Genetic and Environmental Factors in Parkinson's Disease Converge on Immune Function and Inflammation.
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ABSTRACT:
SUBMITTER: Kline EM
PROVIDER: S-EPMC8285924 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Introduction: Parkinson's disease (PD) is a neurodegenerative disorder affecting a substantial proportion of the elderly Cypriot population. The objective of this study was to evaluate PD risk variants that have been identified previously in Genome Wide Association Studies (GWAS) and to find environmental factors that are predictors for PD onset in the Cypriot population. Methods: A case-control study was conducted with a total of 235 PD patients and 464 healthy controls of Greek-Cypriot ethnicity. Demographic and lifestyle characteristics, exposure to PD risk factors and clinical data were collected. Moreover, 13 previously GWAS-identified PD risk variants were genotyped. Univariate and multivariate regression analyses examined the association between a number of environmental and genetic factors and PD. Results: Multivariable regression analysis revealed that exposure to both pesticides and other toxic substances (P = 0.03), severe head injury accompanied with fainting (P = 0.001), nuts consumption (P = 0.004), red meat consumption (P = 0.02), and soft drinks consumption (P = 0.008) were increasing the risk for PD, whereas cumulative smoking (P = 0.02), and fish consumption (P = 0.02) were decreasing the risk for PD. Five out of the 13 tested SNPs (rs12185268, rs6599389, rs356220, rs13312, and rs17649553) were confirmed to be nominally significantly associated (P < 0.05) with PD risk in the Cypriot population. Conclusions: Collectively, this case-control study has shed some light on the nature of PD epidemiology in Cyprus, by demonstrating a number of genetic and environmental determinants of PD in the Cypriot population.
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Project description:BackgroundRisk factors for Parkinson's disease (PD) can be more or less relevant to a population due to population-specific genetic architecture, local lifestyle habits, and environmental exposures. Therefore, it is essential to study PD at a local, regional, and continental scale in order to increase the knowledge on disease etiology.ObjectiveWe aimed to investigate the contribution of genetic and environmental factors to PD in a new Swedish case-control cohort.MethodsPD patients (n = 929) and matched population-based controls (n = 935) from the southernmost county in Sweden were included in the cohort. Information on environmental exposures was obtained using questionnaires at inclusion. Genetic analyses included a genome-wide association study (GWAS), haplotype assessment, and a risk profile analysis using cumulative genetic risk scores.ResultsThe cohort is a representative PD case-control cohort (64% men, mean age at diagnosis = 67 years, median Hoehn and Yahr score 2.0), in which previously reported associations between PD and environmental factors, such as tobacco, could be confirmed. We describe the first GWAS of PD solely composed of PD patients from Sweden, and confirm associations to well-established risk alleles in SNCA. In addition, we nominate an unconfirmed and potentially population-specific genome-wide significant association in the PLPP4 locus (rs12771445).ConclusionThis work provides an in-depth description of a new PD case-control cohort from southern Sweden, giving insights into environmental and genetic risk factors for PD in the Swedish population.
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Project description:BACKGROUND:Gastrointestinal symptoms are common in Parkinson's disease and frequently precede the development of motor impairments. Intestinal inflammation has been proposed as a driver of disease pathology, and evaluation of inflammatory mediators in stool could possibly identify valuable early-stage biomarkers. We measured immune- and angiogenesis-related proteins in human stool to examine inflammatory profiles associated with Parkinson's disease. METHODS:Stool samples and subjects' self-reported metadata were obtained from 156 individuals with Parkinson's disease and 110 without, including spouse and nonhousehold controls. Metadata were probed for disease-associated differences, and levels of 37 immune and angiogenesis factors in stool homogenates were measured by multiplexed immunoassay and compared across experimental groups. RESULTS:Parkinson's disease patients reported greater incidence of intestinal disease and digestive problems than controls. Direct comparison of levels of stool analytes in patients and controls revealed elevated vascular endothelial growth factor receptor 1, interleukin-1α, and CXCL8 in patients' stool. Paired comparison of patients and spouses suggested higher levels of multiple factors in patients, but this was complicated by sex differences. Sex, body mass index, a history of smoking, and use of probiotics were found to strongly influence levels of stool analytes. Multivariate analysis accounting for these and other potential confounders confirmed elevated levels of interleukin-1α and CXCL8 and also revealed increased interleukin-1β and C-reactive protein in stool in Parkinson's disease. These differences were not dependent on subject age or disease duration. CONCLUSIONS:Levels of stool immune factors indicate that intestinal inflammation is present in patients with Parkinson's disease. © 2018 International Parkinson and Movement Disorder Society.
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Project description:Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disease, with a complex risk structure thought to be influenced by interactions between genetic variants and environmental exposures, although the full aetiology is unknown. Environmental factors, including pesticides, have been reported to increase the risk of developing the disease. Growing evidence suggests epigenetic changes are key mechanisms by which these environmental factors act upon gene regulation, in disease-relevant cell types. We present a systematic review critically appraising and summarising the current body of evidence of the relationship between epigenetic mechanisms and environmental risk factors in PD to inform future research in this area. Epigenetic studies of relevant environmental risk factors in animal and cell models have yielded promising results, however, research in humans is just emerging. While published studies in humans are currently relatively limited, the importance of the field for the elucidation of molecular mechanisms of pathogenesis opens clear and promising avenues for the future of PD research. Carefully designed epidemiological studies carried out in PD patients hold great potential to uncover disease-relevant gene regulatory mechanisms. Therefore, to advance this burgeoning field, we recommend broadening the scope of investigations to include more environmental exposures, increasing sample sizes, focusing on disease-relevant cell types, and recruiting more diverse cohorts.
