Dataset Information

Immune System and Neuroinflammation in Idiopathic Parkinson's Disease: Association Analysis of Genetic Variants and miRNAs Interactions.

ABSTRACT: The present study investigated the association of SNPs involved in the regulation of immune response, cellular degenerative and neuroinflammatory pathways with the susceptibility and progression of idiopathic Parkinson's Disease (PD). In particular, 342 PD patients were subjected to a genotyping analysis of a panel of 120 SNPs by Open Array Technology. As control group, 503 samples representative of the European general population were utilized. The genetic analysis identified 26 SNPs associated with PD susceptibility. Of them, 12 SNPs were described as significant expression Quantitative Loci (eQTL) variants in different brain regions associated with motor and non-motor PD phenomenology. Moreover, the study highlighted 11 novel susceptibility genes for PD, which may alter multiple signaling pathways critically involved in peripheral immune response, neuroinflammation, neurodegeneration and dopaminergic neurons wiring. The study of miRNA-target genes highlighted a possible role of miR-499a, miR-196a2, and miR-29a in the modulation of multiple neuroinflammatory and neurodegenerative mechanisms underlying PD physiopathology. The study described a network of interconnected genes (APOE, CLU, IL6, IL7R, IL12B, INPP5D, MAPK1, MEF2C, MIF, and TNFSF14), which may act as upstream regulators in the modulation of biological pathways relevant to PD. Intriguingly, IL6 stands out as a master gene regulator since it may indirectly regulate the network of interconnected genes. The study highlighted different genes and miRNAs interactions potentially involved in PD physiopathology, which are worth to be further explored to improve the knowledge of disease and the research of novel treatments strategies.

SUBMITTER: Strafella C

PROVIDER: S-EPMC8209518 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Immune System and Neuroinflammation in Idiopathic Parkinson's Disease: Association Analysis of Genetic Variants and miRNAs Interactions.

Strafella Claudia C Caputo Valerio V Termine Andrea A Assogna Francesca F Pellicano Clelia C Pontieri Francesco E FE Macchiusi Lucia L Minozzi Giulietta G Gambardella Stefano S Centonze Diego D Bossù Paola P Spalletta Gianfranco G Caltagirone Carlo C Giardina Emiliano E Cascella Raffaella R

Frontiers in genetics 20210603

The present study investigated the association of SNPs involved in the regulation of immune response, cellular degenerative and neuroinflammatory pathways with the susceptibility and progression of idiopathic Parkinson's Disease (PD). In particular, 342 PD patients were subjected to a genotyping analysis of a panel of 120 SNPs by Open Array Technology. As control group, 503 samples representative of the European general population were utilized. The genetic analysis identified 26 SNPs associated ...[more]

