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Blanka Stiburkova - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the influence of genetic variants of SLC2A9 glut9 and slc22a12 urat1 on the development of hyperuricemia and gout
Journal of Clinical Medicine, 2020Co-Authors: K Pavelcova, Jana Bohata, Marketa Pavlikova, Karel Pavelka, Eliska Bubenikova, Blanka StiburkovaAbstract:Urate transporters, which are located in the kidneys, significantly affect the level of uric acid in the body. We looked at genetic variants of genes encoding the major reabsorption proteins GLUT9 (SLC2A9) and URAT1 (SLC22A12) and their association with hyperuricemia and gout. In a cohort of 250 individuals with primary hyperuricemia and gout, we used direct sequencing to examine the SLC22A12 and SLC2A9 genes. Identified variants were evaluated in relation to clinical data, biochemical parameters, metabolic syndrome criteria, and our previous analysis of the major secretory urate transporter ABCG2. We detected seven nonsynonymous variants of SLC2A9. There were no nonsynonymous variants of SLC22A12. Eleven variants of SLC2A9 and two variants of SLC22A12 were significantly more common in our cohort than in the European population (p = 0), while variants p.V282I and c.1002+78A>G had a low frequency in our cohort (p = 0). Since the association between variants and the level of uric acid was not demonstrated, the influence of variants on the development of hyperuricemia and gout should be evaluated with caution. However, consistent with the findings of other studies, our data suggest that p.V282I and c.1002+78A>G (SLC2A9) reduce the risk of gout, while p.N82N (SLC22A12) increases the risk.
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p107 polymorphisms in SLC2A9 and slc22a12 genes are related to hyperuricemia gout and also to hypouricemia
Annals of the Rheumatic Diseases, 2019Co-Authors: K Pavelcova, Jana Bohata, Karel Pavelka, Blanka StiburkovaAbstract:Career situation of first and presenting author Student for a master or a PhD. Introduction Serum uric acid concentration is significantly influenced by urate transporters, such as ABCG2 (encoded by ABCG2 gene), GLUT9 (SLC2A9 gene) and URAT1 (SLC22A12 gene). The main function of ABCG2 is uric acid secretion, whereas GLU9 and URAT1 also ensure reabsorption. Pathogenic allelic variants in SLC2A9 and SLC22A12 are not only associated with hyperuricemia and gout, but they also lead to rare hereditary renal hypouricemia (type 1 – OMIM #220150 or type 2 – OMIM # 612076). Objectives Previously, we analyzed ABCG2 gene and detected non-synonymous variants that lead to hyperuricemia and early onset of the gout.1 The aim of this study was to find a possible correlation between variants in SLC2A9 and SLC22A12 and hypouricemia, hyperuricemia and gout.2 Methods We recruited a cohort of 232 individuals with primary gout and hyperuricemia. We examined coding regions of SLC2A9 (13 exons) and SLC22A12 (10 exons) by Sanger sequencing. We also analyzed SLC2A9 and SLC22A12 in five patients with suspect hypouricemia. Results In the cohort of 232 individuals, we detected five synonymous variants, 18 intron variants and seven missense variants in SLC2A9: A17T, G25R, T275M, D281H, V282I, R294H, and P350L. In SLC22A12 gene, we found six synonymous variants and seven intron variants. We detected several pathogenic variants in patients with suspect hypouricemia. Intronic variant c.1419+1G>A in SLC2A9 most likely affects the splicing. In SLC22A12, we found rare pathogenic variants T467M and L415_G417del. These variants have according to our previous study high frequency in the Czech and Slovak Roma population.3 Conclusions The uric acid level is determined by a complex mechanism that is not yet fully understood. Disorders of urate transporters can not only lead to hyperuricemia, but in rare cases also to hypouricemia. References Stiburkova B, et al. Rheumatology (Oxford) 2017 November 1;56(11):1982–1992. doi:10.1093/rheumatology/kex295 Hurba O, et al. PLoS One 2014 September 30;9(9):e107902. doi:10.1371/journal.pone.0107902 Gabrikova D, et al. Urolithiasis 2015 October;43(5):441–5. doi:10.1007/s00240-015-0790-4 Acknowledgements This study was supported by the grant from the Czech Republic Ministry of Health AZV 15-26693A. Disclosure of Interest None declared.
