The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts.
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ABSTRACT:
SUBMITTER: Li S
PROVIDER: S-EPMC2065883 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Uric acid is the primary end product of purine metabolism. Increased serum uric acid levels have been associated with gouty arthritis as well as with a variety of cardiovascular-related phenotypes. This study was undertaken to investigate associations between uric acid levels and single-nucleotide polymorphisms (SNPs).A 500,000-SNP genome-wide association study of serum uric acid levels was performed in a cohort of Old Order Amish from Lancaster County, Pennsylvania.The scan confirmed a previously identified region on chromosome 4 to be strongly associated with uric acid levels (P = 4.2 x 10(-11) for rs10489070). Followup genotyping revealed that a nonsynonymous coding SNP (Val253Ile; rs16890979) in GLUT9 was most strongly associated with uric acid levels, with each copy of the minor allele associated with a decrease of 0.47 mg/dl in the uric acid level (95% confidence interval 0.31-0.63 [P = 1.43 x 10(-11)]). The effect of this variant tended to be stronger in women than in men (P = 0.16 for sex-genotype interaction). The genotype effect was not modified by the inclusion of several cardiovascular risk factors, suggesting that GLUT9 is directly related to uric acid homeostasis. The SNP identified in the genome-wide scan in the Amish population (rs10489070) was also significantly associated with gout in the Framingham Heart Study (P = 0.004).Our findings indicate that GLUT9, which is expressed in the kidney, may be a novel regulator of uric acid elimination and that a common nonsynonymous variant in this gene contributes to abnormalities in uric acid homeostasis and gout.
| S-EPMC2779583 | biostudies-literature
Project description:OBJECTIVE: Serum uric acid (SUA) is a cardiovascular risk marker associated with inflammation. The serum amyloid A protein (SAA) is an inflammatory factor and is associated with cardiovascular disease (CVD). However, the relationship between genetic polymorphisms of SAA and SUA levels has not been studied. The objective of this study was to investigate the association between SUA levels and SAA genetic polymorphisms. METHODS: All participants were selected from subjects participating in the Cardiovascular Risk Survey (CRS) study. The single nucleotide polymorphism (SNP) rs12218 of the SAA1 gene was genotyped by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association of SUA levels with genotypes was assessed by using the general liner mode. RESULTS: The SNP rs12218 was associated with SUA levels by analyses of a dominate model (P?=?0.002) and additive model (P?=?0.005), and the difference remained significant after adjustment of sex, age, obesity, ethnicity, HDL-C, alcohol intake, smoking, and creatinine (P?=?0.006 and P?=?0.023, respectively). The TT genotype was associated with an increased SUA concentration of 39.34 mmol/L (95% confidence interval [CI], 3.61-75.06, P?=?0.031) compared with the CC genotype, and the TT genotype was associated with an increased SUA concentration of 2.48 mmol/L (95% CI, 6.86-38.10; P?=?0.005) compared with the CT genotype. CONCLUSIONS: The rs12218 SNP in the SAA1 gene was associated with SUA levels in Chinese subjects, indicating that carriers of the T allele of rs12218 have a high risk of hyperuricemia.
| S-EPMC3386962 | biostudies-literature
Project description:Background. Leprosy reactions are acute inflammatory episodes that occur mainly in the multibacillary forms of the disease. The reactions are classified as type 1 (reverse reaction) or type 2 (erythema nodosum leprosum). Leprosy-associated oxidative stress has been widely demonstrated. Several recent studies have shown uric acid (UA) to have antioxidative effects under pathologic conditions. The objective of this study was to assess serum levels of UA in patients with leprosy reactions, with the aim of monitoring their levels before and after treatment, compared with levels in leprosy patients without reactions. Methods. The study included patients aged 18-69 years assisted at a leprosy treatment reference center in the Central Region of Brazil. Patients who were pregnant; were using immunosuppressant drugs or immunobiologicals; or had an autoimmune disease, human immunodeficiency virus infection, acquired immune deficiency syndrome, or tuberculosis were excluded. Upon recruitment, all individuals were clinically assessed for skin lesions and neural or systemic impairment. Some patients had already completed treatment for leprosy, while others were still undergoing treatment or had initiated treatment after being admitted. The treatment of the reactional episode was started only after the initial evaluation. Laboratory assessments were performed upon admission (baseline) and at approximately 30 and 60 days (time points 1 and 2, respectively). Results. A total of 123 leprosy patients were recruited between June 2012 and June 2015; among them, 56, 42, and 25 presented with type 1, type 2, and no reactions, respectively. Serum UA levels were significantly reduced in patients with type 2 leprosy reactions compared with patients in the control group and remained lower in the two subsequent assessments, after initiation of anti-reaction treatments, with similar values to those recorded before the treatment. Discussion. The decreased serum UA levels in patients with type 2 leprosy reactions might be due to the consumption of UA to neutralize the enhanced production of oxygen- and nitrogen-reactive species that occurs during type 2 reactions. The maintenance of the reduced levels in the follow-up assessments may indicate persistence of oxidative stress in the initial post-treatment stages, despite improved clinical conditions. The results of this study suggest that serum UA may play an antioxidative role during type 2 leprosy reactions.
