The association between genetic polymorphisms in ABCG2 and SLC2A9 and urate: an updated systematic review and meta-analysis.

BACKGROUND: Replication studies showed conflicting effects of ABCG2 and SLC2A9 polymorphisms on gout and serum urate. This meta-analysis therefore aimed to pool their effects across studies. METHODS: Studies were located from MEDLINE and Scopus from inception to 17th June 2018. Observational studies in adults with any polymorphism in ABCG2 or SLC2A9, and outcome including gout, hyperuricemia, and serum urate were included for pooling. Data extractions were performed by two independent reviewers. Genotype effects were pooled stratified by ethnicity using a mixed-effect logistic model and a multivariate meta-analysis for dichotomous and continuous outcomes. RESULTS: Fifty-two studies were included in the analysis. For ABCG2 polymorphisms, mainly studied in Asians, carrying 1-2 minor-allele-genotypes of rs2231142 and rs72552713 were respectively about 2.1-4.5 and 2.5-3.9 times higher odds of gout than non-minor-allele-genotypes. The two rs2231142-risk-genotypes also had higher serum urate about 11-18 µmol/l. Conversely, carrying 1-2 minor alleles of rs2231137 was about 36-57% significantly lower odds of gout. For SLC2A9 polymorphisms, mainly studied in Caucasians, carrying 1-2 minor alleles of rs1014290, rs6449213, rs6855911, and rs7442295 were about 25-43%, 31-62%, 33-64%, and 35-65% significantly lower odds of gout than non-minor-allele-genotypes. In addition, 1-2 minor-allele-genotypes of the latter three polymorphisms had significantly lower serum urate about 20-49, 21-51, and 18-54 µmol/l than non-minor-allele-genotypes. CONCLUSIONS: Our findings should be useful in identifying patients at risk for gout and high serum urate and these polymorphisms may be useful in personalized risk scores. TRIAL REGISTRATION: PROSPERO registration number: CRD42018105275 .

The Time-Feature of Uric Acid Excretion in Hyperuricemia Mice Induced by Potassium Oxonate and Adenine.

Hyperuricemia is an important risk factor of chronic kidney disease, metabolic syndrome and cardiovascular disease. We aimed to assess the time-feature relationship of hyperuricemia mouse model on uric acid excretion and renal function. A hyperuricemia mouse model was established by potassium oxonate (PO) and adenine for 21 days. Ultra Performance Liquid Chromatography was used to determine plasma uric acid level. Hematoxylin-eosin staining was applied to observe kidney pathological changes, and Western blot was used to detect renal urate transporters' expression. In hyperuricemia mice, plasma uric acid level increased significantly from the 3rd day, and tended to be stable from the 7th day, and the clearance rate of uric acid decreased greatly from the 3rd day. Further study found that the renal organ of hyperuricemia mice showed slight damage from the 3rd day, and significantly deteriorated renal function from the 10th day. In addition, the expression levels of GLUT9 and URAT1 were upregulated from the 3rd day, while ABCG2 and OAT1 were downregulated from the 3rd day, and NPT1 were downregulated from the 7th day in hyperuricemia mice kidney. This paper presents a method suitable for experimental hyperuricemia mouse model, and shows the time-feature of each index in a hyperuricemia mice model.

Identifying mechanisms underlying the amelioration effect of Chrysanthemum morifolium Ramat. 'Boju' extract on hyperuricemia using biochemical characterization and UPLC-ESI-QTOF/MS-based metabolomics.

This study was aimed at evaluating the prospect of edible chrysanthemum extract as a potential substance for the prevention and treatment of hyperuricemia. Chrysanthemum morifolium Ramat. 'Boju' extract (CBE), which had the strongest xanthine oxidase inhibitory activity, showed a significant hypouricemic effect on potassium oxonate-induced hyperuricemic rats through inhibiting serum xanthine oxidase activity, regulating renal uric acid transport-related protein (ABCG2, URAT1 and GLUT9) expression and blood lipid levels, and protecting renal function. Serum metabolomics based on UPLC-ESI-QTOF/MS was used to illustrate mechanisms underlying the amelioration effect of CBE on hyperuricemia. A total of 35 potential biomarkers were identified. CBE prevented the pathological process of hyperuricemia by regulating 16/17 biomarkers associated with tryptophan, sphingolipid, glycerophospholipid and arachidonic acid metabolisms. CBE could alleviate hyperuricemia-related diseases including chronic kidney disease, hyperlipidemia and inflammation via reducing indoxyl sulfate, lysophosphatidylcholines and arachidonic acid levels, exhibiting its applicability and superiority in the treatment of hyperuricemia.

