Key result
The SLC2A9 SNP rs12509955 was significantly associated with both urinary uric acid concentration (β = 40.0, corrected p=0.001) and SLC2A9 gene expression levels (corrected p=0.0084).
Cross-Sectional (n=541)
No
Effect estimate: β = 40.0
p-value: p=0.001
Genetic variation in the SLC2A9 gene influences both its gene expression and urinary uric acid excretion, with potential gene-by-diet interactions affecting uric acid levels in individuals consuming higher protein.
rs12509955 may affect uric acid handling via SLC2A9; leaves open replication and gene-diet interaction studies in hyperuricemia.
OBJECTIVES: SLC2A9 gene variants have been associated with urinary uric acid (UA) concentration, but little is known about the functional mechanism linking these gene variants with UA. SLC2A9 encodes a UA transporter present in the proximal tubule of the kidney, and gene expression levels of SLC2A9 and other genes in the uricosuric pathway (ABCG2, SLC17A1, SLC17A3, and SLC22A12) could potentially mediate the relationship between SLC2A9 gene variants and urinary UA excretion. METHODS: The association between urinary UA concentrations and single nucleotide polymorphisms (SNPs) within the SLC2A9 gene region, expression levels of genes in the uricosuric pathway, and dietary protein intake were analyzed for a sample of non-Hispanic white participants from the Genetic Epidemiology Network of Arteriopathy (GENOA) cohort. The SLC2A9 SNP most significantly associated with urinary UA concentration was then tested for associations with gene expression levels from uric acid absorption/secretion associated genes. Models including interactions between dietary protein (total, animal, and vegetable) and genetic factors were also assessed. RESULTS: The most significant SLC2A9 SNP associated with urinary UA (rs12509955, corrected p = 0.001) was also associated with SLC2A9 gene expression levels (corrected p = 0.0084); however, SLC2A9 gene expression levels were not significantly associated with urinary UA concentrations (p = 0.509). The interactions between rs12509955 and total dietary protein, and SLC2A9 gene-level gene expression and dietary vegetable protein on the outcome of urinary UA were marginally significant (p = 0.11 and p = 0.07, respectively). Gene expression level of one SLC2A9 transcript had a significant interaction with dietary animal protein (SLC2A9-001 ENST00000506583, p = 0.01) and a marginally significant interaction with total dietary protein (p = 0.07) on urinary UA. CONCLUSION: Our results illustrate that SNPs in the SLC2A9 gene influence SLC2A9 gene expression as well as urinary UA excretion. Evidence is also suggestive that gene-by-diet interactions may disproportionately increase urinary UA in genetically susceptible individuals that consume higher amounts of protein.
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Ware et al. (2015) conducted a cross-sectional in Urinary uric acid excretion (n=541). SLC2A9 genotype (rs12509955) vs. Alternative alleles was evaluated on Urinary uric acid concentration (β = 40.0, p=0.001). The SLC2A9 SNP rs12509955 was significantly associated with both urinary uric acid concentration (β = 40.0, corrected p=0.001) and SLC2A9 gene expression levels (corrected p=0.0084).
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