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Project description:Current hypothesis of neuronal degeneration in Parkinson's disease (PD) have been proposed, including formation of free radicals and oxidative stress, mitochondrial dysfunction, excitotoxicity, trophic factor deficiency, inflammatory processes, genetic factors, environmental impact factors, toxic action of nitric oxide, apoptosis, and so on. This review mainly discussed oxidative stress, environmental impact factors, and inflammatory processes in PD.
| S-EPMC5550597 | biostudies-other
Project description:The discovery of causative mutations for Parkinson's disease (PD) as well as their functional characterization in cellular and animal models has provided crucial insight into the pathogenesis of this disorder. Today, we know that PD pathogenesis involves multiple related processes including mitochondrial dysfunction, oxidative and nitrative stress, microglial activation and inflammation, and aggregation of α-synuclein and impaired autophagy. However, with the exception of a few families with Mendelian inheritance, the cause of PD in most individuals is yet unknown and the identified genetic susceptibility factors have only small effect size. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, organic solvents, metals, and air pollutants, while reduced risk of PD associated with smoking cigarettes and coffee consumption. The role of environmental exposure, as well as the contribution of single genetic risk factors, is still controversial. In most of PD cases, disease onset is probably triggered by a complex interplay of many genetic and nongenetic factors, each of which conveys a minor increase in the risk of disease. This review summarizes the current knowledge on causal mutation for PD, susceptibility factors increasing disease risk, and the genetic factors that modify the impact of environmental exposure.
| S-EPMC4752982 | biostudies-literature
Project description:ObjectiveTo investigate the associations between Parkinson's disease and other degenerative parkinsonian syndromes and environmental factors in five European countries.MethodsA case-control study of 959 prevalent cases of parkinsonism (767 with Parkinson's disease) and 1989 controls in Scotland, Italy, Sweden, Romania and Malta was carried out. Cases were defined using the United Kingdom Parkinson's Disease Society Brain Bank criteria, and those with drug-induced or vascular parkinsonism or dementia were excluded. Subjects completed an interviewer-administered questionnaire about lifetime occupational and hobby exposure to solvents, pesticides, iron, copper and manganese. Lifetime and average annual exposures were estimated blind to disease status using a job-exposure matrix modified by subjective exposure modelling. Results were analysed using multiple logistic regression, adjusting for age, sex, country, tobacco use, ever knocked unconscious and family history of Parkinson's disease.ResultsAdjusted logistic regression analyses showed significantly increased odds ratios for Parkinson's disease/parkinsonism with an exposure-response relationship for pesticides (low vs no exposure, odds ratio (OR) = 1.13, 95% CI 0.82 to 1.57, high vs no exposure, OR = 1.41, 95% CI 1.06 to 1.88) and ever knocked unconscious (once vs never, OR = 1.35, 95% CI 1.09 to 1.68, more than once vs never, OR = 2.53, 95% CI 1.78 to 3.59). Hypnotic, anxiolytic or antidepressant drug use for more than 1 year and a family history of Parkinson's disease showed significantly increased odds ratios. Tobacco use was protective (OR = 0.50, 95% CI 0.42 to 0.60). Analyses confined to subjects with Parkinson's disease gave similar results.ConclusionsThe association of pesticide exposure with Parkinson's disease suggests a causative role. Repeated traumatic loss of consciousness is associated with increased risk.
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Project description:Parkinson's disease (PD) is a common human neurodegenerative movement disorder. Studies of the genetic forms of PD have helped to reveal disease mechanisms. Functional interactions between some Parkinson's disease (PD) genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1 and alpha-synuclein, a protein with a key role in the pathogenesis of both sporadic and familial PD. We extend our findings from yeast to an animal model and show these interactions are conserved in neurons. We also connect VPS35 impairments to neurodegeneration in alpha-synuclein transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to alpha-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future genetic and functional interrogation. Ribosome profiling (RiboSeq) of wild type and VPS35 deletion yeast strains, with or without overexpression of the TIF4631 initiation factor
2014-12-19 | E-GEOD-64304 | biostudies-arrayexpress
Project description:INTRODUCTION:Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population. METHODS:The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls. We screened for known genetic risk variants in GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT. In addition, DNA from 225 patients with early-onset Parkinson's disease was subjected to whole exome sequencing (WES). RESULTS:We detected a significant difference in the length variation of the CAG repeat in POLG1 between patients with early-onset PD compared to controls. The p.N370S and p.L444P variants in GBA contributed to a relative risk of 3.8 in early-onset PD and 2.5 in late-onset PD. WES revealed five variants in LRRK2 and SMPD1 that were found in the patients but not in the Finnish ExAC sequences. These are possible risk variants that require further confirmation. The p.G2019S variant in LRRK2, common in North African Arabs and Ashkenazi Jews, was not detected in any of the 849 PD patients. CONCLUSIONS:The POLG1 CAG repeat length variation and the GBA p.L444P variant are associated with PD in the Finnish population.
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