PMID: 34149802

Similar Datasets

Project description:BackgroundPost-mortem Lewy body and Lewy neuritic inclusions are a defining feature of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). With the discovery of missense and multiplication mutations in the alpha-synuclein gene (SNCA) in familial parkinsonism, Lewy inclusions were found to stain intensely with antibodies raised against the protein. Yeast-two-hybrid studies identified synphilin-1 as an interacting partner of alpha-synuclein, and both proteins show co-immunolocalization in a subset of Lewy body inclusions. In the present study, we have investigated whether common variability in synphilin-1, including coding substitutions are genetically associated with disease pathogenesis.MethodsWe screened the synphilin-1 gene for 11 single nucleotide polymorphisms (SNPs) in 300 affected subjects with idiopathic Parkinson's disease and 412 healthy controls. Six of these were rare variants including five previously identified amino acid substitutions that were chosen in a direct approach for association of rare disease causing mutations. An additional five highly heterozygous SNPs were chosen for an indirect association approach including haplotype analysis, based on the assumption that any disease causing mutations might be in linkage disequilibrium with the SNPs selected. We also genotyped a microsatellite marker (D5S2950) within intron 6 of the gene and five additional microsatellites clustered downstream of the 5p23.1-23.3 synphilin-1 locus. Genome-wide linkage analysis, in a number of independent studies, has previously highlighted suggestive linkage to PD in this region of chromosome 5.ResultsScreening of previously known amino acid substitutions in the synphilin-1 gene, identified the C1861>T (R621C) substitution in four patients (chromosomes n = 600) and 10 control subjects (chromosomes n = 824), whereas the G2125>C (E706Q) substitution was detected in one patient and four control subject, suggesting both these substitutions are not associated with susceptibility to PD. Heterozygous non-synonymous T131>C (V44A) and synonymous C636>T (P212P) amino acid substitutions were each detected in only one patient with PD. Heterozygous C1134>T (L378L) synonymous substitutions were found in two patients with PD and one control subject. D5S2010 the most distal telomeric microsatellite marker genotyped,15.3 Mb from synphilin-1, was genetically associated with PD (p = 0.006, 27df) independently adjusted for multiple testing according to its high amount of alleles but not the total number of other markers investigated. Other flanking and intronic SNP and microsatellite markers showed no evidence for genetic association with disease.ConclusionIn this study rare synphilin-1 SNPs were assessed in a direct association approach to identify amino acid substitutions that might confer risk of PD in a homozygous or compound heterozygous state. We found none of these rare variations were associated with disease. In contrast to prior studies the frequency of the R621C substitution was not significantly different between PD and control subjects, neither were the V44A or E706Q substitutions. Similarly, our indirect study of more heterozygous SNPs, including both single marker and haplotype analyses, showed no significant association to PD. However, marginal association of microsatellite alleles with idiopathic PD, within the chromosome 5q21 region, indicates further studies are warranted.

Project description:The brain-age gap, i.e. the difference between the brain age estimated from structural MRI data and the chronological age of an individual, has been proposed as a summary measure of brain integrity in neurodegenerative diseases. Here, we aimed to determine the brain-age gap in genetic and idiopathic Parkinson's disease and its association with surrogate markers of Alzheimer's disease and Parkinson's disease pathology and with rates of cognitive and motor function decline. We studied 1200 cases from the Parkinson's Progression Markers Initiative cohort, including idiopathic Parkinson's disease, asymptomatic and clinical mutation carriers in the leucine-rich repeat kinase 2 gene (LRRK2) and the glucocerebrosidase gene (GBA), and normal controls using a cohort study design. For comparison, we studied 187 Alzheimer's disease dementia cases and 254 controls from the Alzheimer's Disease Neuroimaging Initiative cohort. We used Bayesian ANOVA to determine associations of the brain-age gap with diagnosis, and baseline measures of motor and cognitive function, dopamine transporter activity and CSF markers of Alzheimer's disease type amyloid-β42 and phosphotau pathology. Associations of brain-age gap with rates of cognitive and motor function decline were determined using Bayesian generalized mixed effect models. The brain-age gap in idiopathic Parkinson's disease patients was 0.7 years compared to controls, but 5.9 years in Alzheimer's disease dementia cases. In contrast, asymptomatic LRRK2 individuals had a 1.1. year younger brain age than controls. Across all cases, the brain-age gap was associated with motor impairment and (in the clinically manifest PD cases) reduced dopamine transporter activity, but less with CSF amyloid-β42 and phosphotau. In idiopathic Parkinson's disease cases, however, the brain-age gap was associated with lower CSF amyloid-β42 levels. In sporadic and genetic Parkinson's disease cases, a higher brain-age gap was associated with faster decline in episodic memory, and executive and motor function, whereas in asymptomatic LRRK2 cases, a smaller brain-age gap was associated with faster cognitive decline. In conclusion, brain age was sensitive to Alzheimer's disease like rather than Parkinson's disease like brain atrophy. Once an individual had idiopathic Parkinson's disease, their brain age was associated with markers of Alzheimer's disease rather than Parkinson's disease. Asymptomatic LRRK2 cases had seemingly younger brains than controls, and in these cases, younger brain age was associated with poorer cognitive outcome. This suggests that the term brain age is misleading when applied to disease stages where reactive brain changes with apparent volume increases rather than atrophy may drive the calculation of the brain age.

Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a devastating disease that probably involves several genetic loci. Several rare genetic variants and one common single nucleotide polymorphism (SNP) of MUC5B have been associated with the disease. Our aim was to identify additional common variants associated with susceptibility and ultimately mortality in IPF.MethodsFirst, we did a three-stage genome-wide association study (GWAS): stage one was a discovery GWAS; and stages two and three were independent case-control studies. DNA samples from European-American patients with IPF meeting standard criteria were obtained from several US centres for each stage. Data for European-American control individuals for stage one were gathered from the database of genotypes and phenotypes; additional control individuals were recruited at the University of Pittsburgh to increase the number. For controls in stages two and three, we gathered data for additional sex-matched European-American control individuals who had been recruited in another study. DNA samples from patients and from control individuals were genotyped to identify SNPs associated with IPF. SNPs identified in stage one were carried forward to stage two, and those that achieved genome-wide significance (p<5 × 10(-8)) in a meta-analysis were carried forward to stage three. Three case series with follow-up data were selected from stages one and two of the GWAS using samples with follow-up data. Mortality analyses were done in these case series to assess the SNPs associated with IPF that had achieved genome-wide significance in the meta-analysis of stages one and two. Finally, we obtained gene-expression profiling data for lungs of patients with IPF from the Lung Genomics Research Consortium and analysed correlation with SNP genotypes.FindingsIn stage one of the GWAS (542 patients with IPF, 542 control individuals matched one-by-one to cases by genetic ancestry estimates), we identified 20 loci. Six SNPs reached genome-wide significance in stage two (544 patients, 687 control individuals): three TOLLIP SNPs (rs111521887, rs5743894, rs5743890) and one MUC5B SNP (rs35705950) at 11p15.5; one MDGA2 SNP (rs7144383) at 14q21.3; and one SPPL2C SNP (rs17690703) at 17q21.31. Stage three (324 patients, 702 control individuals) confirmed the associations for all these SNPs, except for rs7144383. Linkage disequilibrium between the MUC5B SNP (rs35705950) and TOLLIP SNPs (rs111521887 [r(2)=0·07], rs5743894 [r(2)=0·16], and rs5743890 [r(2)=0·01]) was low. 683 patients from the GWAS were included in the mortality analysis. Individuals who developed IPF despite having the protective TOLLIP minor allele of rs5743890 carried an increased mortality risk (meta-analysis with fixed-effect model: hazard ratio 1·72 [95% CI 1·24-2·38]; p=0·0012). TOLLIP expression was decreased by 20% in individuals carrying the minor allele of rs5743890 (p=0·097), 40% in those with the minor allele of rs111521887 (p=3·0 × 10(-4)), and 50% in those with the minor allele of rs5743894 (p=2·93 × 10(-5)) compared with homozygous carriers of common alleles for these SNPs.InterpretationNovel variants in TOLLIP and SPPL2C are associated with IPF susceptibility. One novel variant of TOLLIP, rs5743890, is also associated with mortality. These associations and the reduced expression of TOLLIP in patients with IPF who carry TOLLIP SNPs emphasise the importance of this gene in the disease.FundingNational Institutes of Health; National Heart, Lung, and Blood Institute; Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis; and Instituto de Salud Carlos III.

Dataset Information

Immune System and Neuroinflammation in Idiopathic Parkinson's Disease: Association Analysis of Genetic Variants and miRNAs Interactions.

Publications

Immune System and Neuroinflammation in Idiopathic Parkinson's Disease: Association Analysis of Genetic Variants and miRNAs Interactions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets