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NPJ Parkinsons Dis. 2016;2. pii: 16004. Epub 2016 Mar 10.

SCARB2 variants and glucocerebrosidase activity in Parkinson's disease.

Author information

1
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
2
Biologics Structural and Functional Research, Biopharmaceutics Development, Genzyme, a Sanofi company, Framingham, MA, USA.
3
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
4
Département de médicine, Université de Montréal, Montréal, QC, Canada; Laboratoire de neurogénétique, Centre de recherche, Institut universitaire en santé mentale de Montréal, Montréal, QC, Canada.
5
Laboratoire de neurogénétique, Centre de recherche, Institut universitaire en santé mentale de Montréal, Montréal, QC, Canada; Département de psychiatrie, Université de Montréal, Montréal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
6
Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada; Montréal Neurological Institute & Hospital, and the Department of Human Genetics, McGill University, Montreal, QC, Canada.
7
Department of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
8
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Abstract

Mutations in glucocerebrosidase (GBA) are a common risk factor for Parkinson's disease (PD). The scavenger receptor class B member 2 (SCARB2) gene encodes a receptor responsible for the transport of glucocerebrosidase (GCase) to the lysosome. Two common SNPs in linkage disequilibrium with SCARB2, 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 SCARB2 SNPs are associated with PD and with reduced GCase activity. The GBA gene was fully sequenced, and the LRRK2 G2019S and SCARB2 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 SCARB2 genotypes and PD risk in regression models adjusted for gender, age, and LRRK2 G2019S and GBA 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 SCARB2 genotype at rs6812193 and PD, but suggest that the increased risk is not mediated by GCase activity.

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