AUTHOR=Gorecki Anastazja M. , Bakeberg Megan C. , Theunissen Frances , Kenna Jade E. , Hoes Madison E. , Pfaff Abigail L. , Akkari P. Anthony , Dunlop Sarah A. , Kõks Sulev , Mastaglia Frank L. , Anderton Ryan S. 

TITLE=Single Nucleotide Polymorphisms Associated With Gut Homeostasis Influence Risk and Age-at-Onset of Parkinson's Disease

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=12

YEAR=2020

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2020.603849

DOI=10.3389/fnagi.2020.603849

ISSN=1663-4365

ABSTRACT=<p>Research is increasingly focusing on gut inflammation as a contributor to Parkinson's disease (PD). Such gut inflammation is proposed to arise from a complex interaction between various genetic, environmental, and lifestyle factors, however these factors are under-characterized. This study investigated the association between PD and single-nucleotide polymorphisms (SNPs) in genes responsible for binding of bacterial metabolites and intestinal homeostasis, which have been implicated in intestinal infections or inflammatory bowel disease. A case-control analysis was performed utilizing the following cohorts: (i) patients from the Australian Parkinson's Disease Registry (APDR) (<italic>n</italic> = 212); (ii) a Caucasian subset of the Parkinson's Progression Markers Initiative (PPMI) cohort (<italic>n</italic> = 376); (iii) a combined control group (<italic>n</italic> = 404). The following SNPs were analyzed: <italic>PGLYRP2</italic> rs892145, <italic>PGLYRP4</italic> rs10888557, <italic>TLR1</italic> rs4833095, <italic>TLR2</italic> rs3804099, <italic>TLR4</italic> rs7873784, <italic>CD14</italic> rs2569190, <italic>MUC1</italic> rs4072037, <italic>MUC2</italic> rs11825977, <italic>CLDN2</italic> rs12008279 and rs12014762, and <italic>CLDN4</italic> rs8629. PD risk was significantly associated with <italic>PGLYRP4</italic> rs10888557 genotype in both cohorts. <italic>PGLYRP2</italic> rs892145 and <italic>TLR1</italic> rs4833095 were also associated with disease risk in the APDR cohort, and <italic>TLR2</italic> rs3804099 and <italic>MUC2</italic> rs11825977 genotypes in the PPMI cohort. Interactive risk effects between <italic>PGLYRP2</italic>/<italic>PGLYRP4</italic> and <italic>PGLYRP4</italic>/<italic>TLR2</italic> were evident in the APDR and PPMI cohorts, respectively. In the APDR cohort, the <italic>PGLYRP4</italic> GC genotype was significantly associated with age of symptom onset, independently of gender, toxin exposure or smoking status. This study demonstrates that genetic variation in the bacterial receptor <italic>PGLYRP4</italic> may modulate risk and age-of-onset in idiopathic PD, while variants in <italic>PGLYRP2, TLR1/2</italic>, and <italic>MUC2</italic> may also influence PD risk. Overall, this study provides evidence to support the role of dysregulated host-microbiome signaling and gut inflammation in PD, and further investigation of these SNPs and proteins may help identify people at risk of developing PD or increase understanding of early disease mechanisms.</p>