Association of sequence alterations in the putative promoter of RAB7L1 with a reduced parkinson disease risk

Arch Neurol. 2012 Jan;69(1):105-10. doi: 10.1001/archneurol.2011.924.


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.

Design: Case-control study.

Setting: 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.

Main outcome measures: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Arthritis / complications
  • Arthritis / genetics
  • Binding Sites / genetics
  • Case-Control Studies
  • Computational Biology
  • Deafness / complications
  • Deafness / genetics
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Judaism
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Male
  • Middle Aged
  • Odds Ratio
  • Parkinson Disease / complications
  • Parkinson Disease / ethnology
  • Parkinson Disease / genetics*
  • Polychondritis, Relapsing / complications
  • Polychondritis, Relapsing / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Promoter Regions, Genetic / genetics*
  • Protein-Serine-Threonine Kinases / genetics
  • Risk Factors
  • beta-Glucosidase / genetics
  • rab GTP-Binding Proteins / genetics*


  • rab7 protein
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases
  • beta-Glucosidase
  • rab GTP-Binding Proteins

Supplementary concepts

  • Meyenburg-Altherr-Uehlinger syndrome