The human propensity for high levels of serum uric acid (SUA) is a trait that has defied explanation. Is it beneficial? Is it pathogenic? Its role in the human diseases like gout and kidney stones ...was discovered over a century ago Richette P, Bardin T. Lancet 375: 318-328, 2010; Rivard C, Thomas J, Lanaspa MA, Johnson RJ. Rheumatology (Oxford) 52: 421-426, 2013, but today emerging new genetic and epidemiological techniques have revived an age-old debate over whether high uric acid levels (hyperuricemia) independently increase risk for diseases like hypertension and chronic kidney disease Feig DI. J Clin Hypertens (Greenwich) 14: 346-352, 2012; Feig DI, Madero M, Jalal DI, Sanchez-Lozada LG, Johnson RJ. J Pediatr 162: 896-902, 2013; Feig DI, Soletsky B, Johnson RJ. JAMA 300: 924-932, 2008; Wang J, Qin T, Chen J, Li Y, Wang L, Huang H, Li J. PLoS One 9: e114259, 2014; Zhu P, Liu Y, Han L, Xu G, Ran JM. PLoS One 9: e100801, 2014. Part of the mystery of the role uric acid plays in human health stems from our lack of understanding of how humans regulate uric acid homeostasis, an understanding that could shed light on the historic role of uric acid in human adaptation and its present role in human pathogenesis. This review will highlight the recent work to identify the first important human uric acid secretory transporter, ABCG2, and the identification of a common causal ABCG2 variant, Q141K, for hyperuricemia and gout.
Genome-wide association studies (GWAS) have successfully identified common single nucleotide polymorphisms (SNPs) associated with a wide variety of complex diseases, but do not address gene function ...or establish causality of disease-associated SNPs. We recently used GWAS to identify SNPs in a genomic region on chromosome 4 that associate with serum urate levels and gout, a consequence of elevated urate levels. Here we show using functional assays that human ATP-binding cassette, subfamily G, 2 (ABCG2), encoded by the ABCG2 gene contained in this region, is a hitherto unknown urate efflux transporter. We further show that native ABCG2 is located in the brush border membrane of kidney proximal tubule cells, where it mediates renal urate secretion. Introduction of the mutation Q141K encoded by the common SNP rs223H42 by site-directed mutagenesis resulted in 53% reduced urate transport rates compared to wild-type ABCG2 (P < 0.001). Data from a population-based study of 14,783 individuals support rs223H42 as the causal variant in the region and show highly significant associations with urate levels whites: P = 10⁻³⁰, minor allele frequency (MAF) 0.11; blacks P = 10⁻⁴, MAF 0.03 and gout (adjusted odds ratio 1.68 per risk allele, both races). Our data indicate that at least 10% of all gout cases in whites are attributable to this causal variant. With approximately 3 million US individuals suffering from often insufficiently treated gout, ABCG2 represents an attractive drug target. Our study completes the chain of evidence from association to causation and supports the common disease-common variant hypothesis in the etiology of gout.
Sex Differences in Urate Handling Halperin Kuhns, Victoria L; Woodward, Owen M
International journal of molecular sciences,
06/2020, Volume:
21, Issue:
12
Journal Article
Peer reviewed
Open access
Hyperuricemia, or elevated serum urate, causes urate kidney stones and gout and also increases the incidence of many other conditions including renal disease, cardiovascular disease, and metabolic ...syndrome. As we gain mechanistic insight into how urate contributes to human disease, a clear sex difference has emerged in the physiological regulation of urate homeostasis. This review summarizes our current understanding of urate as a disease risk factor and how being of the female sex appears protective. Further, we review the mechanisms of renal handling of urate and the significant contributions from powerful genome-wide association studies of serum urate. We also explore the role of sex in the regulation of specific renal urate transporters and the power of new animal models of hyperuricemia to inform on the role of sex and hyperuricemia in disease pathogenesis. Finally, we advocate the use of sex differences in urate handling as a potent tool in gaining a further understanding of physiological regulation of urate homeostasis and for presenting new avenues for treating the constellation of urate related pathologies.
