Association of sequence alterations in the putative promoter of RAB7L1 with a reduced parkinson disease risk.
OBJECTIVE
To examine whether PARK16, which was recently identified as a protective locus for Parkinson disease (PD) in Asian, white, and South American populations, is also associated with PD in the genetically homogeneous Ashkenazi Jewish population.


METHODS
Case-control study.


METHODS
A medical center affiliated with a university. Subjects  Five single-nucleotide polymorphisms (SNPs) located between RAB7L1 and SLC41A1 were analyzed in 720 patients with PD and 642 controls, all of Ashkenazi Jewish origin.


METHODS
Haplotypes were defined and risk estimates were determined for each SNP and haplotype. Bioinformatic analysis defined the putative promoter region of RAB7L1 and the transcription factor binding sites that are potentially affected by 2 of the tested SNPs.


RESULTS
All tested SNPs were significantly associated with PD (odds ratios = 0.64-0.76; P = .0002-.014). Two of them, rs1572931 and rs823144, were localized to the putative promoter region of RAB7L1 and their sequence variations altered the predicted transcription factor binding sites of CdxA, p300, GATA-1, Sp1, and c-Ets-1. Only 0.4% of patients were homozygous for the protective rs1572931 genotype (T/T), compared with 3.0% among controls (P = 5 × 10(-5)). This SNP was included in a haplotype that reduced the risk for PD by 10- to 12-fold (P = .002-.01) in all patients with PD and in a subgroup of patients who do not carry the Ashkenazi founder mutations in the GBA or LRRK2 genes.


CONCLUSIONS
Our data demonstrate that specific SNP variations and haplotypes in the PARK16 locus are associated with reduced risk for PD in Ashkenazim. Although it is possible that alterations in the putative promoter of RAB7L1 are associated with this effect, the role of other genes in this locus cannot be ruled out.
Genetic Institute, Tel Aviv Sourasky Medical Center, 6 Weizmann St, Tel Aviv 64239, Israel.
Ziv
Z
Gan-Or
Anat
A
Bar-Shira
Dvir
D
Dahary
Anat
A
Mirelman
Merav
M
Kedmi
Tanya
T
Gurevich
Nir
N
Giladi
Avi
A
Orr-Urtreger
D000368:Aged; D000369:Aged, 80 and over; D001168:Arthritis / Q000150:complications / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D019295:Computational Biology; D003638:Deafness / Q000150:complications / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007599:Judaism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010300:Parkinson Disease / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D011081:Polychondritis, Relapsing / Q000150:complications / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012307:Risk Factors; D001617:beta-Glucosidase / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000235:genetics*; D000090802:rab7 GTP-Binding Proteins
D000090802:rab7 GTP-Binding Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D001617:beta-Glucosidase; D020691:rab GTP-Binding Proteins