Plasma Urate, Cancer Incidence, and All-Cause Mortality: A Mendelian Randomization Study.

BACKGROUND: Observationally, high plasma urate is associated with high risk of cancer. We used a Mendelian randomization design to test the hypothesis that high concentrations of plasma urate are associated with high cancer incidence and all-cause mortality observationally and genetically. METHODS: We performed observational and genetic analyses using plasma urate and the urate solute carrier family 2 member 9 (SLC2A9) rs7442295 genotype in 86210 individuals from the Copenhagen General Population Study. Cancer and mortality end points were from national cancer and death registries. Incidences and risk of cancer and all-cause mortality were calculated using Cox regression, Fine and Gray competing-risks regression, and instrumental variable analyses. RESULTS: During a median follow-up time of 3.9 years for cancer and 4.9 years for all-cause mortality, 3243 individuals received a diagnosis of cancer and 3978 died. Observationally, 50% higher plasma urate was associated with multivariable-adjusted hazard ratios of 1.11 (95% CI, 1.05-1.18) for cancer incidence and 1.07 (1.01-1.13) for all-cause mortality. Each A-allele of the SLC2A9 rs7442295 was associated with 9% higher plasma urate and hazard ratios of 1.07 (1.01-1.14) for cancer incidence and 1.07 (1.02-1.13) for all-cause mortality. In instrumental variable analyses, the odds ratios for a genetically determined 50% higher plasma urate was 1.22 (1.02-1.47) for cancer incidence and 1.49 (1.13-1.93) for all-cause mortality. CONCLUSIONS: High plasma urate was both observationally and genetically associated with high cancer incidence and high all-cause mortality, suggesting causal relationships.

Genome wide association study of uric acid in Indian population and interaction of identified variants with Type 2 diabetes.

Abnormal level of Serum Uric Acid (SUA) is an important marker and risk factor for complex diseases including Type 2 Diabetes. Since genetic determinant of uric acid in Indians is totally unexplored, we tried to identify common variants associated with SUA in Indians using Genome Wide Association Study (GWAS). Association of five known variants in SLC2A9 and SLC22A11 genes with SUA level in 4,834 normoglycemics (1,109 in discovery and 3,725 in validation phase) was revealed with different effect size in Indians compared to other major ethnic population of the world. Combined analysis of 1,077 T2DM subjects (772 in discovery and 305 in validation phase) and normoglycemics revealed additional GWAS signal in ABCG2 gene. Differences in effect sizes of ABCG2 and SLC2A9 gene variants were observed between normoglycemics and T2DM patients. We identified two novel variants near long non-coding RNA genes AL356739.1 and AC064865.1 with nearly genome wide significance level. Meta-analysis and in silico replication in 11,745 individuals from AUSTWIN consortium improved association for rs12206002 in AL356739.1 gene to sub-genome wide association level. Our results extends association of SLC2A9, SLC22A11 and ABCG2 genes with SUA level in Indians and enrich the assemblages of evidence for SUA level and T2DM interrelationship.

Metabolic syndrome, alcohol consumption and genetic factors are associated with serum uric acid concentration.

OBJECTIVE: Uric acid is the end product of purine metabolism in humans, and increased serum uric acid concentrations lead to gout. The objective of the current study was to identify factors that are independently associated with serum uric acid concentrations in a cohort of Czech control individuals. METHODS: The cohort consisted of 589 healthy subjects aged 18-65 years. We studied the associations between the serum uric acid concentration and the following: (i) demographic, anthropometric and other variables previously reported to be associated with serum uric acid concentrations; (ii) the presence of metabolic syndrome and the levels of metabolic syndrome components; and (iii) selected genetic variants of the MTHFR (c.665C>T, c.1286A>C), SLC2A9 (c.844G>A, c.881G>A) and ABCG2 genes (c.421C>A). A backward model selection procedure was used to build two multiple linear regression models; in the second model, the number of metabolic syndrome criteria that were met replaced the metabolic syndrome-related variables. RESULTS: The models had coefficients of determination of 0.59 and 0.53. The serum uric acid concentration strongly correlated with conventional determinants including male sex, and with metabolic syndrome-related variables. In the simplified second model, the serum uric acid concentration positively correlated with the number of metabolic syndrome criteria that were met, and this model retained the explanatory power of the first model. Moderate wine drinking did not increase serum uric acid concentrations, and the urate transporter ABCG2, unlike MTHFR, was a genetic determinant of serum uric acid concentrations. CONCLUSION: Metabolic syndrome, moderate wine drinking and the c.421C>A variant in the ABCG gene are independently associated with the serum uric acid concentration. Our model indicates that uric acid should be clinically monitored in persons with metabolic syndrome.

