blood levels of albumin and apoA-I/HDL. These findings raise the possibility that therapeutic increase of renal cubilin expression might reduce proteinuria and increase blood levels of albumin and HDL.

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Section: Discussionmentioning

confidence: 99%

Cubilin Maintains Blood Levels of HDL and Albumin

Aseem

Smith

Cooley

et al. 2014

Journal of the American Society of Nephrology

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“…We manually curated a list of SNPs that both passed genome-wide significance and were associated with kidney disease traits (Table S7). [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] To acquire independent loci, we removed any SNPs having r 2 R 0.2. In total, we analyzed 110 leading SNPs and 2,357 tagging SNPs with r 2 R 0.8 (Table S7).…”

Section: Kidney Eqtl Highlights the Genetics Of Disease Traitsmentioning

confidence: 99%

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Qiu

et al. 2017

The American Journal of Human Genetics

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Chronic kidney disease (CKD) is a complex gene-environmental disease affecting close to 10% of the US population. Genome-wide association studies (GWASs) have identified sequence variants, localized to non-coding genomic regions, associated with kidney function. Despite these robust observations, the mechanism by which variants lead to CKD remains a critical unanswered question. Expression quantitative trait loci (eQTL) analysis is a method to identify genetic variation associated with gene expression changes in specific tissue types. We hypothesized that an integrative analysis combining CKD GWAS and kidney eQTL results can identify candidate genes for CKD. We performed eQTL analysis by correlating genotype with RNA-seq-based gene expression levels in 96 human kidney samples. Applying stringent statistical criteria, we detected 1,886 genes whose expression differs with the sequence variants. Using direct overlap and Bayesian methods, we identified new potential target genes for CKD. With respect to one of the target genes, lysosomal beta A mannosidase (MANBA), we observed that genetic variants associated with MANBA expression in the kidney showed statistically significant colocalization with variants identified in CKD GWASs, indicating that MANBA is a potential target gene for CKD. The expression of MANBA was significantly lower in kidneys of subjects with risk alleles. Suppressing manba expression in zebrafish resulted in renal tubule defects and pericardial edema, phenotypes typically induced by kidney dysfunction. Our analysis shows that gene-expression changes driven by genetic variation in the kidney can highlight potential new target genes for CKD development.

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“…[15][16][17][18][19][20][21] The strongest of these associations is at the UMOD locus, 15,17,18,20,22,23 a gene in which rare variants are known to cause autosomal-dominant kidney diseases with high risk for ESRD: MCKD2 (Online Mendelian Inheritance in Man [OMIM] database #603860), HNFJ1 (OMIM #162000), or GCKD (OMIM #609886). In addition, other kidney disease genes in which mutations follow Mendelian inheritance patterns were uncovered in GWAS of kidney function (SLC7A9, SLC34A1) 17 and albuminuria (CUBN) 21 in the general population. Similar examples exist for traits such as hypertension and dyslipidemia, in which common variants in genes causing inherited Mendelian diseases are identified in population-based GWAS.…”

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confidence: 99%

Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function

Parsa

Fuchsberger

Köttgen

et al. 2013

Journal of the American Society of Nephrology

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Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency .5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.J Am Soc Nephrol 24: 2105 -2117, 2013 . doi: 10.1681 CKD affects approximately 10% of the general population in industrialized nations, and is significantly associated with cardiovascular morbidity and mortality. [1][2][3][4] Traditional risk factors for CKD, including diabetes and hypertension, fail to fully explain the increased risk of CKD, 5-9 suggesting other factors including a genetic component. Family studies indicate familial aggregation of CKD and ESRD risk. 10 For example, family studies have shown that genetic factors account for 36%-75% of the variability in kidney function, with similar estimates for disease susceptibility and CKD progression. [10][11][12][13][14] Therefore, unraveling the genetic underpinnings of CKD bears the potential of discovering novel disease mechanisms as a basis for research into much needed therapeutic targets and strategies.Genome-wide association studies (GWAS) recently identified several genomic loci associated with kidney traits. [15][16][17][18][19][20][21] The strongest of these associations is at the UMOD locus, 15,17,18,20,22,23 a gene in which rare variants are known to cause autosomal-dominant kidney diseases with high risk for ESRD: MCKD2 (Online Mendelian Inheritance in Man [OMIM] database #603860), HNFJ1 (OMIM #162000), or GCKD (OMIM #609886). In addition, other kidney disease genes in which mutations follow Mendelian inheritance patterns were uncovered in GWAS of kidney function (SLC7A9, SLC34A1) 17 and albuminuria (CUBN) 21 in the general population. Similar examples exist for traits such as hypertension and dyslipidemia, in which common variants in genes c...

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CUBN Is a Gene Locus for Albuminuria

Cited by 211 publications

References 76 publications

Cubilin Maintains Blood Levels of HDL and Albumin

Cubilin Maintains Blood Levels of HDL and Albumin

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function

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