Single Nucleotide Polymorphisms In SLC2A9 Research Articles

Influence of Genetic and Non-Genetic Risk Factors for Serum Uric Acid Levels and Hyperuricemia in Mexicans.

Risk of hyperuricemia is modified by genetic and environmental factors. Our aim was to identify factors associated with serum uric acid levels and hyperuricemia in Mexicans. A pilot Genome-wide association study GWAS was performed in a subgroup of participants (n = 411) from the Health Workers Cohort Study (HWCS). Single nucleotide polymorphisms (SNPs) associated with serum uric acid levels were validated in all the HWCS participants (n = 1939) and replicated in independent children (n = 1080) and adult (n = 1073) case-control studies. The meta-analysis of the whole HWCS and replication samples identified three SLC2A9 SNPs: rs1014290 (p = 2.3 × 10−64), rs3775948 (p = 8.2 × 10−64) and rs11722228 (p = 1.1 × 10−17); and an ABCG2 missense SNP, rs2231142 (p = 1.0 × 10−18). Among the non-genetic factors identified, the visceral adiposity index, smoking, the metabolic syndrome and its components (waist circumference, blood pressure, glucose and hyperlipidemia) were associated with increased serum uric acid levels and hyperuricemia (p < 0.05). Among the female HWCS participants, the odds ratio for hyperuricemia was 1.24 (95% CI, 1.01–1.53) per unit increase in soft drink consumption. As reported in other studies, our findings indicate that diet, adiposity and genetic variation contribute to the elevated prevalence of hyperuricemia in Mexico.

Association between SLC2A9 Genetic Variants and Risk of Hyperuricemia in a Uygur Population.

EN: Summary]This study aimed to test the effects of five single nucleotide polymorphisms within SLC2A9 on uric acid level in a special ethnic population, the Uygurs in Xinjiang, China. According to our inclusion and exclusion criteria, Uygur adults from Xinjiang constituted the study population. There were 1053 Uygur adults with hyperuricemia and 1373 normal Uygur adults who served as controls. Five single nucleotide polymorphisms within SLC2A9 (rs938557, rs7679916, rs7349721, rs13101785, and rs13137343) were selected with the HapMap dataset and TaqMan assays. We found that, in normouricemia group, rs938557 was significantly correlated with uric acid (β=11.39±3.74, P=0.0024) adjusting for age, gender and BMI; rs7679916 and rs13137343 were marginally associated with uric acid concentration (β=5.77±3.09, P=0.0626; β= 5.99±3.08, P=0.0520). In the hyperuricemia group, no SNP was found to possibly influence uric acid concentration. None of these SNPs showed significant association with hyperuricemia after controlling for age, gender and BMI. There were significant or marginal correlations between certain single nucleotide polymorphisms in the SLC2A9 region and uric acid concentration in Uygur normouricemia samples. In turn, some of these single nucleotide polymorphisms in SLC2A9 may increase the risk of hyperuricemia.

Genetic variants related to urate and risk of Parkinson's disease

IntroductionHigher urate concentrations have been associated with a lower risk of developing Parkinson's disease (PD) and with slower rates of clinical decline in PD patients. Whether these associations reflect a neuroprotective effect of urate is unclear. Our objective was to assess whether genetic variants that modify circulating urate levels are also associated with altered PD risk. MethodsParticipants were from three large ongoing cohort studies: the Nurses' Health Study (NHS), the Health Professionals Follow-up Study (HPFS), and the Cancer Prevention Study II Nutrition Cohort (CPS-IIN). We examined associations between single nucleotide polymorphisms (SNPs) in SLC2A9 and other genes involved in urate transport and PD risk using conditional logistic regression among 1451 cases and 3135 matched controls. We assessed associations between SNPs and plasma urate levels in a subset of 1174 control participants with linear regression models. ResultsWe found the expected associations between SNPs in SLC2A9 and plasma urate levels among men and women; however, SNPs in other genes tended not to be associated with urate. Each SNP in SLC2A9 explained less than 7% of the variance in plasma urate. We did not find significant associations between the SNPs in SLC2A9 and PD risk among men or women. ConclusionOur results do not support an association between genetic variants associated with circulating urate levels and risk of PD, but larger investigations are needed to determine whether the modest genetic effects on blood urate contribute to predict PD risk.

