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New loci associated with kidney function and chronic kidney disease.

ABSTRACT: Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

SUBMITTER: Kottgen A

PROVIDER: S-EPMC2997674 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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New loci associated with kidney function and chronic kidney disease.

Köttgen Anna A Pattaro Cristian C Böger Carsten A CA Fuchsberger Christian C Olden Matthias M Glazer Nicole L NL Parsa Afshin A Gao Xiaoyi X Yang Qiong Q Smith Albert V AV O'Connell Jeffrey R JR Li Man M Schmidt Helena H Tanaka Toshiko T Isaacs Aaron A Ketkar Shamika S Hwang Shih-Jen SJ Johnson Andrew D AD Dehghan Abbas A Teumer Alexander A Paré Guillaume G Atkinson Elizabeth J EJ Zeller Tanja T Lohman Kurt K Cornelis Marilyn C MC Probst-Hensch Nicole M NM Kronenberg Florian F Tönjes Anke A Hayward Caroline C Aspelund Thor T Eiriksdottir Gudny G Launer Lenore J LJ Harris Tamara B TB Rampersaud Evadnie E Mitchell Braxton D BD Arking Dan E DE Boerwinkle Eric E Struchalin Maksim M Cavalieri Margherita M Singleton Andrew A Giallauria Francesco F Metter Jeffrey J de Boer Ian H IH Haritunians Talin T Lumley Thomas T Siscovick David D Psaty Bruce M BM Zillikens M Carola MC Oostra Ben A BA Feitosa Mary M Province Michael M de Andrade Mariza M Turner Stephen T ST Schillert Arne A Ziegler Andreas A Wild Philipp S PS Schnabel Renate B RB Wilde Sandra S Munzel Thomas F TF Leak Tennille S TS Illig Thomas T Klopp Norman N Meisinger Christa C Wichmann H-Erich HE Koenig Wolfgang W Zgaga Lina L Zemunik Tatijana T Kolcic Ivana I Minelli Cosetta C Hu Frank B FB Johansson Asa A Igl Wilmar W Zaboli Ghazal G Wild Sarah H SH Wright Alan F AF Campbell Harry H Ellinghaus David D Schreiber Stefan S Aulchenko Yurii S YS Felix Janine F JF Rivadeneira Fernando F Uitterlinden Andre G AG Hofman Albert A Imboden Medea M Nitsch Dorothea D Brandstätter Anita A Kollerits Barbara B Kedenko Lyudmyla L Mägi Reedik R Stumvoll Michael M Kovacs Peter P Boban Mladen M Campbell Susan S Endlich Karlhans K Völzke Henry H Kroemer Heyo K HK Nauck Matthias M Völker Uwe U Polasek Ozren O Vitart Veronique V Badola Sunita S Parker Alexander N AN Ridker Paul M PM Kardia Sharon L R SL Blankenberg Stefan S Liu Yongmei Y Curhan Gary C GC Franke Andre A Rochat Thierry T Paulweber Bernhard B Prokopenko Inga I Wang Wei W Gudnason Vilmundur V Shuldiner Alan R AR Coresh Josef J Schmidt Reinhold R Ferrucci Luigi L Shlipak Michael G MG van Duijn Cornelia M CM Borecki Ingrid I Krämer Bernhard K BK Rudan Igor I Gyllensten Ulf U Wilson James F JF Witteman Jacqueline C JC Pramstaller Peter P PP Rettig Rainer R Hastie Nick N Chasman Daniel I DI Kao W H WH Heid Iris M IM Fox Caroline S CS

Nature genetics 20100411 5

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2 ...[more]

PMID: 20383146

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Project description:BackgroundChronic kidney disease (CKD) in children is characterized by rapid progression and a high incidence of end-stage renal disease and therefore constitutes an important health problem. While unbiased genetic screens have identified common risk variants influencing renal function and CKD in adults, the presence and identity of such variants in pediatric CKD are unknown.MethodsThe international Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) and Cardiovascular Comorbidity in Children with CKD (4C). Clean genotype data from > 10 million genotyped or imputed single-nucleotide polymorphisms (SNPs) were available for 1136 patients with measurements of serum creatinine at study enrollment. Genome-wide association studies were conducted to relate the SNPs to creatinine-based estimated glomerular filtration rate (eGFR crea) and proteinuria (urinary albumin- or protein-to-creatinine ratio ≥ 300 and ≥ 500 mg/g, respectively). In addition, European-ancestry PediGFR patients (cases) were compared with 1347 European-ancestry children without kidney disease (controls) to identify genetic variants associated with the presence of CKD.ResultsSNPs with suggestive association P-values < 1 × 10(-5) were identified in 10 regions for eGFR crea, four regions for proteinuria and six regions for CKD including some plausible biological candidates. No SNP was associated at genome-wide significance (P < 5 × 10(-8)). Investigation of the candidate genes for proteinuria in adults from the general population provided support for a region on chromosome 15 near RSL24D1/UNC13C/RAB27A. Conversely, targeted investigation of genes harboring GFR-associated variants in adults from the general population did not reveal significantly associated SNPs in children with CKD.ConclusionsOur findings suggest that larger collaborative efforts will be needed to draw reliable conclusions about the presence and identity of common variants associated with eGFR, proteinuria and CKD in pediatric populations.

