Parkinson's Disease Risk Is Associated with Variants in Genes That Bind Bacterial Cell-Wall Peptidoglycan (P05.051)

OBJECTIVE: To investigate the possible association of Parkinson9s disease (PD) risk with variants in genes involved in the binding of bacterial cell-wall peptidoglycan. BACKGROUND: Peptidoglycan is a structural component of the bacterial cell wall, which binds recognition proteins encoded by PGLYRP genes. Peptidoglycan-recognition-proteins play a role in maintenance of healthy gut microbial flora and immune system activation. Lipopolysaccharide (LPS) from the cell membrane of gram negative bacteria has been shown to induce a parkinsonian syndrome in animal models, but peptidoglycan has not been well-studied. DESIGN/METHODS: DNA was obtained from 385 PD cases and 159 matched controls from eight North American movement disorders centers. Subjects were genotyped for 30 tag single nucleotide polymorphisms (SNPs) in the 4 PGLYRPs genes. After assessing Hardy-Weinberg equilibrium, we used logistic regression to estimate odds ratios (ORs) adjusted for gender, age, race and smoking. RESULTS: 22 SNPs had sufficient variation to analyze. 1 of 5 PGLYRP3 SNPs and 6 of 9 PGLYRP4 SNPs were significantly associated with PD risk. For rs2987763 in the flanking_59UTR of PGLYRP3, ORs and 95%CIs were: TT ref, AT 1.2 (0.8-1.8), AA 1.8 (1.02-3.1), p=0.044. For PGLYRP4, associations were strongest for rs10888557 in the flanking_59UTR: CC ref, CG 3.6 (0.8-15.2), GG 5.2 (1.3-21.2), p=0.01; and rs3006458, a missense SNP in exon 1: TT ref, TG 2.1 (0.8-5.6), GG 2.7 (1.02-6.9), p= 0.04. CONCLUSIONS: Common variants in PGLYRP genes are associated with PD risk. Intestinal abnormalities, altered gut flora and immune activation have all been proposed to contribute to PD pathogenesis, but information is limited. Studying peptidoglycan exposure and interaction with PGLYRP variants may provide new insights into these associations. Supported by: James and Sharron Clark. Disclosure: Dr. Goldman has nothing to disclose. Dr. Jewell has nothing to disclose. Dr. Meng has nothing to disclose. Dr. Ross has received research support from the Michael J. Fox Foundation. Dr. Chade has nothing to disclose. Dr. Kasten has nothing to disclose. Dr. Bhudhikanok has nothing to disclose. Dr. Comyns has nothing to disclose. Dr. Korell has nothing to disclose. Dr. Langston has nothing to disclose. Dr. Tanner has received personal compensation for activities with Adamas Pharmaceuticals as a consultant.