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URAT1 and GLUT9 mutations in Spanish patients with renal hypouricemia
Clinica Chimica Acta, 2018Co-Authors: Felix Claverie-martin, Jorge Trujillo-suarez, Cristina Aparicio, Maria L. Justa Roldan, Blanka Stiburkova, Maria A. Martín-gomez, Maria Herrero Goñi, Hilaria González-acosta, Kimiyoshi Ichida, Marta Carrasco Hidalgo-barqueroAbstract:Abstract Background Renal hypouricemia (RHUC), a rare inherited disorder characterized by impaired uric acid (UA) reabsorption in the proximal tubule, is caused by mutations in SLC22A12 or SLC2A9. Most mutations have been identified in Japanese patients, and only a few have been detected in Europeans. Methods We report clinical, biochemical and genetics findings of fourteen Spanish patients, six Caucasians and eight of Roma ethnia, diagnosed with idiopathic RHUC. Two of the patients presented exercise-induced acute renal failure and another one had several episodes of nephrolithiasis and four of them had progressive deterioration of renal function, while the rest were asymptomatic. Results Molecular analysis revealed SLC22A12 mutations in ten of the patients, and SLC2A9 mutations in the other four. A new heterozygous SLC22A12 missense mutation, c.1427C>A (p.A476D), was identified in two affected members of the same family. The rest of the patients presented homozygous, heterozygous or compound heterozygous mutations that have been previously identified in patients with RHUC; SLC22A12 p.T467M and p.L415_G417del, and SLC2A9 p.T125M. Expression studies in Xenopus oocytes revealed that c.1427C>A reduced UA transport but did not alter the location of URAT1 protein on the plasma membrane. Conclusions The biochemical and clinical features of our patients together with the genetic analysis results confirmed the diagnosis of RHUC. This is the first report describing SLC22A12 and SLC2A9 mutations in Spanish patients.
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Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2
Clinical and Experimental Nephrology, 2016Co-Authors: Andrea Mancikova, I. Sebesta, Makiko Nakamura, Olha Hurba, Vladimir Krylov, Kimiyoshi Ichida, Blanka StiburkovaAbstract:Background Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and nephrolithiasis. Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9). Methods and results In this article we present clinical, biochemical and molecular genetics of two Czech patients. The serum uric acid in the probands was 57 and 98 µmol/l and expressed as an increase in the fractional excretion of uric acid (40 and 18 %). The sequencing analysis of SLC22A12 and SLC2A9 revealed novel variants p.R92C and p.R203C in URAT1 and p.G72D in GLUT9. Functional studies were performed for these novel variants and for previously reported variants p.I118HfsX27, p.G216R and p.N333S in GLUT9 responsible for renal hypouricemia in three probands from Czech Republic and United Kingdom. Functional studies showed significantly decreased urate uptake for all variants. However, urate uptake of GLUT9 variants prepared for both isoforms were not significantly different. Conclusions This is the first complex function characterization of non-synonymous allelic variants in patients with renal hypouricemia regarding both GLUT9 isoforms. Our finding of defects in the SLC2A9 and SLC22A12 genes show the following: renal hypouricemia is not restricted to East Asia populations; urate uptake of GLUT9 variants prepared for both isoforms were not significantly different; renal hypouricemia type 2 has more wide clinical variability than type 1; the phenotypic severity of renal hypouricemia is not correlated with results of functional characterizations of URAT1 and GLUT9 variants.
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Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2
Clinical and Experimental Nephrology, 2015Co-Authors: Andrea Mancikova, I. Sebesta, Makiko Nakamura, Krylov, Hurba O, Kimiyoshi Ichida, Blanka StiburkovaAbstract:Background Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and nephrolithiasis. Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9).
Veronique Vitart - One of the best experts on this subject based on the ideXlab platform.
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Characterisation of genome-wide association epistasis signals for serum uric acid in human population isolates.
