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

Abstract

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

Sex-specific Association Between Uric Acid and Outcomes After Acute Ischemic Stroke: A Prospective Study from CATIS Trial

“…A sex-difference protective effect of UA on nervous system disease (such as Parkinson disease) had also been reported2627. For example, a recent nested case-control study based on 3 ongoing US cohorts suggested that men, but not women, with higher urate concentrations had a lower future risk of developing Parkinson disease26. The biological mechanisms underlying such sex specificity remain unclear.…”

Epidemiology of Parkinson's Disease—East Versus West

“…A meta-analysis of three prospective cohort studies and a nested case-control study of three US cohorts obtained a pooled RR of 0.63 (95% CI: 0.42-0.95) in men and 0.89 (95% CI: 0.57-1.40) in women comparing the two extreme quartiles of urate. 60 Higher urate concentrations were found to be protective against PD risk in men, but not in women. 60 Similar findings were obtained in an earlier meta-analysis of four cohort studies performed in the Netherlands and the USA, and two nested case-control studies performed in the USA (RR 0.67, 95% CI: 0.50-0.91); with further subgroup analysis showing protective effects of serum urate in men, but not in women.…”

“…60 Higher urate concentrations were found to be protective against PD risk in men, but not in women. 60 Similar findings were obtained in an earlier meta-analysis of four cohort studies performed in the Netherlands and the USA, and two nested case-control studies performed in the USA (RR 0.67, 95% CI: 0.50-0.91); with further subgroup analysis showing protective effects of serum urate in men, but not in women. 61 Gout is a metabolic disorder that tends to occur in individuals with higher levels of serum uric acid, although other risk factors are also implicated.…”

“…A number of studies have been performed looking at the association of uric acid and the risk of Parkinson's disease. A meta‐analysis of three prospective cohort studies and a nested case‐control study of three US cohorts obtained a pooled RR of 0.63 (95% CI: 0.42–0.95) in men and 0.89 (95% CI: 0.57–1.40) in women comparing the two extreme quartiles of urate . Higher urate concentrations were found to be protective against PD risk in men, but not in women .…”

Alcohol consumption and probable rapid eye movement sleep behavior disorder

“…To examine the robustness of the observed results, we conducted a sensitivity analysis by excluding individuals with hyperuricemia (1462 in men and 175 in women) because urate concentration is strongly associated with alcohol consumption and PD status 23, 24. For the same reason, we conducted another sensitivity analysis using the alternative cut‐off point (range 0–70, >7) for determining pRBD based on seven subgroup behavioral factors of RBDQ‐HK, including sleep talking, shouting, limb movements, and sleep‐related injuries.…”