Peptidoglycan recognition protein genes and risk of Parkinson's disease.
Increased gut permeability, inflammation, and colonic α-synuclein pathology are present in early Parkinson's disease (PD) and have been proposed to contribute to PD pathogenesis. Peptidoglycan is a structural component of the bacterial cell wall. Peptidoglycan recognition proteins (PGRPs) maintain healthy gut microbial flora by regulating the immune response to both commensal and harmful bacteria. We tested the hypothesis that variants in genes that encode PGRPs are associated with PD risk. Participants in two independent case-control studies were genotyped for 30 single-nucleotide polymorphisms (SNPs) in the four PGLYRP genes. Using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for potential confounding variables, we conducted analyses in each study, separately and pooled. One SNP failed the assay, and three had little to no variation. The ORs were similar in both study populations. In pooled analyses, three of seven PGLYRP2 SNPs (rs3813135, rs733731, rs892145), one of five PGLYRP3 SNPs (rs2987763), and six of nine PGLYRP4 SNPs (rs10888557, rs12063091, rs3006440, rs3006448, rs3006458, and rs3014864) were significantly associated with PD risk. Association was strongest for PGLYRP4 5'untranslated region (UTR) SNP rs10888557 (GG reference, CG OR 0.6 [95%CI 0.4-0.9], CC OR 0.15 [95%CI 0.04-0.6]; log-additive P-trend, 0.0004). Common variants in PGLYRP genes are associated with PD risk in two independent studies. These results require replication, but they are consistent with hypotheses of a causative role for the gut microbiota and gastrointestinal immune response in PD.
San Francisco Veterans Affairs Medical Center, San Francisco, California, USA; University of California, San Francisco, San Francisco, California, USA; The Parkinson's Institute, Sunnyvale, California, USA.
Samuel M
SM
Goldman
Freya
F
Kamel
G Webster
GW
Ross
Sarah A
SA
Jewell
Connie
C
Marras
Jane A
JA
Hoppin
David M
DM
Umbach
Grace S
GS
Bhudhikanok
Cheryl
C
Meng
Monica
M
Korell
Kathleen
K
Comyns
Robert A
RA
Hauser
Joseph
J
Jankovic
Stewart A
SA
Factor
Susan
S
Bressman
Kelly E
KE
Lyons
Dale P
DP
Sandler
J William
JW
Langston
Caroline M
CM
Tanner
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D064307:Microbiota / Q000235:genetics; D008875:Middle Aged; D016017:Odds Ratio; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D002352:Carrier Proteins; C118897:peptidoglycan recognition protein
PGLYRP; Parkinson's disease; gut; microbiome; peptidoglycan