Dataset Information

Long-term effects of the SLC2A9 G844A and SLC22A12 C246T variants on serum uric acid concentrations in children.

ABSTRACT:

Background

We evaluated the effects of two single-nucleotide polymorphisms on UA concentrations in the first decade of life using repeated-measures data.

Methods

We included all subjects who were followed-up at least once and for whom we had both UA and genotypic data (i.e., 375, 204, 307, and 363 patients aged 3, 5, 7, and 9 years, respectively). All participated in the Ewha Birth and Growth Cohort study. We used a mixed model analysis to estimate the longitudinal association of serum UA concentration due to the rs3825017 (SLC22A12 c. 246C > T) and rs16890979 (SLC2A9 c. 844G > A) genotypes.

Results

Overall, the tracking coefficient of UA concentrations in children 3 to 9 years of age was 0.31, and was higher in boys than in girls (0.34 vs. 0.29, respectively). Regarding individual variance, serum UA concentrations decreased as age increased (β = - 0.07, p < 0.05), but there were no significant differences by sex. The effects of rs3825017 on UA concentration were significant in boys, but not in girls. Boys with the T allele of rs3825017 had higher concentrations than their counterparts regardless of the time of follow-up. The rs16890979 genotypes were not significantly associated with serum UA concentration in either sex.

Conclusion

This study showed that rs3825017 in the SLC22A12 gene was associated with UA concentration in childhood.

SUBMITTER: Lee HA

PROVIDER: S-EPMC6127956 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Long-term effects of the SLC2A9 G844A and SLC22A12 C246T variants on serum uric acid concentrations in children.

Lee Hye Ah HA Park Bo Hyun BH Park Eun Ae EA Cho Su Jin SJ Kim Hae Soon HS Park Hyesook H

BMC pediatrics 20180906 1

<h4>Background</h4>We evaluated the effects of two single-nucleotide polymorphisms on UA concentrations in the first decade of life using repeated-measures data.<h4>Methods</h4>We included all subjects who were followed-up at least once and for whom we had both UA and genotypic data (i.e., 375, 204, 307, and 363 patients aged 3, 5, 7, and 9 years, respectively). All participated in the Ewha Birth and Growth Cohort study. We used a mixed model analysis to estimate the longitudinal association of ...[more]

PMID: 30189835

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Project description:ObjectivesSLC2A9 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.MethodsThe 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.ResultsThe 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.ConclusionOur 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.

Project description:Introduction: The excretion and absorption of uric acid (UA) by the kidneys helps regulate serum UA levels. GLUT9, encoded by SLC2A9, is mainly expressed in the renal tubules responsible for UA absorption. SLC2A9 polymorphisms are associated with different serum UA levels. However, the lack of proper in vitro models has stalled research on the mechanisms of single nucleotide polymorphisms (SNPs) that affect UA metabolism in human urate transporters. Methods: In this study, we constructed a gene-edited human embryonic stem cells-9 (ESC-H9) derived kidney organoid bearing rs16890979, an SLC2A9 missense mutation with undetermined associations with hyperuricemia or hypouricemia. Kidney organoids derived from ESC-H9 with genetical overexpression (OE) and low expression (shRNA) of SLC2A9 to serve as controls to study the function of SLC2A9. The function of rs16890979 on UA metabolism was evaluated after placing the organoids to urate-containing medium and following histopathological analysis. Results: The kidney organoids with heterozygous or homozygous rs16890979 mutations showed normal SLC2A9 expression levels and histological distribution, phenotypically similar to the wild-type controls. However, reduced absorption of UA by the kidney organoids with rs16890979 mutants was observed. This finding together with the observation that UA absorption is increased in organoids with SLC2A9 overexpression and decreased in those with SLC2A9 knockdown, suggest that GLUT9 is responsible for UA absorption, and the rs16890979 SNP may compromise this functionality. Moreover, epithelial-mesenchymal transition (EMT) was detected in organoids after UA treatment, especially in the kidney organoid carrying GLUT9OE, suggesting the cytobiological mechanism explaining the pathological features in hyperuricosuria-related renal injury. Discussion: This study showing the transitional value of kidney organoid modeling the function of SNPs on UA metabolism. With a defined genetic background and a confirmed UA absorption function should be useful for studies on renal histological, cellular, and molecular mechanisms with this organoid model.

Dataset Information

Long-term effects of the SLC2A9 G844A and SLC22A12 C246T variants on serum uric acid concentrations in children.

Background

Methods

Results

Conclusion

Publications

Long-term effects of the SLC2A9 G844A and SLC22A12 C246T variants on serum uric acid concentrations in children.

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