Genetic variability related to serum uric acid concentration and risk of Parkinson's disease

González‐Aramburu, Isabel; Sánchez‐Juan, Pascual; Jesús, Silvia; Gorostidi, Ana; Fernández-Juan, Eduardo; Carrillo, Fátima; Sierra, María; Gómez‐Garre, Pilar; Cáceres‐Redondo, María T.; Berciano, José; Ruíz‐Martínez, Javier; Combarros, Onofre; Mir, Pablo; Infante, Jon

doi:10.1002/mds.25507

Cited by 40 publications

(35 citation statements)

References 17 publications

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“…25 Further, in a PD case-control study, participants carrying more genetic alleles associated with lower serum urate concentrations were more likely to have PD. 26 Individuals with gout, a chronic condition associated with hyperuricemia, have been also found to have lower risk of PD in 2 previous studies, 27,28 but not in a recent one. 29 Another possible interpretation for the observed urate-PD association is that urate may slow disease progression during the preclinical stage of PD.…”

Section: Resultsmentioning

confidence: 90%

Prospective study of plasma urate and risk of Parkinson disease in men and women

et al. 2016

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Objective: To examine whether higher plasma urate concentrations are associated with a lower risk of developing Parkinson disease (PD) and whether there is a sex difference in the potential urate-PD relationship. Methods:We conducted a nested case-control study based on 90,214 participants of 3 ongoing US cohorts. We identified 388 new PD cases (202 men and 186 women) since blood collection, which were then matched to 1,267 controls. PD cases were confirmed by medical record review. Conditional logistic regression estimated relative risks (RRs) and 95% confidence intervals (95% CIs), after adjustment for age, smoking, caffeine intake, plasma concentrations of cholesterol and ferritin, and other covariates. We also conducted a meta-analysis to combine our study with 3 previously published prospective studies on urate and PD risk. Results:In the present nested case-control study, the multivariate-adjusted RRs of PD comparing extreme quartiles of urate were 0.63 (95% CI 0.35, 1.10; p trend 5 0.049) in men and 1.04 (95% CI 0.61, 1.78; p trend 5 0.44) in women (p heterogeneity 5 0.001). In the meta-analysis, the pooled RRs comparing 2 extreme quartiles of urate were 0.63 (95% CI 0.42, 0.95) in men and 0.89 (95% CI 0.57, 1.40) in women. Conclusion:We observed that men, but not women, with higher urate concentrations had a lower future risk of developing PD, suggesting that urate could be protective against PD risk or could slow disease progression during the preclinical stage of disease. Urate is a potent antioxidant and contributes to approximately 60% of the free radical scavenging activity in human serum.1,2 Serum urate concentrations in humans and apes are many-fold higher than those in other mammals as a consequence of evolutionary urate oxidase gene mutations.1 Results from in vitro and in vivo experimental studies suggest that urate could be a potential neuroprotective agent via its capacity to modify the cerebral damage induced by reactive nitrogen and oxidative species.2,3 In most, 4-8 but not all, 9 prospective observational studies in humans, higher concentrations of plasma urate were associated with a lower risk of developing Parkinson disease (PD). Further, patients with PD with higher urate levels have been found to have a slower disease progression relative to those with lower urate concentrations. 10,11 However, significant associations of higher urate levels with lower PD risk and slower progression were observed only in men. [4][5][6][7][8][9] Studies relating blood urate levels to PD risk were limited by their small sample sizes (PD case number , 160 in all studies) and underrepresentation of women. Therefore, it remains unclear whether this sex difference reflects a true difference in underlying biology or is due to lack of statistical power because women generally have lower urate concentration and lower PD incidence compared with men. Further, only one previous study 7 controlled for plasma ferritin and cholesterol levels, which have been found to be

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Section: Resultsmentioning

confidence: 90%

Prospective study of plasma urate and risk of Parkinson disease in men and women

et al. 2016

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“…26 In the second, a case-control study in Spain, individuals in the highest tertile of a genetic score predicting lower serum urate were found to have a 50% higher risk of PD. 11 In the third study, only one of 12 genotyped SNPs in SLC2A9 was associated with a significantly increased PD risk in women, and none in men. 27 In this last study, however, serum urate levels were not available, and it is thus possible that the association between the genotyped SNPs and serum urate in the study population was weaker than expected.…”