Computer vision is a tool that could provide livestock producers with digital body measures and records that are important for animal health and production, namely body height and length, and chest ...girth. However, to build these tools, the scarcity of labeled training data sets with uniform images (pose, lighting) that also represent real-world livestock can be a challenge. Collecting images in a standard way, with manual image labeling is the gold standard to create such training data, but the time and cost can be prohibitive. We introduce the PreciseEdge image segmentation algorithm to address these issues by employing a standard image collection protocol with a semi-automated image labeling method, and a highly precise image segmentation for automated body measurement extraction directly from each image. These elements, from image collection to extraction are designed to work together to yield values highly correlated to real-world body measurements. PreciseEdge adds a brief preprocessing step inspired by chromakey to a modified GrabCut procedure to generate image masks for data extraction (body measurements) directly from the images. Three hundred RGB (red, green, blue) image samples were collected uniformly per the African Goat Improvement Network Image Collection Protocol (AGIN-ICP), which prescribes camera distance, poses, a blue backdrop, and a custom AGIN-ICP calibration sign. Images were taken in natural settings outdoors and in barns under high and low light, using a Ricoh digital camera producing JPG images (converted to PNG prior to processing). The rear and side AGIN-ICP poses were used for this study. PreciseEdge and GrabCut image segmentation methods were compared for differences in user input required to segment the images. The initial bounding box image output was captured for visual comparison. Automated digital body measurements extracted were compared to manual measures for each method. Both methods allow additional optional refinement (mouse strokes) to aid the segmentation algorithm. These optional mouse strokes were captured automatically and compared. Stroke count distributions for both methods were not normally distributed per Kolmogorov-Smirnov tests. Non-parametric Wilcoxon tests showed the distributions were different (p< 0.001) and the GrabCut stroke count was significantly higher (p = 5.115 e-49), with a mean of 577.08 (std 248.45) versus 221.57 (std 149.45) with PreciseEdge. Digital body measures were highly correlated to manual height, length, and girth measures, (0.931, 0.943, 0.893) for PreciseEdge and (0.936, 0. 944, 0.869) for GrabCut (Pearson correlation coefficient). PreciseEdge image segmentation allowed for masks yielding accurate digital body measurements highly correlated to manual, real-world measurements with over 38% less user input for an efficient, reliable, non-invasive alternative to livestock hand-held direct measuring tools.
The pathophysiological nature of the common ABCG2 gout and hyperuricemia associated variant Q141K (rs2231142) remains undefined. Here, we use a human interventional cohort study (ACTRN12615001302549) ...to understand the physiological role of ABCG2 and find that participants with the Q141K ABCG2 variant display elevated serum urate, unaltered FEUA, and significant evidence of reduced extra-renal urate excretion. We explore mechanisms by generating a mouse model of the orthologous Q140K Abcg2 variant and find male mice have significant hyperuricemia and metabolic alterations, but only subtle alterations of renal urate excretion and ABCG2 abundance. By contrast, these mice display a severe defect in ABCG2 abundance and function in the intestinal tract. These results suggest a tissue specific pathobiology of the Q141K variant, support an important role for ABCG2 in urate excretion in both the human kidney and intestinal tract, and provide insight into the importance of intestinal urate excretion for serum urate homeostasis.
Introduction Le diabète de type 2 (DT2) est causé par des facteurs génétiques et environnementaux et leurs interactions. La moitié des patients diabétiques développent des complications suite aux ...désordres micro- et macrovasculaires affectant les organes cibles. Patients et méthodes Notre étude génétique est basée sur l’essai clinique ADVANCE chez les sujets DT2 à risque élevé de complications. Des résultats récents ont révélé que plusieurs biomarqueurs améliorent l’estimation du risque cardiovasculaire (Diabetes Care Oct 2, 2013). Ici, nous proposons que le criblage génomique (GWAS) des taux plasmatiques de biomarqueurs comme phénotype offre une possibilité d’identifier les sujets à risque avant l’élévation de ces taux. Les GWAS de 3 449 patients Caucasiens ont été fait à l’aide de puces Affymetrix GeneChip® SNP 5,0 et 6,0, IMPUTE2 pour les imputations et SNPTEST pour les GWAS. Résultats Nos résultats démontrent que le rs876537 (chr1), à moins de 8Kb du gène CRP est associé aux taux circulants de hsCRP (p < 4x10-7 ). Plusieurs SNPs dont le plus significatif (rs429358, p < 8x10-14 ) se trouve à proximité du locus des gènes APOE , APOC1 et TMME40 sur le chr19. L’association avec sRAGE a identifié le rs2856437 ( p< 2x10-18 ) qui se trouve à 5kb du gène AGER codant pour son récepteur. Le rs6668352 qui est associé (p < 1x10-7 ) aux taux circulants de BNP est situé à proximité de deux gènes précurseurs pour ce biomarqueur (NPPA et NPPB) sur le chr1. Des résultats similaires ont été observés pour le biomarqueur IL-6 avec un marqueur rs4129267 associé (p < 5x10-7 ) au récepteur de ce biomarqueur. Conclusion Nos résultats suggèrent que la variance dans les taux de ces biomarqueurs circulants peut-être déterminée par leurs gènes (hsCRP et BNP), par leurs récepteurs (sRAGE, IL-6) ou encore par les gènes des facteurs de risque (hsCRP) dont on a ignoré la relation dans le développement des complications du DT2.