PLOS ONE, 2011Co-Authors: Gibran Hemani, Jennifer E Huffman, Andrew A. Hicks, Caroline Hayward, Veronique Vitart, Claudia Cabrera-cardenas, Pau Navarro, Sara Knott, Igor RudanAbstract:Genome-wide association (GWA) studies have identified a number of loci underlying variation in human serum uric acid (SUA) levels with the SLC2A9 gene having the largest effect identified so far. Gene-gene interactions (epistasis) are largely unexplored in these GWA studies. We performed a full pair-wise genome scan in the Italian MICROS population (n=1201) to characterise epistasis signals in SUA levels. In the resultant epistasis profile, no SNP pairs reached the Bonferroni adjusted threshold for the pair-wise genome-wide significance. However, SLC2A9 was found interacting with multiple loci across the genome, with NFIA - SLC2A9 and SLC2A9 - ESRRAP2 being significant based on a threshold derived for interactions between GWA significant SNPs and the genome and jointly explaining 8.0% of the phenotypic variance in SUA levels (3.4% by interaction components). Epistasis signal replication in a CROATIAN population (n=1772) was limited at the SNP level but improved dramatically at the gene ontology level. In addition, gene ontology terms enriched by the epistasis signals in each population support links between SUA levels and neurological disorders. We conclude that GWA epistasis analysis is useful despite relatively low power in small isolated populations.
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Variation in the Uric Acid Transporter Gene SLC2A9 and Its Association with AAO of Parkinson’s Disease
Journal of Molecular Neuroscience, 2011Co-Authors: Maurizio F. Facheris, Andrew A. Hicks, Cosetta Minelli, Johann M. Hagenah, Vladimir Kostic, Susan Campbell, Caroline Hayward, Claudia B. Volpato, Cristian Pattaro, Veronique VitartAbstract:Based on the observed inverse association between hyperuricemia and Parkinson’s disease (PD) risk, the natural antioxidant activity of uric acid has been suggested to play a protective role. SLC2A9 has been indicated as the most effective of all uric acid transporters, and SLC2A9 variants have been shown to influence circulating uric acid levels. With this study, we aimed to test the association between such SLC2A9 polymorphisms and age at onset (AAO) of PD. Variants rs733175, rs737267, rs1014290, and rs6449213 within SLC2A9 were genotyped in 664 PD individuals from three European centers. The effect of each polymorphism on AAO was estimated within each center using a linear regression model adjusted for gender and genotype at the other SNPs and assuming an additive genetic model. Results across centers were combined using inverse-variance weighted fixed-effect meta-analysis. The minor allele of rs1014290, previously shown to be associated with lower serum uric acid levels, was found to be associated with a lower AAO of PD (pooled estimate −4.56 years; 95% CI −8.13, −1.00; p = 0.012). The association remained significant after adjustment for multiple comparisons and was highly consistent across centers (heterogeneity, I ^2 0%). No gender differences were observed. Our study suggests that SLC2A9 genetic variants influence age of onset of Parkinson’s disease.
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variation in the uric acid transporter gene SLC2A9 and its association with aao of parkinson s disease
Journal of Molecular Neuroscience, 2011Co-Authors: Maurizio F. Facheris, Andrew A. Hicks, Cosetta Minelli, Johann M. Hagenah, Susan Campbell, Caroline Hayward, Claudia B. Volpato, Cristian Pattaro, Vladimir S Kostic, Veronique VitartAbstract:Based on the observed inverse association between hyperuricemia and Parkinson’s disease (PD) risk, the natural antioxidant activity of uric acid has been suggested to play a protective role. SLC2A9 has been indicated as the most effective of all uric acid transporters, and SLC2A9 variants have been shown to influence circulating uric acid levels. With this study, we aimed to test the association between such SLC2A9 polymorphisms and age at onset (AAO) of PD. Variants rs733175, rs737267, rs1014290, and rs6449213 within SLC2A9 were genotyped in 664 PD individuals from three European centers. The effect of each polymorphism on AAO was estimated within each center using a linear regression model adjusted for gender and genotype at the other SNPs and assuming an additive genetic model. Results across centers were combined using inverse-variance weighted fixed-effect meta-analysis. The minor allele of rs1014290, previously shown to be associated with lower serum uric acid levels, was found to be associated with a lower AAO of PD (pooled estimate −4.56 years; 95% CI −8.13, −1.00; p = 0.012). The association remained significant after adjustment for multiple comparisons and was highly consistent across centers (heterogeneity, I 2 0%). No gender differences were observed. Our study suggests that SLC2A9 genetic variants influence age of onset of Parkinson’s disease.
