SCARB2 variants and glucocerebrosidase activity in Parkinson's disease.

Xiaokui Kate Zhang,Christopher Liong,Lan Xiong,Pavlina Wolf,Karen S Marder,Pietro Mazzoni,Sheng Kuo,Un Jung Kang,Blair Ford,Roy N Alcalay,Oren A Levy,Guy A Rouleau,Wendy K Chung,Stanley Fahn,Ziv Gan-Or,Cheryl H Waters,Petra Oliva,Amelie Johnson

doi:10.1038/npjparkd.2016.4

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.

Highlights

Heterozygous mutations and variants in glucocerebrosidase (GBA) are present in 3–5% of individuals with Parkinson’s disease (PD).[1,2] The scavenger receptor class B member 2 (SCARB2) gene encodes a protein, lysosome membrane protein 2 (LIMP-2), that transports β-glucocerebrosidase (GCase) from the endoplasmic reticulum through the Golgi apparatus and endosomes to the lysosome.[3]
(2) that protective variants are associated with higher GCase enzymatic activity as measured in dried blood spots when compared with carriers of the non-protective variant
Genotype at rs6825004 was not associated with PD status in our cohort, nor was it associated with GCase activity

Summary

Introduction

Heterozygous mutations and variants in glucocerebrosidase (GBA) are present in 3–5% of individuals with Parkinson’s disease (PD).[1,2] The scavenger receptor class B member 2 (SCARB2) gene encodes a protein, lysosome membrane protein 2 (LIMP-2), that transports β-glucocerebrosidase (GCase) from the endoplasmic reticulum through the Golgi apparatus and endosomes to the lysosome.[3]. Two common singlenucleotide polymorphisms (SNPs), rs6812193 (refs 5,6; 5′ of SCARB2) and rs68250047,8 (intron in SCARB2), have been shown to be associated with PD5–7,9 and Dementia with Lewy Bodies[8] in several genetic studies, including large genome-wide association studies. Given that homozygous mutations in SCARB2 are associated with reduced GCase activity,[3] it is possible that these SNPs modify the risk for PD via modulation of GCase activity. We tested the hypotheses that (1) these two SNPs would be associated with PD in a New York PD cohort; and (2) that protective variants are associated with higher GCase enzymatic activity as measured in dried blood spots when compared with carriers of the non-protective variant (e.g., if rs6812193 is associated with lower PD risk via SCARB2 carriers of the protective nucleotide, T, will have higher GCase activity than carriers of the C allele)

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Conclusion