Identification of CHCHD10 variants in Chinese patients with Parkinson's disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhou X
PROVIDER: S-EPMC5995111 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
Publications
Identification of CHCHD10 variants in Chinese patients with Parkinson's disease.
Zhou Xiaoxia X Liu Zhenhua Z Guo Jifeng J Sun Qiying Q Xu Qian Q Yan Xinxiang X Tang Beisha B Lei Lifang L
Parkinsonism & related disorders 20171208
Similar Datasets
Project description:Oxidative stress and inflammation play vital roles in Parkinson's disease (PD) development. Thus, telomere length is expected to be shortened in this disease, but current data are inconclusive. We performed a case-control study of 261 patients with PD and 270 sex and age-matched healthy controls treated at the Peking Union Medical College Hospital. We found leucocyte telomere length (LTL) was significantly shortened in PD as compared with controls [1.02 (0.84-1.39) vs. 1.48 (1.08-1.94), P<0.001] and shorter LTL was associated with a dramatically increased risk of PD (lowest vs. highest quartile odds ratio (OR) =9.54, 95% CI: 5.33-17.06, P<0.001). We also investigated the roles of six LRRK2 variants in the susceptibility to PD. R1441C/G/H, G2019S, and I2020T variations were not detected in our study. No significant differences were found in the presence of variants R1398H (15.4% vs. 17.0%, P=0.619) and R1628P (2.3% vs. 0.7%, P=0.159) in PD and controls, while the G2385R variant was found to be a risk factor associated with increased PD susceptibility (OR=2.14, 95% CI: 1.12-4.10, P=0.021). No significant association was found between different LRRK2 variants and telomere length. These findings suggest that shorter LTL might be associated with PD in a manner independent of LRRK2 variants.
| S-EPMC7655166 | biostudies-literature
Project description:Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Accumulated evidence confirms that genetic factors play a considerable role in PD pathogenesis. To examine whether point variants or haplotypes are associated with PD development, genotyping of 35 variants in 22 PD-related genes was performed in a well-characterized cohort of 512 Han Chinese PD patients and 512 normal controls. Both Pearson's χ2 test and haplotype analysis were used to evaluate whether variants or their haplotypes were associated with PD in this cohort. The only statistically significant differences in genotypic and allelic frequencies between the patients and the controls were in the DnaJ heat shock protein family (Hsp40) member C10 gene (DNAJC10) variant rs13414223 (P = 0.004 and 0.002, respectively; odds ratio = 0.652, 95% confidence interval: 0.496-0.857). No other variants or haplotypes exhibited any significant differences between these two groups (all corrected P > 0.05). Our findings indicate that the variant rs13414223 in the DNAJC10 gene, a paralog of PD-related genes DNAJC6 and DNAJC13, may play a protective role in PD. This suggests it may be a PD-associated gene.
| S-EPMC5032117 | biostudies-literature
Project description:Parkinson's disease (PD) is the second most common neurodegenerative disorder and has an elusive etiology. It is likely multifactorial, and genetic defects contribute to its pathogenesis. At least 25 genetic loci and 20 monogenic genes have been identified in monogenic PD. Recessive F-box protein 7 gene (FBXO7) mutations reportedly cause hereditary parkinsonism. To explore the roles of four paralogs (FBXO2, FBXO6, FBXO12, and FBXO41) in PD development, their variants (rs9614, rs28924120, rs6442117, and rs61733550, respectively) were analyzed in 502 Han Chinese patients with PD and 556 age, gender, and ethnicity-matched normal participants in mainland China. Statistically significant differences in genotypic and allelic frequencies were detected only in the FBXO2 variant rs9614 (P = 0.001 and 0.023, respectively; odds ratio 0.819, 95% confidence interval 0.690-0.973) between patients and controls. These results suggest that the FBXO2 variant rs9614 C allele may decrease the PD risk in mainland Han Chinese and may be a biomarker for PD.
| S-EPMC5636729 | biostudies-literature
Project description:Parkinson's disease (PD) is a common neurodegenerative movement disorder. Among the candidate genes, DJ-1 accounts for about 1% of the cases in different populations. We aim to find the contribution of the gene towards PD among Indians. By screening DJ-1 in 308 PD patients of eastern India and 248 ethnically matched controls, a total of 21 nucleotide variants - including two nonsynonymous changes - were detected. p.Arg98Gln was identified in 6 unrelated patients and 2 controls while p.Val35Ile, a novel change, was found only in 2 unrelated patients. A SNP (rs7517357) was observed to be moderately associated with increased risk of PD (p< 0.05). The deletion allele (g.168_185del) of a known 18 bp del/ins/dup polymorphism was found to be over represented (p< 0.05) among older patients (> 40 years) compared to the controls (> 45 years). Two of the patients, also heterozygotes for PINK1 mutation, had more severe disease phenotypes, consistent with the reported interaction between PINK1 and DJ-1 gene products [19]. Our results demonstrate that up to 3.9% (12/308) of PD patients of eastern India harbor DJ-1 variants that should be explored further for any causal relationship with PD.