[Contribution of the CoLaus study to decipher the determinants of serum uric acid]. / Contribution de l'étude CoLaus à l'élucidation des déterminants de l'acide urique sérique.

Asymptomatic hyperuricemia affects one in five adults in the general population and is associated with elevated cardiovascular risk. It is however not clear whether asymptomatic hyperuricemia is a cause or simply a marker of conditions associated with high cardiovascular risk. Sex, age, obesity, renal function and selected drugs are major determinants of serum uric acid. Moreover, recent genome-wide association studies have identified new genes involved in the control of serum uric acid levels, in particular SLC2A9, which encodes a urate transporter located in the kidney. A genetic score based on several genetic variants associated with serum uric acid is strongly associated with the risk of gout, but not with cardiovascular events so far.

Erythrocyte adducin: a structural regulator of the red blood cell membrane.

Adducin is an alpha, beta heterotetramer that performs multiple important functions in the human erythrocyte membrane. First, adducin forms a bridge that connects the spectrin-actin junctional complex to band 3, the major membrane-spanning protein in the bilayer. Rupture of this bridge leads to membrane instability and spontaneous fragmentation. Second, adducin caps the fast growing (barbed) end of actin filaments, preventing the tetradecameric protofilaments from elongating into macroscopic F-actin microfilaments. Third, adducin stabilizes the association between actin and spectrin, assuring that the junctional complex remains intact during the mechanical distortions experienced by the circulating cell. And finally, adducin responds to stimuli that may be important in regulating the global properties of the cell, possibly including cation transport, cell morphology and membrane deformability. The text below summarizes the structural properties of adducin, its multiple functions in erythrocytes, and the consequences of engineered deletions of each of adducin subunits in transgenic mice.

Type-2 diabetes down-regulates glucose transporter proteins and genes of the human blood leukocytes.

OBJECTIVE: White blood cells are essential in mediating immune and inflammatory responses. A prominent feature of these cells during activation of the immune function is increased glucose utilization, and this is dependent on the functioning of specific glucose transporter (GLUT) isoforms. The few data available on leukocyte glucose transporter expression are limited to type-2 diabetes mellitus, and nothing is known about its regulation. MATERIAL AND METHODS: Peripheral blood was drawn from 35 healthy controls and 35 diabetic subjects. Expression of GLUT1, GLUT3 and GLUT4 was determined in the leukocytes of healthy individuals and diabetic patients by flow cytometry, Western blot and semi-quantitative RT-PCR. RESULTS: GLUT 3 was decreased in granulocytes, lymphocytes and monocytes from diabetic patients. In monocytes, GLUT3 and GLUT4 were reduced in type-2 diabetic patients. In leukocytes of diabetic patients, GLUT1 and GLUT4, protein and mRNA were unchanged, but GLUT3 protein and mRNA levels were down-regulated compared to those of healthy controls. CONCLUSION: Elevated glucose concentration affects leukocyte GLUT expression. Decreased expression of GLUT isoforms in leukocytes may be responsible for diminished activation of diabetic leukocytes. These situations possibly contribute to a predisposition to infection and to a decreased immune response in diabetes.

Four grams of glucose.

Four grams of glucose circulates in the blood of a person weighing 70 kg. This glucose is critical for normal function in many cell types. In accordance with the importance of these 4 g of glucose, a sophisticated control system is in place to maintain blood glucose constant. Our focus has been on the mechanisms by which the flux of glucose from liver to blood and from blood to skeletal muscle is regulated. The body has a remarkable capacity to satisfy the nutritional need for glucose, while still maintaining blood glucose homeostasis. The essential role of glucagon and insulin and the importance of distributed control of glucose fluxes are highlighted in this review. With regard to the latter, studies are presented that show how regulation of muscle glucose uptake is regulated by glucose delivery to muscle, glucose transport into muscle, and glucose phosphorylation within muscle.