SCARB2variants and glucocerebrosidase activity in Parkinson's disease.
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 withSCARB2, 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 whetherSCARB2SNPs are associated with PD and with reduced GCase activity. TheGBAgene was fully sequenced, and theLRRK2G2019S andSCARB2rs6812193 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 betweenSCARB2genotypes and PD risk in regression models adjusted for gender, age, andLRRK2G2019S andGBAmutation 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 betweenSCARB2genotype at rs6812193 and PD, but suggest that the increased risk is not mediated by GCase activity.
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.
Roy N
RN
Alcalay
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.
Oren A
OA
Levy
Biologics Structural and Functional Research, Biopharmaceutics Development, Genzyme, a Sanofi company, Framingham, MA, USA.
Pavlina
P
Wolf
Biologics Structural and Functional Research, Biopharmaceutics Development, Genzyme, a Sanofi company, Framingham, MA, USA.
Petra
P
Oliva
Biologics Structural and Functional Research, Biopharmaceutics Development, Genzyme, a Sanofi company, Framingham, MA, USA.
Xiaokui Kate
XK
Zhang
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
Cheryl H
CH
Waters
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
Stanley
S
Fahn
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
Un
U
Kang
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
Christopher
C
Liong
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
Blair
B
Ford
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
Pietro
P
Mazzoni
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
Sheng
S
Kuo
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.
Amelie
A
Johnson
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.
Lan
L
Xiong
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.
Guy A
GA
Rouleau
Department of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
Wendy
W
Chung
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.
Karen S
KS
Marder
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.
Ziv
Z
Gan-Or