Open Access Highly Accessed Research article

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

Robert B Scharpf15*, Lynn Mireles2, Qiong Yang3, Anna Köttgen24, Ingo Ruczinski5, Katalin Susztak6, Eitan Halper-Stromberg7, Adrienne Tin2, Stephen Cristiano8, Aravinda Chakravarti9, Eric Boerwinkle10, Caroline S Fox1111, Josef Coresh2 and Wen Hong Linda Kao2

Author Affiliations

1 550 N. Broadway, Suite 1101, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA

2 Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA

3 Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA

4 Department of Medicine IV, University Hospital Freiburg, Freiburg im Breisgau, Germany

5 Department of Biostatistics, Johns Hopkins School of Public Health, Baltimore, Maryland, USA

6 Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA

7 Computational Biosciences Program, University of Colorado, Denver, Aurora, Colorado, USA

8 Department of Biostatistics, Johns Hopkins School of Public Health, Baltimore, Maryland, USA

9 Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

10 IMM Center for Human Genetics, University of Texas School of Public Health, Houston, Texas, USA

11 Laboratory for Metabolic and Population Health, National Heart Lung and Blood Institute, National Institutes of Health, Framingham, Massachusetts, USA

For all author emails, please log on.

BMC Genetics 2014, 15:81  doi:10.1186/1471-2156-15-81

Published: 9 July 2014



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.


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 (<a onClick="popup('','MathML',630,470);return false;" target="_blank" href="">View MathML</a>, p=3.19×10-23). Effect sizes, expressed as the percentage change in uric acid per deleted copy, are most pronounced among women (3.974.935.87 [ 2.55097.5 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 (<a onClick="popup('','MathML',630,470);return false;" target="_blank" href="">View MathML</a>). 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 (1.414.707.88, p=5.46×10-03).


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.

Copy number polymorphism; Hyperuricemia; Genomewide association study