| S-EPMC3810687 | biostudies-literature
Project description:Background: Recent advanced technologies, such as high-throughput sequencing, have enabled the identification of a broad spectrum of variants. Using targeted-gene-panel resequencing for Parkinson's disease (PD)-associated genes, we have occasionally found several single-nucleotide variants (SNVs), which are thought to be disease-associated, in PD patients. To confirm the significance of these potentially disease-associated variants, we performed genome association analyses, using next-generation target resequencing, to evaluate the associations between the identified SNVs and PD. Methods: We obtained genomic DNA from 766 patients, who were clinically diagnosed with PD, and 336 healthy controls, all of Japanese origin. All data were analyzed using Ion AmpliSeq panel sequences, with 29 PD- or dementia-associated genes in a single panel. We excluded any variants that did not comply with the Hardy-Weinberg equilibrium in the control group. Variant frequencies in the PD and control groups were compared using PLINK. The identified variants were confirmed to a frequency difference of P < 0.05, after applying the Benjamini-Hochberg procedure using Fisher's exact test. The pathogenicity and prevalence of each variant were estimated based on a public gene database. Results: We identified three rare variants that were significantly associated with PD: rs201012663/rs150500694 in SYNJ1 and rs372754391 in DJ-1, which are intronic variants, and rs7412 in ApoE, which is an exonic variant. The variants in SYNJ1 and ApoE were frequently identified in the control group, and rs201012663/rs150500694 in SYNJ1 may play a protective role against PD. The DJ-1 variant was frequently identified in the PD group, with a high odds ratio of 2.2. Conclusion: The detected variants may represent genetic modifiers or disease-related variants in PD. Targeted-gene-panel resequencing may represent a useful method for detecting disease-causing variants and genetic association studies in PD.
| S-EPMC7550729 | biostudies-literature
Project description:CLEC16A is a membrane-associated endosomal protein implicated in regulating autophagy and antigen presentation. Its genetic variants are broadly associated with multiple autoimmune diseases. Parkinson's disease (PD), which undergoes autophagy disruption and neuroinflammation, has been clinically observed, for an extensive amount of time, to be associated with autoimmune diseases. In this study, we aimed to understand whether the autoimmune disease associated CLEC16A variants pleiotropically modulate PD risk. Five of such CLEC16A variants, including rs6498169, rs12708716, rs12917716, rs7200786, and rs2903692, were selected and analyzed in a Han Chinese cohort comprising 515 sporadic PD patients and 504 controls. Results showed that rs6498169 and rs7200786 were significantly associated with PD susceptibility (p = 0.005 and 0.004, respectively; recessive model, p = 0.002 and 0.001, respectively). Rs6498169 was also associated with the PD subtype of postural instability/gait difficulty (p = 0.002). Haplotype analysis showed that the AAG module in order of rs6498169, rs12708716, and rs2903692 was associated with the highest risk for PD (p = 0.0047, OR = 1.42, 95% CI = 1.11-1.82). Functional annotation analyses suggested that rs6498169 had high probability to affect transcription factor binding and target gene expression. In summary, the current study demonstrates that the autoimmune disease associated CLEC16A variants convey risk of PD in Han Chinese. Our findings suggest a pleiotropic role of CLEC16A and strengthen the link between PD and autoimmune diseases.
| S-EPMC9007333 | biostudies-literature
Project description:IntroductionEthnicity differences are an important determinant in the clinical manifestation of Parkinson's disease (PD), but they are not yet widely recognized, particularly regarding the response to dopaminergic medications. The aim of this paper is to analyze the efficacy and safety of safinamide in Chinese patients with PD in the pivotal studies SETTLE and XINDI compared to the non-Chinese population of the SETTLE trial.MethodsSETTLE (NCT00627640) and XINDI (NCT03881371) were phase III, randomized, double-blind, placebo-controlled, multicenter trials. Patients received safinamide or placebo as add-on to levodopa. The primary efficacy endpoint was the change in the mean total daily OFF time. Secondary efficacy endpoints included total daily ON time, ON time with no/non-troublesome dyskinesia, Unified Parkinson's Disease Rating Scale, and Parkinson's Disease Questionnaire-39 items. Safety was evaluated through the frequency of adverse events. Data from 440 non-Chinese and 109 Chinese patients in the SETTLE study, and 305 Chinese patients in the XINDI trial were considered for this post hoc analysis.ResultsSignificant positive results were seen in favor of safinamide in all populations for the primary and secondary endpoints, with no differences in terms of magnitude. No "treatment by ethnicity" interaction was detected for any parameters, confirming the homogeneity of treatment effects between different populations. The safety and tolerability of safinamide in Chinese patients were similar to those in the other ethnic groups, without unexpected adverse reactions.ConclusionsSafinamide was shown to improve PD symptoms and quality of life in different ethnic populations, without any treatment by race interaction. Further studies are warranted to investigate potential differences in a real-life situation.Trial registration numberSETTLE (NCT00627640) and XINDI (NCT03881371).
