title: Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations.
abstract: 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 (χ2df2=3545, 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 (χ2df2=3190,p=7.23×10-08). 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).
  
  
  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.
authors.affiliation: 550 N, Broadway, Suite 1101, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA. rscharpf@jhu.edu.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Scharpf
authors.forename: Lynn
authors.initials: L
authors.lastname: Mireles
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.forename: Katalin
authors.initials: K
authors.lastname: Susztak
authors.forename: Eitan
authors.initials: E
authors.lastname: Halper-Stromberg
authors.forename: Adrienne
authors.initials: A
authors.lastname: Tin
authors.forename: Stephen
authors.initials: S
authors.lastname: Cristiano
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.forename: Wen Hong
authors.initials: WH
authors.lastname: Linda Kao
mesh_terms: D056915:DNA Copy Number Variations; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D027361:Organic Anion Transporters / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D014527:Uric Acid / Q000097:blood*; D044465:White People / Q000235:genetics
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D027361:Organic Anion Transporters; C411811:SLC2A9 protein, human; C103862:urate transporter; D014527:Uric Acid