Higher urate in LRRK2 mutation carriers resistant to Parkinson's disease

Abstract

Objective

LRRK2 mutations, the most common genetic cause of Parkinson's disease (PD) display incomplete penetrance, indicating the importance of other genetic and environmental influences on disease pathogenesis in LRRK2 mutation carriers. The present study investigates whether urate, an antioxidant, Nrf2 activator, and inverse risk factor for idiopathic PD, is one such candidate biomarker of PD risk modulation in pathogenic LRRK2 mutation carriers.

Methods

Banked plasma samples or urate levels were obtained for three cohorts of age‐ and sex‐matched subjects with and without a known LRRK2 mutation in PD and unaffected controls to conduct a pilot study of 192 subjects from the LRRK2 Cohort Consortium (LCC) and two validation studies of 380 additional subjects from the LCC and of 922 subjects from the Parkinson Progression Marker Initiative. Urate levels were compared by multiple regression between subjects with and without a PD diagnosis conditional on LRRK2 status, controlling for age and sex.

Results

Non‐manifesting LRRK2 mutation carriers had significantly higher levels of urate than those who developed PD in each of the three independent cohorts. A meta‐analysis demonstrated an adjusted mean difference of 0.62 mg/dL (p<0.001), with similar results for separate assessments of women (p<0.02) and men (p<0.001). A 2 mg/dL increment in urate concentration decreased the odds of having PD by more than 50% (OR = 0.48; p = 0.004).

Interpretation

These findings identify and substantiate urate as a biomarker of resistance to PD among LRRK2 mutation carriers.

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