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Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations

BACKGROUND: Hyperuricemia is associated with multiple diseases, including gout, cardiovascular disease, and renal disease. Serum urate is highly heritable, yet association studies of single nucleotide polymorphisms (SNPs) and serum uric acid explain a small fraction of the heritability. Whether copy...

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Autores principales: Scharpf, Robert B, Mireles, Lynn, Yang, Qiong, Köttgen, Anna, Ruczinski, Ingo, Susztak, Katalin, Halper-Stromberg, Eitan, Tin, Adrienne, Cristiano, Stephen, Chakravarti, Aravinda, Boerwinkle, Eric, Fox11, Caroline S, Coresh, Josef, Linda Kao, Wen Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118309/
https://www.ncbi.nlm.nih.gov/pubmed/25007794
http://dx.doi.org/10.1186/1471-2156-15-81
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author Scharpf, Robert B
Mireles, Lynn
Yang, Qiong
Köttgen, Anna
Ruczinski, Ingo
Susztak, Katalin
Halper-Stromberg, Eitan
Tin, Adrienne
Cristiano, Stephen
Chakravarti, Aravinda
Boerwinkle, Eric
Fox11, Caroline S
Coresh, Josef
Linda Kao, Wen Hong
author_facet Scharpf, Robert B
Mireles, Lynn
Yang, Qiong
Köttgen, Anna
Ruczinski, Ingo
Susztak, Katalin
Halper-Stromberg, Eitan
Tin, Adrienne
Cristiano, Stephen
Chakravarti, Aravinda
Boerwinkle, Eric
Fox11, Caroline S
Coresh, Josef
Linda Kao, Wen Hong
author_sort Scharpf, Robert B
collection PubMed
description BACKGROUND: Hyperuricemia is associated with multiple diseases, including gout, cardiovascular disease, and renal disease. Serum urate is highly heritable, yet association studies of single nucleotide polymorphisms (SNPs) and serum uric acid explain a small fraction of the heritability. Whether copy number polymorphisms (CNPs) contribute to uric acid levels is unknown. RESULTS: We assessed copy number on a genome-wide scale among 8,411 individuals of European ancestry (EA) who participated in the Atherosclerosis Risk in Communities (ARIC) study. CNPs upstream of the urate transporter SLC2A9 on chromosome 4p16.1 are associated with uric acid ([Formula: see text] , p=3.19×10(-23)). Effect sizes, expressed as the percentage change in uric acid per deleted copy, are most pronounced among women ((3.97)4.93(5.87) [ (2.5)50(97.5) denoting percentiles], p=4.57×10(-23)) and independent of previously reported SNPs in SLC2A9 as assessed by SNP and CNP regression models and the phasing SNP and CNP haplotypes ([Formula: see text]). Our finding is replicated in the Framingham Heart Study (FHS), where the effect size estimated from 4,089 women is comparable to ARIC in direction and magnitude ((1.41)4.70(7.88), p=5.46×10(-03)). CONCLUSIONS: This is the first study to characterize CNPs in ARIC and the first genome-wide analysis of CNPs and uric acid. Our findings suggests a novel, non-coding regulatory mechanism for SLC2A9-mediated modulation of serum uric acid, and detail a bioinformatic approach for assessing the contribution of CNPs to heritable traits in large population-based studies where technical sources of variation are substantial.
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spelling pubmed-41183092014-08-05 Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations Scharpf, Robert B Mireles, Lynn Yang, Qiong Köttgen, Anna Ruczinski, Ingo Susztak, Katalin Halper-Stromberg, Eitan Tin, Adrienne Cristiano, Stephen Chakravarti, Aravinda Boerwinkle, Eric Fox11, Caroline S Coresh, Josef Linda Kao, Wen Hong BMC Genet Research Article BACKGROUND: Hyperuricemia is associated with multiple diseases, including gout, cardiovascular disease, and renal disease. Serum urate is highly heritable, yet association studies of single nucleotide polymorphisms (SNPs) and serum uric acid explain a small fraction of the heritability. Whether copy number polymorphisms (CNPs) contribute to uric acid levels is unknown. RESULTS: We assessed copy number on a genome-wide scale among 8,411 individuals of European ancestry (EA) who participated in the Atherosclerosis Risk in Communities (ARIC) study. CNPs upstream of the urate transporter SLC2A9 on chromosome 4p16.1 are associated with uric acid ([Formula: see text] , p=3.19×10(-23)). Effect sizes, expressed as the percentage change in uric acid per deleted copy, are most pronounced among women ((3.97)4.93(5.87) [ (2.5)50(97.5) denoting percentiles], p=4.57×10(-23)) and independent of previously reported SNPs in SLC2A9 as assessed by SNP and CNP regression models and the phasing SNP and CNP haplotypes ([Formula: see text]). Our finding is replicated in the Framingham Heart Study (FHS), where the effect size estimated from 4,089 women is comparable to ARIC in direction and magnitude ((1.41)4.70(7.88), p=5.46×10(-03)). CONCLUSIONS: This is the first study to characterize CNPs in ARIC and the first genome-wide analysis of CNPs and uric acid. Our findings suggests a novel, non-coding regulatory mechanism for SLC2A9-mediated modulation of serum uric acid, and detail a bioinformatic approach for assessing the contribution of CNPs to heritable traits in large population-based studies where technical sources of variation are substantial. BioMed Central 2014-07-09 /pmc/articles/PMC4118309/ /pubmed/25007794 http://dx.doi.org/10.1186/1471-2156-15-81 Text en Copyright © 2014 Scharpf et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Scharpf, Robert B
Mireles, Lynn
Yang, Qiong
Köttgen, Anna
Ruczinski, Ingo
Susztak, Katalin
Halper-Stromberg, Eitan
Tin, Adrienne
Cristiano, Stephen
Chakravarti, Aravinda
Boerwinkle, Eric
Fox11, Caroline S
Coresh, Josef
Linda Kao, Wen Hong
Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations
title Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations
title_full Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations
title_fullStr Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations
title_full_unstemmed Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations
title_short Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations
title_sort copy number polymorphisms near slc2a9 are associated with serum uric acid concentrations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118309/
https://www.ncbi.nlm.nih.gov/pubmed/25007794
http://dx.doi.org/10.1186/1471-2156-15-81
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