| S-EPMC4793330 | biostudies-literature
Project description:Dysfunctional variants of ATP-binding cassette transporter subfamily G member 2 (ABCG2), a urate transporter in the kidney and intestine, are the major causes of hyperuricemia and gout. A recent study found that ABCG2 is a major transporter of uremic toxins; however, few studies have investigated the relationship between ABCG2 gene polymorphisms and mortality. This prospective cohort study of 1214 hemodialysis patients investigated the association between serum uric acid levels and ABCG2 genotype and mortality. Genotyping of dysfunctional ABCG2 variants, Q126X (rs72552713) and Q141K (rs2231142), was performed using the patients' DNA. During the study period, 220 patients died. Lower serum uric acid levels were associated with higher mortality (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.14-3.10, P ≤ 0.001). ABCG2 dysfunction, estimated by genetic variants, had a significant positive association with serum uric acid levels (full function: 7.4 ± 1.2 mg/dl, 3/4 function: 7.9 ± 1.3 mg/dl, 1/2 function: 8.2 ± 1.4 mg/dl, ≤ 1/4 function: 8.7 ± 1.3 mg/dl, P ≤ 0.001). This association remained significant on multiple regression analysis. The Cox proportional hazard analysis indicated that the ABCG2 ≤ 1/4 function type was significantly associated with higher mortality (HR 6.66, 95% CI 2.49 to 17.8, P ≤ 0.001) than the other function types. These results showed that ABCG2 plays a physiologically important role in uric acid excretion, and that ABCG2 dysfunction is a risk factor for mortality in hemodialysis patients.
| S-EPMC7324430 | biostudies-literature
Project description:Multiterritorial atherosclerosis has dramatically increased annual risk of adverse cardiovascular events than atherosclerotic disease with single-artery affected. Serum uric acid (SUA) is an important predictor of stroke and atherosclerosis; however, which is supported by few direct evidence based on cohort studies. A prospective cohort study including 2644 North Chinese adults aged ≥40 years was performed in 2010-2012 to investigate the association between SUA and multiterritorial vascular stenosis. Hyperuricaemia was defined as SUA levels >6 and >7 mg/dL for males and females, respectively. All participants underwent twice transcranial Doppler (TCD) and bilateral carotid duplex ultrasound to evaluate intracranial artery stenosis (ICAS) and extracranial arterial stenosis (ECAS) and peripheral arterial disease (PAD) was determined by ankle-brachial index (ABI) on January 2010 and January 2012 based on regular health check-ups. The cumulative incidence of vascular stenosis was significantly higher in subjects with hyperuricaemia than in those without hyperuricaemia (54.1% vs. 34.7%, P < 0.001). The adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for new on-set vascular stenosis due to hyperuricaemia and a 1-mg/dL change in SUA level were 1.75 (1.32-2.31) and 1.29 (1.21-1.38), respectively. Furthermore, in the gender-stratified analysis, the association between SUA levels and ICAS was statistically significant in males (OR: 2.02; 95% CI: 1.18-3.46), but not females (OR: 0.85, 95% CI: 0.41-1.76, P for interaction: 0.026).
| S-EPMC6652300 | biostudies-literature
Project description:AimsHyperuricemia has attracted increasing attention. However, limited concern has been paid to the potential dangers of lowering serum uric acid (SUA). We observed lower levels of SUA in patients with COVID-19. Therefore, we aim to explore whether patients with COVID-19 had SUA lower than normal and the relationship of SUA and the severity of COVID-19.MethodsThis was a case-control study based on 91 cases with COVID-19 and 273 age- and sex-matched healthy control subjects. We first compared SUA levels and uric acid/creatinine (UA/Cr) ratio between patients with COVID-19 and the healthy controls. Then, we examined the association of SUA levels and UA/Cr ratios with COVID-19 severity in COVID-19 cases only, defined according to the fifth edition of China's Diagnosis and Treatment Guidelines of COVID-19.ResultsSUA levels in patients with COVID-19 were 2.59% lower, UA/Cr ratios 6.06% lower at admission compared with healthy controls. In sex stratified analysis, levels of SUA and UA/Cr were lower in male patients with COVID-19 while only level of SUA was lower in female patients with COVID-19. Moreover, SUA and UA/Cr values were 4.27 and 8.23% lower in the severe group than that in the moderate group among male COVID-19 patients. Bivariate and partial correlations analysis showed negative correlations between SUA or UA/Cr ratio and COVID-19 after adjusting for age, sex, BMI and eGFR. A multiple linear regression analysis showed that SARS-CoV-2 infection and male sex were independent risk factors associated with lower SUA levels. Male patients with COVID-19 accompanied by low SUA levels had higher risk of developing severe symptoms than those with high SUA levels (incidence rate ratio: 4.05; 95% CI:1.11, 14.72) at admission. Comparing SUA and UA/Cr ratio at three time points (admission, discharge, and follow-up), we found that male patients experienced severe symptoms had lower SUA and UA/Cr ratio levels comparing to moderate patients, but no significant difference between three time points. On the contrary, female patients had lower SUA and UA/Cr ratio at discharge than those at admission, but no significant difference of SUA and UA/Cr ratio between moderate and severe group.ConclusionPatients with COVID-19 had SUA and UA/Cr values lower than normal at admission. Male COVID-19 patients with low SUA levels had a significantly higher crude risk of developing severe symptoms than those with high SUA levels. During disease aggravation, the level of SUA gradually decreased until discharge. At the follow-up exam, the level of SUA was similar to the levels at admission.