Project description:BackgroundHypothyroidism and low free triiodothyronine (FT3) syndrome [low FT3 levels with normal thyroid-stimulating hormone (TSH)] have been associated with reduced kidney function cross-sectionally in chronic kidney disease (CKD) patients with severely reduced estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD). Results on the prospective effects of impaired thyroid function on renal events and mortality for patients with severely reduced eGFR or from population-based cohorts are conflicting. Here we evaluated the association between thyroid and kidney function with eGFR (cross-sectionally) as well as renal events and mortality (prospectively) in a large, prospective cohort of CKD patients with mild to moderately reduced kidney function.MethodsThyroid markers were measured among CKD patients from the German Chronic Kidney Disease study. Incident renal endpoints (combined ESKD, acute kidney injury and renal death) and all-cause mortality were abstracted from hospital records and death certificates. Time to first event analysis of complete data from baseline to the 4-year follow-up (median follow-up time 4.04 years) of 4600 patients was conducted. Multivariable linear regression and Cox proportional hazards models were fitted for single and combined continuous thyroid markers [TSH, free thyroxine (FT4), FT3] and thyroid status.ResultsCross-sectionally, the presence of low-FT3 syndrome showed a significant inverse association with eGFR and continuous FT3 levels alone showed a significant positive association with eGFR; in combination with FT4 and TSH, FT3 levels also showed a positive association and FT4 levels showed a negative association with eGFR. Prospectively, higher FT4 and lower FT3 levels were significantly associated with a higher risk of all-cause mortality (N events = 297). Per picomole per litre higher FT3 levels the risk of reaching the composite renal endpoint was 0.73-fold lower (95% confidence interval 0.65-0.82; N events = 615). Compared with euthyroid patients, patients with low-FT3 syndrome had a 2.2-fold higher risk and patients with hypothyroidism had a 1.6-fold higher risk of experiencing the composite renal endpoint.ConclusionsPatients with mild to moderate CKD suffering from thyroid function abnormalities are at an increased risk of adverse renal events and all-cause mortality over time.

Project description:Epidemiological studies demonstrate an association between migraine and chronic kidney disease (CKD), while the genetic basis underlying the phenotypic association has not been investigated. We aimed to help avoid unnecessary interventions in individuals with migraine through the investigation of phenotypic and genetic relationships underlying migraine, CKD, and kidney function. We first evaluated phenotypic associations using observational data from UK Biobank (N = 255,896). We then investigated genetic relationships leveraging genomic data in European ancestry for migraine (Ncase/Ncontrol = 48,975/540,381), CKD (Ncase/Ncontrol = 41,395/439,303), and two traits of kidney function (estimated glomerular filtration rate [eGFR, N = 567,460] and urinary albumin-to-creatinine ratio [UACR, N = 547,361]). Observational analyses suggested no significant association of migraine with the risk of CKD (HR = 1.13, 95% CI = 0.85-1.50). While we did not find any global genetic correlation in general, we identified four specific genomic regions showing significant for migraine with eGFR. Cross-trait meta-analysis identified one candidate causal variant (rs1047891) underlying migraine, CKD, and kidney function. Transcriptome-wide association study detected 28 shared expression-trait associations between migraine and kidney function. Mendelian randomization analysis suggested no causal effect of migraine on CKD (OR = 1.03, 95% CI = 0.98-1.09; P = 0.28). Despite a putative causal effect of migraine on an increased level of UACR (log-scale-beta = 0.02, 95% CI = 0.01-0.04; P = 1.92 × 10-3), it attenuated to null when accounting for both correlated and uncorrelated pleiotropy. Our work does not find evidence supporting a causal association between migraine and CKD. However, our study highlights significant biological pleiotropy between migraine and kidney function. The value of a migraine prophylactic treatment for reducing future CKD in people with migraine is likely limited.

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New loci associated with kidney function and chronic kidney disease.

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New loci associated with kidney function and chronic kidney disease.

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