Introduction Le diabète et l’hypertension ont une composante génétique dont une proportion de l’héritabilité manquante pourrait être due à des variations du nombre de copies (CNV) de gènes. Afin ...d’identifier ces variations, nous avons procédé à des criblages génomiques complets (GWAS) de CNV avec plusieurs phénotypes et complications du diabète de de type 2 (DT2). Matériels et méthodes Les GWAS ont été faits chez 3 449 patients d’origine caucasienne ayant participé à l’étude clinique ADVANCE. 31 phénotypes micro- et macrovasculaires quantitatifs et 23 phénotypes qualitatifs ont été déterminés. Les génotypes du nombre de copies ont été déterminés à l’aide de puces d’ADN d’Affymetrix 6.0 et 5.0 par les algorithmes PennCNV et ParseCNV. Le niveau de significativité a été déterminé empiriquement en répétant les analyses GWAS avec des données permutées. Résultats 19 délétions et 9 duplications sont significativement associées à 12 phénotypes qualitatifs alors que 7 délétions et 4 duplications sont significativement associées à 9 phénotypes quantitatifs. Parmi ceux-ci, on retrouve plusieurs CNV associés significativement à l’hypertension. Une délétion fréquente au locus 3p14.1 dans le gène FAM19A4 est associée à l’hypertension chez les femmes et une délétion protective au chr2 : 49386546-49394694 à 151,4 kb en amont du gène FSHR est aussi associé à l’hypertension chez les femmes. Or, les souris femelles KO pour ce gène sont hypertendues. Des CNV qui incluent des délétions et des duplications dans un cluster de gènes KRTAP9 sur le chr17q21.2 ainsi qu’une duplication sur le chr11p15.4 dans le gène TRIM22 sont significativement associés à l’hypertension chez les deux sexes. Conclusion Nos résultats ont permis d’identifier des CNV associés à l’hypertension chez les patients diabétiques. Ces CNV seront validés dans d’autres populations et leur importance sera évaluée sur la fonction de ces gènes ainsi que sur leur valeur prédictive des issus cliniques.
The filamentous diazotrophic cyanobacterium Trichodesmium is responsible for a significant fraction of marine di-nitrogen (N
) fixation. Growth and distribution of Trichodesmium and other diazotrophs ...in the vast oligotrophic subtropical gyres is influenced by iron (Fe) and phosphorus (P) availability, while reciprocally influencing the biogeochemistry of these nutrients. Here we use observations across natural inverse gradients in Fe and P in the North Atlantic subtropical gyre (NASG) to demonstrate how Trichodesmium acclimates in situ to resource availability. Transcriptomic analysis identified progressive upregulation of known iron-stress biomarker genes with decreasing Fe availability, and progressive upregulation of genes involved in the acquisition of diverse P sources with decreasing P availability, while genes involved in N
fixation were upregulated at the intersection under moderate Fe and P availability. Enhanced N
fixation within the Fe and P co-stressed transition region was also associated with a distinct, consistent metabolic profile, including the expression of alternative photosynthetic pathways that potentially facilitate ATP generation required for N
fixation with reduced net oxygen production. The observed response of Trichodesmium to availability of both Fe and P supports suggestions that these biogeochemically significant organisms employ unique molecular, and thus physiological responses as adaptations to specifically exploit the Fe and P co-limited niche they construct.
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