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A genome wide association study of plasma uric acid levels in obese cases and never-overweight controls.

ABSTRACT: To identify plasma uric acid-related genes in extremely obese and normal weight individuals using genome-wide association studies (GWASs).Using genotypes from a GWAS focusing on obesity and thinness, quantitative trait association analyses (PLINK) for plasma uric acid levels in 1,060 extremely obese individuals (BMI > 35 kg/m2) and normal-weight controls (BMI < 25 kg/m2) were performed. In 961 samples with uric acid data, 924 were females.Significant associations were found in SLC2A9 gene SNPs and plasma uric acid levels (rs6449213, P = 3.15 × 10(-12) ). DIP2C gene SNP rs877282 also reached genome-wide significance (P = 4.56 × 10(-8)). Weaker associations (P < 1× 10(-5)) were found in F5, PXDNL, FRAS1, LCORL, and MICAL2 genes. Besides SLC2A9, three previously identified uric acid-related genes ABCG2 (rs2622605, P= 0.0026), SLC17A1 (rs3799344, P = 0.0017), and RREB1 (rs1615495, P = 0.00055) received marginal support in our study.Two genes/chromosome regions reached genome-wide association significance (P < 1 × 10(-7) , 550 K SNPs) in our GWAS: SLC2A9, the chromosome 2 60.1 Mb region (rs6723995), and the DIP2C gene region. Five other genes (F5, PXDNL, FRAS1, LCORL, and MICAL2) yielded P < 1 × 10(-5) . Four previous reported associations were replicated in our study, including SLC2A9, ABCG2, RREB, and SLC17A1.

SUBMITTER: Li WD

PROVIDER: S-EPMC3762924 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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A genome wide association study of plasma uric acid levels in obese cases and never-overweight controls.

Li Wei-Dong WD Jiao Hongxiao H Wang Kai K Zhang Clarence K CK Glessner Joseph T JT Grant Struan F A SF Zhao Hongyu H Hakonarson Hakon H Arlen Price R R

Obesity (Silver Spring, Md.) 20130524 9

<h4>Objective</h4>To identify plasma uric acid-related genes in extremely obese and normal weight individuals using genome-wide association studies (GWASs).<h4>Design and methods</h4>Using genotypes from a GWAS focusing on obesity and thinness, quantitative trait association analyses (PLINK) for plasma uric acid levels in 1,060 extremely obese individuals (BMI > 35 kg/m2) and normal-weight controls (BMI < 25 kg/m2) were performed. In 961 samples with uric acid data, 924 were females.<h4>Results< ...[more]

PMID: 23703922

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Project description:The predictive value of serum uric acid (SUA) for adverse cardiovascular events among obese and overweight patients is not known, but potentially important because of the relation between hyperuricaemia and obesity.The relationship between SUA and risk of cardiovascular adverse outcomes (nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death) and all-cause mortality, respectively, was evaluated in a post-hoc analysis of the Sibutramine Cardiovascular OUTcomes (SCOUT) trial. Participants enrolled in SCOUT were obese or overweight with pre-existing diabetes and/or cardiovascular disease (CVD). Cox models were used to assess the role of SUA as an independent risk factor.9742 subjects were included in the study; 83.6% had diabetes, and 75.1% had CVD. During an average follow-up time of 4.2 years, 1043 subjects had a primary outcome (myocardial infarction, resuscitated cardiac arrest, stroke, or cardiovascular death), and 816 died. In a univariate Cox model, the highest SUA quartile was associated with an increased risk of cardiovascular adverse outcomes compared with the lowest SUA quartile in women (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.20-2.10). In multivariate analyses, adjusting for known cardiovascular risk factors the increased risk for the highest SUA quartile was no longer statistically significant among women (HR: 0.99; 95% CI: 0.72-1.36) nor was it among men. Analyses of all-cause mortality found an interaction between sex and SUA. In a multivariate Cox model including women only, the highest SUA quartile was associated with an increased risk in all-cause mortality compared to the lowest SUA quartile (HR: 1.51; 95% CI: 1.08-2.12). No relationship was observed in men (HR: 1.06; 95% CI: 0.82-1.36).SUA was not an independent predictor of cardiovascular disease and death in these high-risk overweight/obese people. However, our results suggested that SUA was an independent predictor of all-cause mortality in women.

Project description:BackgroundPlasmodium falciparum elicits host inflammatory responses that cause the symptoms and severe manifestations of malaria. One proposed mechanism involves formation of immunostimulatory uric acid (UA) precipitates, which are released from sequestered schizonts into microvessels. Another involves hypoxanthine and xanthine, which accumulate in parasitized red blood cells (RBCs) and may be converted by plasma xanthine oxidase to UA at schizont rupture. These two forms of 'parasite-derived' UA stimulate immune cells to produce inflammatory cytokines in vitro.Methods and findingsWe measured plasma levels of soluble UA and inflammatory cytokines and chemokines (IL-6, IL-10, sTNFRII, MCP-1, IL-8, TNF?, IP-10, IFN?, GM-CSF, IL-1?) in 470 Malian children presenting with uncomplicated malaria (UM), non-cerebral severe malaria (NCSM) or cerebral malaria (CM). UA levels were elevated in children with NCSM (median 5.74 mg/dl, 1.21-fold increase, 95% CI 1.09-1.35, n = 23, p = 0.0007) and CM (median 5.69 mg/dl, 1.19-fold increase, 95% CI 0.97-1.41, n = 9, p = 0.0890) compared to those with UM (median 4.60 mg/dl, n = 438). In children with UM, parasite density and plasma creatinine levels correlated with UA levels. These UA levels correlated with the levels of seven cytokines [IL-6 (r = 0.259, p<0.00001), IL-10 (r = 0.242, p<0.00001), sTNFRII (r = 0.221, p<0.00001), MCP-1 (r = 0.220, p<0.00001), IL-8 (r = 0.147, p = 0.002), TNF? (r = 0.132, p = 0.006) and IP-10 (r = 0.120, p = 0.012)]. In 39 children, UA levels were 1.49-fold (95% CI 1.34-1.65; p<0.0001) higher during their malaria episode [geometric mean titer (GMT) 4.67 mg/dl] than when they were previously healthy and aparasitemic (GMT 3.14 mg/dl).ConclusionsElevated UA levels may contribute to the pathogenesis of P. falciparum malaria by activating immune cells to produce inflammatory cytokines. While this study cannot identify the cause of elevated UA levels, their association with parasite density and creatinine levels suggest that parasite-derived UA and renal function may be involved. Defining pathogenic roles for parasite-derived UA precipitates, which we have not directly studied here, requires further investigation.Trial registrationClinicalTrials.gov NCT00669084.

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A genome wide association study of plasma uric acid levels in obese cases and never-overweight controls.

Publications

A genome wide association study of plasma uric acid levels in obese cases and never-overweight controls.

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