Section: Discussionmentioning

confidence: 93%

“…Because urate levels are in part heritable -- the estimate of between person variation due to inherited genetic factors ranges from 25% to 70%, 9 -- we sought to use a mendelian randomization design 10 to investigate whether genetic polymorphisms that predict serum urate levels predict the rate of clinical progression among individuals with early PD. Although several genes are associated with serum urate, and a multiple genes score has been used in a previous study of PD risk 11 , we selected as an instrumental variable for this investigation only the gene for solute carrier family 2 [facilitated glucose transporter], member 9 ( SLC2A9 , also known as GLUT9 ) 12 , which explains most of the genetically specified variability in serum urate. 13-19 By using a single gene with a strong effect on serum urate, but no known direct effects in the central nervous system, we minimized the possibility of violating the assumption that there are no genetic effects on PD progression other than those mediated by urate levels.…”

Section: Introductionmentioning

confidence: 99%

Mendelian randomization of serum urate and parkinson disease progression

Simon

Eberly

Gao

et al. 2014

Annals of Neurology

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Objective 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. Methods The study was conducted among participants in DATATOP and PRECEPT, two randomized trials among patients with early PD. The 808 patients with available DNA were genotyped for three SLC2A9 single nucleotide polymorphisms 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. A SLC2A9 score was created based on the total number of minor alleles at the three SLC2A9 loci . Primary outcome was disability requiring dopaminergic treatment. Results Serum urate concentrations were 0.69mg/dL lower among individuals with 4 or more SLC2A9 minor alleles as compared to those with two or less (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 1.00 to 1.35; p=.056). In a comparative analysis, the HR was 1.27 (1.00 to 1.61; p =0.0497) for a 0.5 mg/dL genetically conferred decrease in serum urate, and 1.05 (1.01 to 1.10; p=0.0133) for a 0.5 mg/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. Interpretation This Mendelian randomization analysis adds to the evidence of a causal protective effect of high urate levels.

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“…Urate level determinants also modify susceptibility to PD. Thus, dietary factors that contribute to higher plasma urate are associated with a lower risk of PD (top vs bottom quintile: relative risk 0.47, p = 0.0008), after adjustment for potential confounders [18], and genetic variability in genes known to influence urate levels is associated with PD risk [19,20]. [13][14][15][16][17][18][19][20] Inverse association with AD risk [21] (urate levels, urate genetic determinants, diet)…”

Section: Urate and Its Determinants Are A Risk Factor For Neurodegenementioning

confidence: 99%

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

Paganoni

Schwarzschild

2017

Neurotherapeutics

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Urate is a naturally occurring antioxidant whose levels are associated with reduced risk of developing Parkinson's disease (PD) and Alzheimer's disease. Urate levels are also associated with favorable progression in PD, amyotrophic lateral sclerosis, Huntington's disease, and multisystem atrophy. These epidemiological data are consistent with laboratory studies showing that urate exhibits neuroprotective effects by virtue of its antioxidant properties in several preclinical models. This body of evidence supports the hypothesis that urate may represent a shared pathophysiologic mechanism across neurodegenerative diseases. Most importantly, beyond its role as a molecular predictor of disease risk and progression, urate may constitute a novel therapeutic target. Indeed, clinical trials of urate elevation in PD and amyotrophic lateral sclerosis are testing the impact of raising peripheral urate levels on disease outcomes. These studies will contribute to unraveling the neuroprotective potential of urate in human pathology. In parallel, preclinical experiments are deepening our understanding of the molecular pathways that underpin urate's activities. Altogether, these efforts will bring about new insights into the translational potential of urate, its determinants, and its targets and their relevance to neurodegeneration.

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Genetic variability related to serum uric acid concentration and risk of Parkinson's disease

Abstract: Genetic variability influencing serum UA levels might modify susceptibility to PD.

Cited by 40 publications

References 17 publications

Prospective study of plasma urate and risk of Parkinson disease in men and women

Prospective study of plasma urate and risk of Parkinson disease in men and women

Mendelian randomization of serum urate and parkinson disease progression

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

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