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SLC2A9 is a newly identified urate transporter influencing serum urate concentration urate excretion and gout
Nature Genetics, 2008Co-Authors: Veronique Vitart, Caroline Hayward, Sara Knott, Igor Rudan, Nicola K Gray, James A B Floyd, Colin N A Palmer, Ivana KolcicAbstract:Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200?500 lM) compared with other mammals (3?120 lM)1. About 70% of daily urate disposal occurs via the kidneys, and in 5?25% of the human population, impaired renal excretion leads to hyperuricemia2. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7?5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter3, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.
Lisa K Stamp - One of the best experts on this subject based on the ideXlab platform.
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Influence of genetic variants on renal uric acid handling in response to frusemide: an acute intervention study.
RMD Open, 2017Co-Authors: Nicola Dalbeth, Gregory D Gamble, Anne Horne, Tanya J Flynn, Lisa K Stamp, Jordyn Allan, Amanda Phipps-green, Borislav Mihov, Robert N. Doughty, Tony R MerrimanAbstract:Objectives Genetic variation in the renal urate transporters SLC2A9 (GLUT9) and SLC22A11 (OAT4) has been reported to interact with diuretics to increase the risk of developing gout. The aim of this study was to determine whether variation in SLC2A9 or SLC22A11 influences acute renal handling of uric acid in response to frusemide. Methods Following an overnight fast, healthy participants (n=100) attended a study visit with oral intake of 40 mg frusemide. Blood and urine samples were obtained at baseline and 30, 60, 120 and 180 min after frusemide intake. The primary end point was change in fractional excretion of uric acid (FEUA). Results Following intake of frusemide, FEUA initially increased (mean (SD) change from baseline +1.9% (3.0%) at 60 min, p SLC2A9 ( rs11942223 and rs13129697 ) and SLC22A11 ( rs207826 ) did not significantly alter the FEUA following a frusemide load. At both 60 and 180 min, change in fractional excretion of sodium was independently associated with change in FEUA (standardised β≥0.40, p Conclusions The tested variants in SLC2A9 and SLC22A11 do not influence acute changes in renal handling of uric acid in response to frusemide. Trial registration number ACTRN12614000871640; Results.
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Population-specific association between ABCG2 variants and tophaceous disease in people with gout.
Arthritis Research & Therapy, 2017Co-Authors: Wendy Shuwen He, Tony R Merriman, Lisa K Stamp, Amanda Phipps-green, Nicola DalbethAbstract:Tophi contribute to musculoskeletal disability, joint damage and poor health-related quality of life in people with gout. The aim of this study was to examine the role of SLC2A9 and ABCG2 variants in tophaceous disease in people with gout. Participants (n = 1778) with gout fulfilling the 1977 American Rheumatism Association (ARA) classification criteria, who were recruited from primary and secondary care, attended a detailed study visit. The presence of palpable tophi was recorded. SLC2A9 rs11942223, ABCG2 rs2231142 and ABCG2 rs10011796 were genotyped. Data were analysed according to tophus status. Compared to participants without tophi, those with tophi were older, had longer disease duration and higher serum creatinine, and were more likely to be of Māori or Pacific (Polynesian) ancestry. SLC2A9 rs11942223 was not associated with tophi. However, the risk alleles for both ABCG2 single nucleotide polymorphisms (SNPs) were present more frequently in those with tophi (OR (95% CI) 1.24 (1.02–1.51) for rs2231142 and 1.33 (1.01–1.74) for rs10011796, p
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association of SLC2A9 genotype with phenotypic variability of serum urate in pre menopausal women
Frontiers in Genetics, 2015Co-Authors: Ruth Topless, Nicola Dalbeth, Murray Cadzow, Tanya J Flynn, Lisa K Stamp, Michael A Black, Tony R MerrimanAbstract:The SLC2A9 gene, that encodes a renal uric acid reuptake transporter, has genetic variants that explain ~3% of variance in urate levels. There are previous reports of non-additive interaction between SLC2A9 genotype and environmental factors which influence urate control. Therefore our aim was to further investigate the general phenomenon that such non-additive interactions contribute to genotype-specific association with variance at SLC2A9. Data from 14135 European individuals were used in this analysis. The measure of variance was derived from a ranked inverse normal transformation of residuals obtained by regressing known urate-influencing factors (sex, age and BMI) against urate. Variant rs6449173 showed the most significant effect on serum urate variance at SLC2A9 (P = 7.9x10-14), which was maintained after accounting for the effect on average serum urate levels (P=0.022). Noting the stronger effect in a sub-cohort that consisted of pre-menopausal women and younger men, the participants were stratified into males and pre-menopausal and post-menopausal women. This revealed a strong effect on variance in pre-menopausal women (P=3.7x10-5) with a weak effect in post-menopausal women (P=0.032) and no effect in men (P=0.22). The T-allele of rs6449173, which associates with increased urate levels, was associated with the greater variance in urate. There was a non-additive interaction between rs6449173 genotype and female gender in control of serum urate levels that was driven by a greater increase in urate levels associated with the T-allele in women. Female hormones, and/or other factors they influence or are associated with (such as iron levels, temperature, testosterone) interact with SLC2A9 genotype in women to determine urate levels. The association of SLC2A9 with greater variance in pre-menopausal women may reflect the cyclical changes resulting from menstruation.
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sugar sweetened beverage consumption a risk factor for prevalent gout with SLC2A9 genotype specific effects on serum urate and risk of gout
Annals of the Rheumatic Diseases, 2014Co-Authors: Caitlin Batt, Marilyn E Merriman, Murray Cadzow, Amanda Phippsgreen, Ruth Topless, Michael A Black, Andrew A Harrison, John Highton, Peter Jones, Lisa K StampAbstract:Objective Consumption of high fructose corn syrup (HFCS)-sweetened beverages increases serum urate and risk of incident gout. Genetic variants in SLC2A9, that exchanges uric acid for glucose and fructose, associate with gout. We tested association between sugar (sucrose)-sweetened beverage (SSB) consumption and prevalent gout. We also tested the hypothesis that SLC2A9 genotype and SSB consumption interact to determine gout risk. Methods Participants were 1634 New Zealand (NZ) European Caucasian, Ma¯ori and Pacific Island people and 7075 European Caucasians from the Atherosclerosis Risk in Communities (ARIC) study. NZ samples were genotyped for rs11942223 and ARIC for rs6449173. Effect estimates were multivariate adjusted. Results SSB consumption increased gout risk. The OR for four drinks/day relative to zero was 6.89 (p=0.045), 5.19 (p=0.010) and 2.84 (p=0.043) for European Caucasian, Ma¯ori and Pacific Islanders, respectively. With each extra daily SSB serving, carriage of the gout-protective allele of SLC2A9 associated with a 15% increase in risk (p=0.078), compared with a 12% increase in non-carriers (p=0.002). The interaction term was significant in pooled (pInteraction=0.01) but not meta-analysed (pInteraction=0.99) data. In ARIC, with each extra daily serving, a greater increase in serum urate protective allele carriers (0.005 (p=8.7×10(-5)) compared with 0.002 (p=0.016) mmol/L) supported the gout data (pInteraction=0.062). Conclusions Association of SSB consumption with prevalent gout supports reduction of SSB in management. The interaction data suggest that SLC2A9-mediated renal uric acid excretion is physiologically influenced by intake of simple sugars derived from SSB, with SSB exposure negating the gout risk discrimination of SLC2A9.
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No evidence for association of Chr 9p21 variant rs1333049 with gout in New Zealand case-control sample sets.
Rheumatology, 2012Co-Authors: Nicola Dalbeth, Lisa K Stamp, Andrew A Harrison, John Highton, Peter B Jones, Tony R MerrimanAbstract:Sir, Gout is characterized by inflammatory attacks in joints, triggered by the deposition of crystallized monosodium urate as a result of hyperuricaemia. It is multi-factorial with genetic and environmental predisposition [1]. Two loci encoding urate transporters have been confirmed as associated with gout: SLC2A9 and ABCG2 [2–4].
Caroline Hayward - One of the best experts on this subject based on the ideXlab platform.
