variants and glucocerebrosidase activity in Parkinson's disease.

Mutations in glucocerebrosidase () are a common risk factor for Parkinson's disease (PD). The scavenger receptor class B member 2 () gene encodes a receptor responsible for the transport of glucocerebrosidase (GCase) to the lysosome. Two common SNPs in linkage disequilibrium with , rs6812193 and rs6825004, have been associated with PD and Lewy Body Disease in genome wide association studies. Whether these SNPs are associated with altered glucocerebrosidase enzymatic activity is unknown. Our objective was to determine whether SNPs are associated with PD and with reduced GCase activity. The gene was fully sequenced, and the G2019S and rs6812193 and rs6825004 SNPs were genotyped in 548 PD patients and 272 controls. GCase activity in dried blood spots was measured by tandem mass spectrometry. We tested the association between genotypes and PD risk in regression models adjusted for gender, age, and G2019S and mutation status. We compared GCase activity between participants with different genotypes at rs6812193 and rs6825004. Genotype at rs6812193 was associated with PD status. PD cases were less likely to carry the T allele than the C allele (OR=0.71; p=0.004), but GCase enzymatic activity was similar across rs6812193 genotypes (C/C: 11.88 μmol/l/h; C/T: 11.80 μmol/l/h; T/T: 12.02 μmol/l/h; p=0.867). Genotype at rs6825004 was not associated with either PD status or GCase activity. In conclusion, our results support an association between genotype at rs6812193 and PD, but suggest that the increased risk is not mediated by GCase activity.