| S-EPMC10838837 | biostudies-literature
Project description:ObjectiveTo identify and characterize the pathogenicity of novel variants in Chinese patients with Charcot-Marie-Tooth disease.MethodsMultiplex ligation-dependent probe amplification (MLPA) and whole-exome sequencing (WES) were performed in 30 unrelated CMT patients. Minigene assay was used to verify the effect of a novel splicing variant (c.694+1G>A) on pre-mRNA. Primary fibroblast cell lines were established from skin biopsies to characterize the biological effects of the novel variants p.L26R and p.S169fs. The mitochondrial structure was observed by an electron microscope. The expression level of protein was analyzed by Western Blotting. Mitochondrial dynamics and mitochondrial membrane potential (MMP, Δψm) were analyzed via immunofluorescence study. Mitochondrial ATP levels were analyzed via bioluminescence assay. The rate of oxygen consumption was measured with a Seahorse Bioscience XF-96 extracellular flux analyzer.ResultsWe identified 10 pathogenic variants in three known CMT related genes, including three novel variants (p.L26R, p.S169fs, c.694+1G>A) and one known pathogenic variant (p.R120W) in GDAP1. Further, we described the clinical features of patients carrying pathogenic variants in GDAP1 and found that almost all Chinese CMT patients with GDAP1 variants present axonal type. The effect of c.694+1G>A on pre-mRNA was verified via minigene splice assay. Cellular biological effects showed ultrastructure damage of mitochondrial, reduced protein levels, different patterns of mitochondrial dynamics, decreased mitochondrial membrane potential (Δψm), ATP content, and defects in respiratory capacity in the patient carrying p.L26R and p.S169fs in GDAP1.InterpretationOur results broaden the genetic spectrum of GDAP1 and provided functional evidence for mitochondrial pathways in the pathogenesis of GDAP1 variants.
| S-EPMC7732252 | biostudies-literature
Project description:Mutations of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and 10 (CHCHD10) have been found to be linked to Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and/or frontotemporal lobe dementia (FTD). CHCHD2 and CHCHD10 proteins, which are homologous proteins with 54% identity in amino acid sequence, belong to the mitochondrial coiled-coil-helix-coiled-coil-helix (CHCH) domain protein family. A series of studies reveals that these twin proteins form a multimodal complex, producing a variety of pathophysiology by the disease-causing variants of these proteins. In this review, we summarize the present knowledge about the physiological and pathological roles of twin proteins, CHCHD2 and CHCHD10, in neurodegenerative diseases.
| S-EPMC6412816 | biostudies-literature
Project description:The SNCA (Synuclein Alpha) gene represents a major risk gene for Parkinson's disease (PD) and SNCA polymorphisms have been associated with the common sporadic form of PD. Numerous Genome-Wide Association Studies showed strong signals located in the SNCA 3' UTR (untranslated region) region indicating that variants in 3' UTRs of PD-associated genes could contribute to neurodegeneration and may regulate the risk for PD. Genetic variants in 3' UTR can affect miRNA activity and consequently change the translation process. The aim of this study was to access the differences in 3' UTR variants of SNCA genes in a cohort of PD patients and control subjects from Croatia. The cohort consisted of 52 PD patients and 23 healthy control subjects. Differences between 3' UTR allele and genotype frequencies were accessed through next generation sequencing approach from whole blood samples. In our study, we identified four previously reported single nucleotide polymorphisms (SNPs) and one insertion in the 3' UTR region of SNCA gene, namely rs1045722, rs3857053, rs577490090, rs356165, and rs777296100, and five variants not reported in the literature, namely rs35270750, rs529553259, rs377356638, rs571454522, and rs750347645. Our results indicate a significantly higher occurrence of the rs571454522 variant in the PD population. To the best of our knowledge, this variant has not been reported until now in the literature. We analyzed our results in the context of previous research, creating a brief overview of the importance of 3' UTR variants of the SNCA gene. Further studies will be needed to gain a more profound insight regarding their role in PD development, which will help to assess the role and impact of post-transcriptional regulation on disease pathology.
| S-EPMC8698872 | biostudies-literature