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Characterisation of genome-wide association epistasis signals for serum uric acid in human population isolates.
PLOS ONE, 2011Co-Authors: Gibran Hemani, Jennifer E Huffman, Andrew A. Hicks, Caroline Hayward, Veronique Vitart, Claudia Cabrera-cardenas, Pau Navarro, Sara Knott, Igor RudanAbstract:Genome-wide association (GWA) studies have identified a number of loci underlying variation in human serum uric acid (SUA) levels with the SLC2A9 gene having the largest effect identified so far. Gene-gene interactions (epistasis) are largely unexplored in these GWA studies. We performed a full pair-wise genome scan in the Italian MICROS population (n=1201) to characterise epistasis signals in SUA levels. In the resultant epistasis profile, no SNP pairs reached the Bonferroni adjusted threshold for the pair-wise genome-wide significance. However, SLC2A9 was found interacting with multiple loci across the genome, with NFIA - SLC2A9 and SLC2A9 - ESRRAP2 being significant based on a threshold derived for interactions between GWA significant SNPs and the genome and jointly explaining 8.0% of the phenotypic variance in SUA levels (3.4% by interaction components). Epistasis signal replication in a CROATIAN population (n=1772) was limited at the SNP level but improved dramatically at the gene ontology level. In addition, gene ontology terms enriched by the epistasis signals in each population support links between SUA levels and neurological disorders. We conclude that GWA epistasis analysis is useful despite relatively low power in small isolated populations.
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Variation in the Uric Acid Transporter Gene SLC2A9 and Its Association with AAO of Parkinson’s Disease
Journal of Molecular Neuroscience, 2011Co-Authors: Maurizio F. Facheris, Andrew A. Hicks, Cosetta Minelli, Johann M. Hagenah, Vladimir Kostic, Susan Campbell, Caroline Hayward, Claudia B. Volpato, Cristian Pattaro, Veronique VitartAbstract:Based on the observed inverse association between hyperuricemia and Parkinson’s disease (PD) risk, the natural antioxidant activity of uric acid has been suggested to play a protective role. SLC2A9 has been indicated as the most effective of all uric acid transporters, and SLC2A9 variants have been shown to influence circulating uric acid levels. With this study, we aimed to test the association between such SLC2A9 polymorphisms and age at onset (AAO) of PD. Variants rs733175, rs737267, rs1014290, and rs6449213 within SLC2A9 were genotyped in 664 PD individuals from three European centers. The effect of each polymorphism on AAO was estimated within each center using a linear regression model adjusted for gender and genotype at the other SNPs and assuming an additive genetic model. Results across centers were combined using inverse-variance weighted fixed-effect meta-analysis. The minor allele of rs1014290, previously shown to be associated with lower serum uric acid levels, was found to be associated with a lower AAO of PD (pooled estimate −4.56 years; 95% CI −8.13, −1.00; p = 0.012). The association remained significant after adjustment for multiple comparisons and was highly consistent across centers (heterogeneity, I ^2 0%). No gender differences were observed. Our study suggests that SLC2A9 genetic variants influence age of onset of Parkinson’s disease.
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variation in the uric acid transporter gene SLC2A9 and its association with aao of parkinson s disease
Journal of Molecular Neuroscience, 2011Co-Authors: Maurizio F. Facheris, Andrew A. Hicks, Cosetta Minelli, Johann M. Hagenah, Susan Campbell, Caroline Hayward, Claudia B. Volpato, Cristian Pattaro, Vladimir S Kostic, Veronique VitartAbstract:Based on the observed inverse association between hyperuricemia and Parkinson’s disease (PD) risk, the natural antioxidant activity of uric acid has been suggested to play a protective role. SLC2A9 has been indicated as the most effective of all uric acid transporters, and SLC2A9 variants have been shown to influence circulating uric acid levels. With this study, we aimed to test the association between such SLC2A9 polymorphisms and age at onset (AAO) of PD. Variants rs733175, rs737267, rs1014290, and rs6449213 within SLC2A9 were genotyped in 664 PD individuals from three European centers. The effect of each polymorphism on AAO was estimated within each center using a linear regression model adjusted for gender and genotype at the other SNPs and assuming an additive genetic model. Results across centers were combined using inverse-variance weighted fixed-effect meta-analysis. The minor allele of rs1014290, previously shown to be associated with lower serum uric acid levels, was found to be associated with a lower AAO of PD (pooled estimate −4.56 years; 95% CI −8.13, −1.00; p = 0.012). The association remained significant after adjustment for multiple comparisons and was highly consistent across centers (heterogeneity, I 2 0%). No gender differences were observed. Our study suggests that SLC2A9 genetic variants influence age of onset of Parkinson’s disease.