Analysis of ABCG2 and other urate transporters in uric acid homeostasis in chronic kidney disease: potential role of remote sensing and signaling.

BackgroundIn the setting of chronic kidney disease (CKD), altered extra-renal urate handling may be necessary to regulate plasma uric acid. The Remote Sensing and Signaling Hypothesis (Nigam S. What do drug transporters really do? Nat Rev Drug Discov 2015; 14: 29–44) suggests that multispecific solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters in different tissues are part of an inter-organ communication system that maintains levels of urate and other metabolites after organ injury.MethodsData from the Chronic Renal Insufficiency Cohort (CRIC; n = 3598) were used to study associations between serum uric acid and single nucleotide polymorphisms (SNPs) on the following uric acid transporters: ABCG2 (BRCP), SLC22A6 (OAT1), SLC22A8 (OAT3), SLC22A10 (OAT5), SLC22A11 (OAT4), SLC22A12 (URAT1), SLC22A13 (OAT10), SLC17A1-A3 (NPTs), SLC2A9 (GLUT9), ABCC2 (MRP2) and ABCC4 (MRP4). Regression models, controlling for principal components age, gender and renal function, were run separately for those of European (EA) and African ancestry (AA), and P-values corrected for multiple comparisons. A twin cohort with participants of EA and normal renal function was used for comparison.ResultsAmong those of EA in CRIC, statistically significant signals were observed for SNPs in ABCG2 (rs4148157; beta-coefficient = 0.68; P = 4.78E-13) and SNPs in SLC2A9 (rs13125646; beta-coefficient = −0.30; P = 1.06E-5). Among those of AA, the strongest (but not statistically significant) signals were observed for SNPs in SLC2A9, followed by SNPs in ABCG2. In the twin study (normal renal function), only SNPs in SLC2A9 were significant (rs4481233; beta-coefficient=−0.45; P = 7.0E-6). In CRIC, weaker associations were also found for SLC17A3 (NPT4) and gender-specific associations found for SLC22A8 (OAT3), SLC22A11 (OAT4), and ABCC4 (MRP4).ConclusionsIn patients of EA with CKD (CRIC cohort), we found striking associations between uric acid and SNPs on ABCG2, a key transporter of uric acid by intestine. Compared with ABCG2, SLC2A9 played a much less significant role in this subset of patients with CKD. SNPs in other SLC (e.g. SLC22A8 or OAT3) and ABC (e.g. ABCC4 or MRP4) genes appear to make a weak gender-dependent contribution to uric acid homeostasis in CKD. As renal urate transport is affected in the setting of declining kidney function, extra-renal ABCG2 appears to play a compensatory role—a notion consistent with animal studies and the Remote Sensing and Signaling Hypothesis. Overall, the data indicate how different urate transporters become more or less important depending on renal function, ethnicity and gender. Therapies focused on enhancing ABCG2 urate handling may be helpful in the setting of CKD and hyperuricemia.

Case Report SLC2A9 and ZNF518B polymorphisms correlate with gout-related metabolic indices in Chinese Tibetan populations

