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Influence of common genetic variants on childhood kidney outcomes.

ABSTRACT: Kidney measures in early life are associated with kidney disease in later life. We hypothesized that these associations are partly explained by common genetic variants that lead to both smaller kidneys with lower kidney function in early childhood and kidney disease in adulthood.We examined in a population-based prospective cohort study among 4,119 children the associations of a weighted genetic risk score combining 20 previously identified common genetic variants related to adult eGFRcreat with kidney outcomes in children aged 6.0 years (95% range 5.7-7.8). Childhood kidney outcomes included combined kidney volume, glomerular filtration rate (eGFR) based on creatinine levels, and microalbuminuria based on albumin and creatinine urine levels.We observed that the genetic risk score based on variants related to impaired kidney function in adults was associated with a smaller combined kidney volume (P value 3.0?×?10(-3)) and with a lower eGFR (P value 4.0?×?10(-4)) in children. The genetic risk score was not associated with microalbuminuria.Common genetic variants related to impaired kidney function in adults already lead to subclinical changes in childhood kidney outcomes. The well-known associations of kidney measures in early life with kidney disease in later life may at least be partly explained by common genetic variants.

SUBMITTER: Miliku K

PROVIDER: S-EPMC5496666 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Influence of common genetic variants on childhood kidney outcomes.

Miliku Kozeta K Vogelezang Suzanne S Franco Oscar H OH Hofman Albert A Jaddoe Vincent W V VW Felix Janine F JF

Pediatric research 20160309 1

<h4>Background</h4>Kidney measures in early life are associated with kidney disease in later life. We hypothesized that these associations are partly explained by common genetic variants that lead to both smaller kidneys with lower kidney function in early childhood and kidney disease in adulthood.<h4>Methods</h4>We examined in a population-based prospective cohort study among 4,119 children the associations of a weighted genetic risk score combining 20 previously identified common genetic varia ...[more]

PMID: 26959481

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Project description:The genetic etiology of sporadic neuroblastoma is still largely obscure. In a genome-wide association study, we identified single-nucleotide polymorphisms (SNP) associated with neuroblastoma at the CASC15, BARD1, LMO1, DUSP12, HSD17B12, HACE1, and LIN28B gene loci, but these explain only a small fraction of neuroblastoma heritability. Other neuroblastoma susceptibility genes are likely hidden among signals discarded by the multiple testing corrections. In this study, we evaluated eight additional genes selected as candidates for further study based on proven involvement in neuroblastoma differentiation. SNPs at these candidate genes were tested for association with disease susceptibility in 2,101 cases and 4,202 controls, with the associations found replicated in an independent cohort of 459 cases and 809 controls. Replicated associations were further studied for cis-effect using gene expression, transient overexpression, silencing, and cellular differentiation assays. The neurofilament gene NEFL harbored three SNPs associated with neuroblastoma (rs11994014: Pcombined = 0.0050; OR, 0.88; rs2979704: Pcombined = 0.0072; OR, 0.87; rs1059111: Pcombined = 0.0049; OR, 0.86). The protective allele of rs1059111 correlated with increased NEFL expression. Biologic investigations showed that ectopic overexpression of NEFL inhibited cell growth specifically in neuroblastoma cells carrying the protective allele. NEFL overexpression also enhanced differentiation and impaired the proliferation and anchorage-independent growth of cells with protective allele and basal NEFL expression, while impairing invasiveness and proliferation of cells homozygous for the risk genotype. Clinically, high levels of NEFL expression in primary neuroblastoma specimens were associated with better overall survival (P = 0.03; HR, 0.68). Our results show that common variants of NEFL influence neuroblastoma susceptibility and they establish that NEFL expression influences disease initiation and progression.

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Influence of common genetic variants on childhood kidney outcomes.

Publications

Influence of common genetic variants on childhood kidney outcomes.

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