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variation in the uric acid transporter gene SLC2A9 and memory performance
Human Molecular Genetics, 2010Co-Authors: Lorna M Houlihan, Caroline Hayward, Niki D Wyatt, Sarah E Harris, Riccardo E Marioni, Mark W J Strachan, Jackie F Price, John M Starr, Alan F Wright, Ian J DearyAbstract:Understanding human cognitive ageing is important to improve the health of an increasing elderly population. Serum uric acid levels have been linked to many ageing illnesses and are also linked to cognitive functioning, though the direction of the association is equivocal. SLC2A9, a urate transporter, influences uric acid levels. This study first tested four SLC2A9 SNPs, previously associated with uric acid levels, in ~1000 Scots: the Lothian Birth Cohort 1936 (LBC1936). These participants were tested on general cognitive ability at ages 11 and 70. At age 70, they took a battery of diverse cognitive tests. Two replication cohorts were investigated. First, the LBC1921, who were tested on general cognitive ability at age 11. At ages 79 (n = 520), 83 (n = 281) and age 87 (n = 177), they completed cognitive ability test batteries. Second, the Edinburgh Type 2 Diabetes Study (ET2DS) were tested for cognitive abilities aged between 60 and 75 years (n = 1066). All analyses were adjusted for age, gender, body mass index and either childhood cognitive ability test score (LBC) or vocabulary-a measure of prior cognitive ability in ET2DS. Significant associations were detected with SLC2A9 and a general memory factor in LBC1936 and other individual cognitive ability tests (lowest P = 0.0002). The association with logical memory replicated in LBC1921 at all ages (all P 0.1). If the positive associations withstand, then this study could suggest that higher uric acid levels may be associated with increased performance on memory-related tasks.
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SLC2A9 is a newly identified urate transporter influencing serum urate concentration urate excretion and gout
Nature Genetics, 2008Co-Authors: Veronique Vitart, Caroline Hayward, Sara Knott, Igor Rudan, Nicola K Gray, James A B Floyd, Colin N A Palmer, Ivana KolcicAbstract:Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200?500 lM) compared with other mammals (3?120 lM)1. About 70% of daily urate disposal occurs via the kidneys, and in 5?25% of the human population, impaired renal excretion leads to hyperuricemia2. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7?5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter3, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.
Shelley A Cole - One of the best experts on this subject based on the ideXlab platform.
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serum uric acid concentrations and SLC2A9 genetic variation in hispanic children the viva la familia study
The American Journal of Clinical Nutrition, 2015Co-Authors: Saroja V Voruganti, Shelley A Cole, Karin Haack, Sandra Laston, Nitesh R Mehta, Nancy F Butte, Anthony G ComuzzieAbstract:Background: Elevated concentrations of serum uric acid are associated with increased risk of gout and renal and cardiovascular diseases. Genetic studies in adults have consistently identified associations of solute carrier family 2, member 9 (SLC2A9), polymorphisms with variation in serum uric acid. However, it is not known whether the association of serum uric acid with SLC2A9 polymorphisms manifests in children. Objective: The aim was to investigate whether variation in serum uric acid is under genetic influence and whether the association with SLC2A9 polymorphisms generalizes to Hispanic children of the Viva La Familia Study. Design: We conducted a genomewide association study with 1.1 million genetic markers in 815 children. Results: We found serum uric acid to be significantly heritable [h2 ± SD = 0.45 ± 0.08, P = 5.8 × 10−11] and associated with SLC2A9 variants (P values between 10−16 and 10−7). Several of the significantly associated polymorphisms were previously identified in studies in adults. We also found positive genetic correlations between serum uric acid and BMI z score (ρG = 0.45, P = 0.002), percentage of body fat (ρG = 0.28, P = 0.04), fat mass (ρG = 0.34, P = 0.02), waist circumference (ρG = 0.42, P = 0.003), and waist-to-height ratio (ρG = 0.46, P = 0.001). Conclusions: Our results show that variation in serum uric acid in Hispanic children is under considerable genetic influence and is associated with obesity-related phenotypes. As in adults, genetic variation in SLC2A9 is associated with serum uric acid concentrations, an important biomarker of renal and cardiovascular disease risk, in Hispanic children.
