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Targeted sequencing of Parkinson's disease loci genes highlights SYT11, FGF20 and other associations.


  • 影响因子:7.52
  • DOI:10.1093/brain/awaa401
  • 作者列表:"Rudakou U","Yu E","Krohn L","Ruskey JA","Asayesh F","Dauvilliers Y","Spiegelman D","Greenbaum L","Fahn S","Waters CH","Dupré N","Rouleau GA","Hassin-Baer S","Fon EA","Alcalay RN","Gan-Or Z
  • 发表时间:2021-03-03

:Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2657 patients and 3647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests. The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (P = 5.23 × 10-5 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5' UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's disease is driven by rare non-synonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in 10 and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson's disease in MAPT, TMEM175, BST1, SNCA and GPNMB, which are all in strong linkage disequilibrium with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (odds ratio 0.73, 95% confidence interval 0.60-0.89, P = 1.161 × 10-3). This variant is not in linkage disequilibrium with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.


: 全基因组关联研究 (GWAS) 已经鉴定了许多与帕金森病相关的基因座。驱动绝大多数这些基因座内关联的特定基因和变体是未知的。我们旨在对选定的基因进行全面分析,以确定这些基因座中罕见和常见遗传变异的潜在作用。我们对来自三个队列的2657例患者和3647例对照的25个位点的32个基因进行了完全测序。使用靶向感兴趣基因的外显子、外显子-内含子边界和非翻译区 (utr) 的分子反转探针进行捕获,然后测序。进行质量控制以仅包括高质量变体。我们使用优化的序列内核关联检验检查了罕见变体 (次要等位基因频率 <0.01) 的作用。根据每个队列的要求,使用针对年龄,性别和种族调整的回归模型估计常见变异的相关性,然后进行荟萃分析。Bonferroni校正后,我们发现SYT11、FGF20和GCH1中罕见变异的负担与帕金森病相关。在另外21个基因中鉴定了标称关联。以前的报道表明SYT11 GWAS关联是由附近GBA基因中的变体驱动的。然而,SYT11的关联主要由罕见的3 'UTR变体 (rs945006601) 驱动,并且独立于GBA变体 (在排除所有GBA变体携带者后,p = 5.23 × 10-5)。FGF20的关联由位于启动子区的罕见的5'utr变体 (rs1034608171) 驱动。先前报道的GCH1与帕金森病的关联是由罕见的非同义变体驱动的,其中一些已知会导致多巴胺反应性肌张力障碍。我们还在10个和8个对照中分别鉴定了两个LRRK2变体,p.Arg793Met和p.Gln1353Lys,但在患者中没有。我们在MAPT、TMEM175、BST1、SNCA和GPNMB中鉴定了与帕金森病相关的常见变异,这些变异都与各自位点的已知GWAS命中存在强连锁不平衡。一个常见的编码PM20D1变异,p.Ile149Val,名义上与帕金森病风险降低相关 (比值比0.73,95% 置信区间0.60-0.89,p = 1.161 × 10-3)。该变体与该基因座内的顶部GWAS命中不处于连锁不平衡,并且可能代表新的关联。这些结果进一步证明了GWAS位点精细定位的重要性,并表明SYT11、FGF20和潜在的PM20D1、BST1和GPNMB应被视为未来研究中可能的帕金森病相关基因。



作者列表:["Juan-Carlos PM","Perla-Lidia PP","Stephanie-Talia MM","Mónica-Griselda AM","Luz-María TE"]

METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.

翻译标题与摘要 下载文献
作者列表:["Sawada H","Oeda T","Kohsaka M","Tomita S","Umemura A","Park K","Yamamoto K","Kiyohara K"]

METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

翻译标题与摘要 下载文献
作者列表:["Louvrier A","Terranova L","Meyer C","Meyer F","Euvrard E","Kroemer M","Rolin G"]

METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.

翻译标题与摘要 下载文献