Current evidence suggests that heredity and metabolic syndrome contribute to gout progression. SLC2A9 and ZNF518B may play a role in gout progression in different populations, but no studies have focused on the Tibetan Chinese population. In this study, we determined whether variations in these 2 genes were correlated with gout-related indices in Chinese-Tibetan gout patients. We detected 6 single nucleotide polymorphisms in SLC2A9 and ZNF518B in 319 Chinese Tibetan gout patients. One-way analysis of variance was used to evaluate the polymorphisms' effects on gout based on mean serum levels of metabolism indicators. Polymorphisms in SLC2A9 and ZNF518B affected multiple risk factors related to gout development. Significant differences in serum triglyceride levels and high-density lipoprotein-cholesterol level were detected between different genotypic groups with SLC2A9 polymorphisms rs13129697 (P = 0.022), rs4447863 (P = 0.018), and rs1014290 (P = 0.045). Similarly in ZNF518B, rs3217 (P = 0.016) and rs10016022 (P = 0.046) were associated with high creatinine and glucose levels, respectively. This study is the first to investigate and identify positive correlations between SLC2A9 and ZNF518B gene polymorphisms and metabolic indices in Tibetan gout patients. We found significant evidence indicating that genetic polymorphisms affect gout-related factors in Chinese Tibetan populations.

Mendelian randomization of serum urate and parkinson disease progression.

Higher serum urate concentrations predict more favorable prognosis in individuals with Parkinson disease (PD). The purpose of this study was to test the causality of this association using a Mendelian randomization approach. The study was conducted among participants in DATATOP and PRECEPT, 2 randomized trials among patients with early PD. The 808 patients with available DNA were genotyped for 3 SLC2A9 single nucleotide polymorphisms (SNPs) that identify an allele associated with lower urate concentrations, and for selected SNPs in other genes encoding urate transporters that have modest or no effect on serum urate levels. An SLC2A9 score was created based on the total number of minor alleles at the 3 SLC2A9 loci. Primary outcome was disability requiring dopaminergic treatment. Serum urate concentrations were 0.69mg/dl lower among individuals with ≥4 SLC2A9 minor alleles as compared to those with ≤2 (p = 0.0002). The hazard ratio (HR) for progression to disability requiring dopaminergic treatment increased with increasing SLC2A9 score (HR = 1.16, 95% confidence interval [CI] = 1.00-1.35, p = 0.056). In a comparative analysis, the HR was 1.27 (95% CI = 1.00-1.61, p = 0.0497) for a 0.5mg/dl genetically conferred decrease in serum urate, and 1.05 (95% CI = 1.01-1.10, p = 0.0133) for a 0.5mg/dl decrease in measured serum urate. No associations were found between polymorphisms in other genes associated with urate that do not affect serum urate and PD progression. This Mendelian randomization analysis adds to the evidence of a causal protective effect of high urate levels.

Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations.

BackgroundHyperuricemia 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.ResultsWe 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 (, 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 (). 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).ConclusionsThis 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.

Changes in Uric Acid Levels following Bariatric Surgery Are Not Associated with SLC2A9 Variants in the Swedish Obese Subjects Study

Context and ObjectiveObesity and SLC2A9 genotype are strong determinants of uric acid levels. However, data on SLC2A9 variants and weight loss induced changes in uric acid levels are missing. We examined whether the changes in uric acid levels two- and ten-years after weight loss induced by bariatric surgery were associated with SLC2A9 single nucleotide polymorphisms (SNPs) in the Swedish Obese Subjects study.MethodsSNPs (N = 14) identified by genome-wide association studies and exonic SNPs in the SLC2A9 gene locus were genotyped. Cross-sectional associations were tested before (N = 1806), two (N = 1664) and ten years (N = 1201) after bariatric surgery. Changes in uric acid were compared between baseline and Year 2 (N = 1660) and years 2 and 10 (N = 1172). A multiple testing corrected threshold of P = 0.007 was used for statistical significance.ResultsOverall, 11 of the 14 tested SLC2A9 SNPs were significantly associated with cross-sectional uric acid levels at all three time points, with rs13113918 showing the strongest association at each time point (R2 = 3.7−5.2%, 3.9×10−22≤p≤7.7×10−11). One SNP (rs737267) showed a significant association (R2 = 0.60%, P = 0.002) with change in uric acid levels from baseline to Year 2, as common allele homozygotes (C/C, N = 957) showed a larger decrease in uric acid (−61.4 µmol/L) compared to minor allele carriers (A/X: −51.7 µmol/L, N = 702). No SNPs were associated with changes in uric acid from years 2 to 10.ConclusionsSNPs in the SLC2A9 locus contribute significantly to uric acid levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, we found little evidence for an interaction between genotype and weight change on the response of uric acid to bariatric surgery over ten years. Thus, the fluctuations in uric acid levels among the surgery group appear to be driven by the weight losses and gains, independent of SLC2A9 genotypes.

Genome‐Wide Association of Serum Uric Acid Concentration: Replication of Sequence Variants in an Island Population of the Adriatic Coast of Croatia

A genome-wide association study of serum uric acid (SUA) laevels was performed in a relatively isolated population of European descent from an island of the Adriatic coast of Croatia. The study sample included 532 unrelated and 768 related individuals from 235 pedigrees. Inflation due to relatedness was controlled by using genomic control. Genetic association was assessed with 2,241,249 single nucleotide polymorphisms (SNPs) in 1300 samples after adjusting for age and gender. Our study replicated four previously reported SUA loci (SLC2A9, ABCG2, RREB1, and SLC22A12). The strongest association was found with a SNP in SLC2A9 (rs13129697, P=2.33×10(-19)), which exhibited significant gender-specific effects, 35.76 μmol/L (P=2.11×10(-19)) in females and 19.58 μmol/L (P=5.40×10(-5)) in males. Within this region of high linkage disequilibrium, we also detected a strong association with a nonsynonymous SNP, rs16890979 (P=2.24×10(-17)), a putative causal variant for SUA variation. In addition, we identified several novel loci suggestive of association with uric acid levels (SEMA5A, TMEM18, SLC28A2, and ODZ2), although the P-values (P<5×10(-6)) did not reach the threshold of genome-wide significance. Together, these findings provide further confirmation of previously reported uric-acid-related genetic variants and highlight suggestive new loci for additional investigation.

Association of an intronic SNP of SLC2A9 gene with serum uric acid levels in the Chinese male Han population by high-resolution melting method

SLC2A9 is a novel identified urate transporter influencing uric acid metabolism. It has been suggested that the single-nucleotide polymorphisms in SLC2A9 may affect the serum UA levels. The present study was designed to investigate rs6855911 polymorphism in intron 7 of SLC2A9 in a total of 372 Chinese male subjects. We examined 166 gout patients, as well as 206 healthy male volunteers in this study. DNA was purified from peripheral blood, and the rs6855911 polymorphism was evaluated using high-resolution melting (HRM) analysis and direct sequencing. Demographic and clinical data obtained from the patients and controls among the genotype groups were analyzed. A/A and A/G genotypes were unambiguously distinguished with HRM technology. The occurrence of the homozygous type (G/G) was completely absent among the study population. The prevalence of the A/A and A/G genotype was 96.0% and 4.0%, respectively. Genotyping based on HRM was fully concordant with sequencing. The G allele frequency was significantly higher in the low-uric-acid group than in the high-uric-acid group. The genotype distribution and allele frequencies were not significantly different between gout and control subjects (p = 0.04). However, serum uric acid levels in the A/G genotype subjects were significantly lower than those with the A/A genotypes (p < 0.01). Rapid and accurate genotyping analysis of SLC2A9 can be done with HRM. The polymorphism rs6855911 in SLC2A9 may be a genetic marker to assess risk of hyperuricemia among Chinese male Han population.

