Abstract
BackgroundReduced renal excretion of uric acid plays a significant role in the development of hyperuricemia and gout in adults. Hyperuricemia has been associated with chronic kidney disease and cardiovascular disease in children and adults. There are limited genome-wide association studies associating genetic polymorphisms with renal urate excretion measures. Therefore, we investigated the genetic factors that influence the excretion of uric acid and related indices in 768 Hispanic children of the Viva La Familia Study.MethodsWe performed a genome-wide association analysis for 24-h urinary excretion measures such as urinary uric acid/urinary creatinine ratio, uric acid clearance, fractional excretion of uric acid, and glomerular load of uric acid in SOLAR, while accounting for non-independence among family members.ResultsAll renal urate excretion measures were significantly heritable (p <2 × 10−6) and ranged from 0.41 to 0.74. Empirical threshold for genome-wide significance was set at p <1 × 10−7. We observed a strong association (p < 8 × 10−8) of uric acid clearance with a single nucleotide polymorphism (SNP) in zinc finger protein 446 (ZNF446) (rs2033711 (A/G), MAF: 0.30). The minor allele (G) was associated with increased uric acid clearance. Also, we found suggestive associations of uric acid clearance with SNPs in ZNF324, ZNF584, and ZNF132 (in a 72 kb region of 19q13; p <1 × 10−6, MAFs: 0.28–0.31).ConclusionFor the first time, we showed the importance of 19q13 region in the regulation of renal urate excretion in Hispanic children. Our findings indicate differences in inherent genetic architecture and shared environmental risk factors between our cohort and other pediatric and adult populations.
Highlights
Reduced renal excretion of uric acid plays a significant role in the development of hyperuricemia and gout in adults
Measured Genotype Analysis (MGA) was conducted using a variance components approach in 768 Viva La Familia Study (VFS) Hispanic children that accounted for family kinships (Table 2)
Genome-wide significant evidence of association was found for single nucleotide polymorphism (SNP) rs2033711, an intronic variant, in zinc finger protein 446 (ZNF446) on chromosome 19 with uric acid clearance (UACl) (p
Summary
Reduced renal excretion of uric acid plays a significant role in the development of hyperuricemia and gout in adults. Hyperuricemia has been associated with chronic kidney disease and cardiovascular disease in children and adults. Hyperuricemia and hyperuricosuria (increased urinary uric acid (UrUA) concentrations) can lead to uric acid nephrolithiasis [5,6,7]. These two are common multifactorial disorders that have been shown to have a familial inheritance and further associated with progression to chronic kidney disease [4, 8, 9]. Hyperuricemia is shown to cluster within families, heritabilities ranged from 39 to 45% in our family studies [10, 11], and twin studies up to 80% for serum uric acid [12], 60% for renal clearance of urate and 87% for fractional excretion of urate [13]
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