| S-EPMC8106517 | biostudies-literature
Project description:Hyperuricemia is defined as serum uric acid level of more than 7 mg/dL and blood levels of uric acid are causally associated with gout, as implicated by evidence from randomized clinical trials using urate lowering therapies. Uric acid as a cardiovascular risk factor often accompanies metabolic syndrome, hypertension, diabetes, dyslipidemia, chronic renal disease, and obesity. Despite the association of hyperuricemia with cardiovascular risk factors, it has remained controversial as to whether uric acid is an independent predictor of cardiovascular disease. To settle this issue, and in the absence of large randomized controlled trials, Mendelian randomization analysis in which the exposure is defined based on the presence or absence of a specific allele that influences a risk factor of interest have tried to shed light on this.
| S-EPMC5179380 | biostudies-other
Project description:Our aim was to determine the serum uric acid (SUA) levels associated with an increased risk of cardiovascular (CV) and all-cause death in the general adult population. We analyzed data obtained in two independent cross-sectional surveys performed in the Czech Republic in 2006-09 and 2015-18, involving 1% population random samples in nine districts, aged 25-64 years, stratified by age and gender. Ten-year mortality data were obtained in a cohort with examination in 2006-09. Final analyses included 3542 individuals (48.2% men) examined in 2006-09, and 2304 (47.4% men) examined in 2015-18. From a cohort examined in 2006-09, 122 men and 60 women were reported dead (33% and 27% from CV disease). In men, there was no association of baseline SUA levels with baseline SCORE category or 10-year mortality rates. In women, each 10 µmol/L increase in baseline SUA levels was associated with an increase in baseline SCORE category (P < .001). Receiver operating characteristic curve analyses in women identified the baseline SUA cutoff values discriminating: 1. between low/intermediate and high/very high SCORE categories (309 µmol/L), 2. CV mortality (325 µmol/L), and 3. all-cause mortality (298 µmol/L). After adjusting for confounders including SCORE, Cox regression analysis confirmed that the baseline SUA cutoffs of 309 µmol/L and 325 µmol/L were associated with 4-times (P = .010) and 6-times (P = .036) greater risk of CV mortality, whereas the cutoff of 298 µmol/L was associated with 87% greater risk of all-cause mortality (P = .025). In conclusion, the SUA cutoff value of 309 µmol/L identified women at high/very high SCORE category and was associated with 4-times greater risk of observed CV mortality over 10 years.
| S-EPMC8029678 | biostudies-literature
Project description:Recently, extensive efforts have been made to understand the importance of the extra-renal uric acid (UA) excretion pathways and their contribution to UA-related diseases. However, the method typically used to measure UA concentrations in the intestinal lumen is difficult to real time and dynamic analysis. In this study, UA excretion in the rat intestinal lumen was measured in real time using an electrochemical method. A sensitive electrode to detect UA was constructed using a gold electrode modified with a mixed self-assembled monolayer. Excretion rate of UA in the intestine was calculated using time course data. A decrease in UA excretion rate was observed in the intestine after administration of serum UA-lowering drugs (benzbromarone, febuxostat, and topiroxostat). Inhibition of ATP-binding cassette transporter G2 (ABCG2) which has been reported as an important exporter of UA was suggested by administration of these drugs. On the other hand, an increase in excretion rate of UA was observed in the intestine of 5/6 nephrectomy rats. Upregulation of mRNA expression of the UA transporter organic anion transporter OAT3, which is related to the secretion at the basal membrane, suggested an enhancement of UA excretion by ABCG2, a high-capacity UA exporter. Observed urate excretion dynamics and mRNA expression of UA transporters in the intestine upon administration of serum UA-lowering drugs and 5/6 nephrectomy improve our understanding of the underlying mechanisms of intestinal UA excretion.
| S-EPMC6938314 | biostudies-literature
Project description:Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5?×?10-8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci-TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A-are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.
| S-EPMC6453927 | biostudies-literature