Genetic loci associated with renal function measures and chronic kidney disease in children

TY - JOUR

T1 - Genetic loci associated with renal function measures and chronic kidney disease in children

T2 - the Pediatric Investigation for Genetic Factors Linked with Renal Progression Consortium

AU - Wuttke, Matthias

AU - Wong, Craig S

AU - Wühl, Elke

AU - Epting, Daniel

AU - Luo, Li

AU - Hoppmann, Anselm

AU - Doyon, Anke

AU - Li, Yong

AU - Sözeri, Betül

AU - Thurn, Daniela

AU - Helmstädter, Martin

AU - Huber, Tobias B

AU - Blydt-Hansen, Tom D

AU - Kramer-Zucker, Albrecht

AU - Mehls, Otto

AU - Melk, Anette

AU - Querfeld, Uwe

AU - Furth, Susan L

AU - Warady, Bradley A

AU - Schaefer, Franz

AU - Köttgen, Anna

AU - CKDGen Consortium

N1 - © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

PY - 2016/2

Y1 - 2016/2

N2 - BACKGROUND: Chronic 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.METHODS: The 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.RESULTS: SNPs 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.CONCLUSIONS: Our 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.

AB - BACKGROUND: Chronic 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.METHODS: The 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.RESULTS: SNPs 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.CONCLUSIONS: Our 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.

KW - Adolescent

KW - Child

KW - Child, Preschool

KW - Disease Progression

KW - Europe

KW - Female

KW - Genetic Loci

KW - Genome-Wide Association Study

KW - Genotype

KW - Glomerular Filtration Rate

KW - Humans

KW - Infant

KW - Male

KW - Morbidity

KW - Polymorphism, Single Nucleotide

KW - Renal Insufficiency, Chronic

KW - Risk Factors

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/ndt/gfv342

DO - 10.1093/ndt/gfv342

M3 - SCORING: Journal article

C2 - 26420894

VL - 31

SP - 262

EP - 269

JO - NEPHROL DIAL TRANSPL

JF - NEPHROL DIAL TRANSPL

SN - 0931-0509

IS - 2

ER -