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replication of the effect of SLC2A9 genetic variation on serum uric acid levels in american indians
European Journal of Human Genetics, 2014Co-Authors: Saroja V Voruganti, Karin Haack, Sandra Laston, Anthony G Comuzzie, Nora Franceschini, Jean W Maccluer, Jason G Umans, Kari E North, Shelley A ColeAbstract:Increased serum uric acid (SUA) or hyperuricemia, a risk factor for gout, renal and cardiovascular diseases, is caused by either increased production or decreased excretion of uric acid or a mix of both. The solute carrier protein 2 family, member 9 (SLC2A9) gene encodes a transporter that mediates urate flux across the renal proximal tubule. Genome-wide association studies have consistently shown the association of single-nucleotide polymorphisms in this gene with SUA in majority populations. American Indian participants of the Strong Heart Family Study, belonging to multigenerational families, have high prevalence of hyperuricemia. We conducted measured genotype analyses, based on variance components decomposition method and accounting for family relationships, to assess whether the association between SUA and SLC2A9 gene polymorphisms generalized to American Indians (n=3604) of this study. Seven polymorphisms were selected for genotyping based on their association with SUA levels in other populations. A strong association was found between SLC2A9 gene polymorphisms and SUA in all centers combined (P-values: 1.3 × 10−31–5.1 × 10−23) and also when stratified by recruitment center; P-values: 1.2 × 10−14–1.0 × 10−5. These polymorphisms were also associated with the estimated glomerular filtration rate and serum creatinine but not albumin–creatinine ratio. In summary, the association of polymorphisms in the uric acid transporter gene with SUA levels extends to a new population of American Indians.
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genome wide association analysis confirms and extends the association of SLC2A9 with serum uric acid levels to mexican americans
Frontiers in Genetics, 2013Co-Authors: Venkata Saroja Voruganti, Jack W Kent, Subrata Debnath, Shelley A Cole, Karin Haack, Harald H H Goring, Melanie A Carless, Joanne E Curran, Matthew P JohnsonAbstract:Increased serum uric acid (SUA) is a risk factor for gout and renal and cardiovascular disease. The purpose of this study was to identify genetic factors that affect the variation in SUA in 632 Mexican Americans participants of the San Antonio Family Heart Study (SAFHS). A genome-wide association analysis was performed using the Illumina Human Hap 550K single nucleotide polymorphism (SNP) microarray. We used a linear regression-based association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. All analyses were performed in the software package SOLAR. SNPs rs6832439, rs13131257 and rs737267 in solute carrier protein 2 family, member 9 (SLC2A9) were associated with SUA at genome-wide significance (p <1.3×10-7). The minor alleles of these SNPs had frequencies of 36.2%, 36.2%, and 38.2 %, respectively, and were associated with decreasing SUA levels. All of these SNPs were located in introns 3-7 of SLC2A9, the location of the previously reported associations in European populations. When analyzed for association with cardiovascular-renal disease risk factors, conditional on SLC2A9 SNPs strongly associated with SUA, significant associations were found for SLC2A9 SNPs with BMI, body weight and waist circumference (p < 1.4 x 10-3) and suggestive associations with albumin-creatinine ratio and total antioxidant status. The SLC2A9 gene encodes an urate transporter that has considerable influence on variation in SUA. In addition to the primary association locus, suggestive evidence (p<1.9×10-6) for joint linkage/association was found at a previously-reported urate quantitative trait locus (Logarithm of odds score = 3.6) on 3p26.3. In summary, our GWAS extends and confirms the association of SLC2A9 with SUA for the first time in a Mexican American cohort and also shows for the first time its association with cardiovascular-renal disease risk factors.