Solute carrier family 2, member 9 and uric acid homeostasis

The goal of this article is to review the possible physiological roles of the recently identified urate transporter, solute carrier family 2 (facilitated glucose transporter), member 9 (SLC2A9), in the renal handling of urate. Glucose transporter 9 is a high affinity hexose transporter encoded by the SLC2A9 gene found on human chromosome 4. The two splice variants SLC2A9b and SLC2A9a are expressed in the apical and basolateral membranes, respectively, of the proximal convoluted tubule. Recent reports have found significant correlations between two different sets of single nucleotide polymorphisms in SLC2A9. In one case, they are associated with increases in plasma urate levels and/or the incidence of hypertension or gout. The second set of single nucleotide polymorphisms correlate with hypouricaemia in Japanese patients. Expression of SLC2A9a and b in Xenopus laevis oocytes shows that these proteins mediate rapid urate fluxes and can exchange glucose for urate. Indirect evidence also suggests that the transporter is electrogenic. This review proposes that SLC2A9 contributes significantly in two ways to the fluxes of urate across the proximal convoluted tubule. Firstly, the apical expression of SLC2A9b secretes urate back into the urine in exchange for lumenal glucose. Secondly, the basolateral membrane SLC2A9a could be the primary route for urate movement out of the epithelium into the peritubular space.

Associations of a non-synonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese subjects and Solomon Islanders

ObjectiveTo study the associations of gout, tophi and uric acid levels with the gout-related SLC2A9 (solute carrier family 2, member 9) single nucleotide polymorphisms (SNPs) between two different racial groups.MethodsEight...

A sugar transporter regulates serum urate levels: Implications for prevention and management of hyperuricemia in gout

Introduction: Gout is increasing in prevalence in the United States. More patients with refractory tophaceous disease are being seen, including older patients and those with multiple comorbidities such as diabetes, hypertension, chronic kidney disease, and congestive heart failure. There is also growing but as yet unresolved evidence for the potential of hyperuricemia to directly impact on blood pressure and cardiovascular diseases. New treatments, such as febuxostat and pegloticase, are emerging for refractory hyperuricemia. However, in most gout patients hyperuricemia is caused by long-standing renal underexcretion of uric acid, an abnormality that is often precipitated or exacerbated by diuretic therapy, insulin resistance, hypertension, and development of even moderate degrees of renal insuffi ciency [1]. This scenario points to opportunities to intervene at the level of both prophylaxis and treatment of hyperuricemia by more advanced uricosuric therapies. This will be aided by recent clinical-translational advances in understanding renal uric acid disposition. The primary uricosuric drugs (probenecid, benzbromarone, sulfi npyrazone) and the weaker secondary uricosuric drug (losartan) work in large part by inhibiting the urate anion exchanger URAT1 (SLC22A12) at the apical (brush border) membrane of the renal proximal tubule epithelial cell [2]. Furthermore, several URAT1 single nucleotide polymorphisms (SNPs) were linked with prominent regulatory effects on serum urate and susceptibility to gout in Asian and European cohorts [2]. Although URAT1 appears to be the linchpin for urate reabsorption at the apical surface of the renal proximal tubule epithelial cell, URAT1 knockout mice showed an unexpectedly small loss in renal urate reabsorption [3]. Secondary changes in renal urate secretion were believed to be partly responsible. SLC2A9 (also known as GLUT9, URATv1) promotes transport of hexose sugars and is a potent electrogenic transporter of urate anion [4]. Recently, probenecid and benzbromarone (and also indomethacin) were discovered to inhibit the activity of SLC2A9 at the basolateral membrane of the proximal renal tubule epithelial cell [4], the interface where urate is reabsorbed into the peritubular interstitium and ultimately back into the venous circulation. Not only URAT1, but also SLC2A9 mutations, have now been implicated in the etiology of the uncommon disorder idiopathic renal hypouricemia. Furthermore, SLC2A9 mutations were linked to hyperuricemia and bladder uric acid calculi in dalmatian-breed dogs [5]. This was a stunning observation that indicates how robust the role for SLC2A9 can be in renal urate handling, as dogs, like other lower mammals, are generally protected from hyperuricemia via uricase expression. More recently, several SLC2A9 SNPs have been linked by genome-wide association (GWA) studies with hyperuricemia, altered renal uric handling, and susceptibility to gout [6–9].