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1.
Evidence for novel loci for late-onset Parkinson’s disease in a genetic isolate from the Netherlands
Bertoli-Avella AM Dekker MC Aulchenko YS Houwing-Duistermaat JJ Simons E Testers L Pardo LM Rademaker TA Snijders PJ van Swieten JC Bonifati V Heutink P van Duijn CM Oostra BA 《Human genetics》2006,119(1-2):51-60
We studied patients with idiopathic Parkinson’s disease (PD) from an isolated population in the Netherlands aiming to map
gene(s) involved in PD susceptibility. A total of 109 parkinsonism patients were independently ascertained, of whom 62 presented
late-onset, idiopathic PD. Genealogical research showed that 45 index cases with idiopathic PD were linked to a common ancestor,
indicating familiar clustering among the patients. This strong familial clustering was highly significant (P=0.005) when compared to random controls from the same population. We performed a genome wide scan using 382 polymorphic markers
in 44 distantly related PD patients plus 112 unaffected first-degree relatives and spouses. Our genome wide association analysis
(DISLAMB) revealed evidence of association at a nominal P-value<0.01 for markers D2S2333, D4S405, D9S158, D13S153. Other regions on chromosomes 3p, 4q, 14q, 17p and 17q were found
at a significance level of P<0.05. In a follow-up study, we investigated all the positive regions using a denser marker set and a larger sample (total
of 630 individuals including all late-onset PD patients). The strongest evidence for association remained for the 9q and 14q
region. A significant association was found for marker D9S1838 (OR=2.0, 95% CI 1.1–3.5, P=0.014) and D14S65 (OR=3.2, 95% CI 1.7–6.1, P<0.001). Moreover, a common haplotype with excess of sharing among late-onset PD cases was observed on both regions. Our results
suggest the existence of two loci influencing PD susceptibility on chromosome 9q and 14q. 相似文献
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A hypothesis is proposed that reconciles the epidemiological observation of elevated homocysteine in Alzheimer's disease (AD) with clinical features of the disease, particularly evidence of increased oxidative stress. We propose homocysteine is involved in an iron dysregulation/oxidative stress cycle that has a central role in the pathogenesis of AD. The implications of the hypothesis and some strategies for testing it are discussed. 相似文献
4.
Tao Wu Kung Yee Liang Jacqueline B. Hetmanski Ingo Ruczinski Margaret Daniele Fallin Roxann G. Ingersoll Hong Wang Shangzhi Huang Xiaoqian Ye Yah-Huei Wu-Chou Philip K. Chen Ethylin W. Jabs Bing Shi Richard Redett Alan F. Scott Terri H. Beaty 《Human genetics》2010,128(4):401-410
Although multiple genes have been identified as genetic risk factors for isolated, non-syndromic cleft lip with/without cleft palate (CL/P), a complex and heterogeneous birth defect, interferon regulatory factor 6 gene (IRF6) is one of the best documented genetic risk factors. In this study, we tested for association between markers in IRF6 and CL/P in 326 Chinese case–parent trios, considering gene–environment interaction for two common maternal exposures, and parent-of-origin effects. CL/P case–parent trios from three sites in mainland China and Taiwan were genotyped for 22 single nucleotide polymorphisms (SNPs) in IRF6. The transmission disequilibrium test was used to test for marginal effects of individual SNPs. We used PBAT to screen the SNPs and haplotypes for gene–environment (G × E) interaction and conditional logistic regression models to quantify effect sizes for SNP–environment interaction. After Bonferroni correction, 14 SNPs showed statistically significant association with CL/P. Evidence of G × E interaction was found for both maternal exposures, multivitamin supplementation and environmental tobacco smoke (ETS). Two SNPs showed evidence of interaction with multivitamin supplementation in conditional logistic regression models (rs2076153 nominal P = 0.019, rs17015218 nominal P = 0.012). In addition, rs1044516 yielded evidence for interaction with maternal ETS (nominal P = 0.041). Haplotype analysis using PBAT also suggested interaction between SNPs in IRF6 and both multivitamin supplementation and ETS. However, no evidence for maternal genotypic effects or significant parent-of-origin effects was seen in these data. These results suggest IRF6 gene may influence risk of CL/P through interaction with multivitamin supplementation and ETS in the Chinese population. 相似文献
5.
Association between coding variability in the LRP gene and the risk of late-onset Alzheimer’s disease 总被引:3,自引:0,他引:3
Fabienne Wavrant-DeVrièze Jean-Charles Lambert L. Stas Richard Crook Dominique Cottel Florence Pasquier Bernard Frigard Martine Lambrechts E. Thiry Philippe Amouyel J. Pérez-Tur M. C. Chartier-Harlin John Hardy Fred Van Leuven 《Human genetics》1999,104(5):432-434
We have sequenced the entire (89 exons) open reading frame of the LRP gene in 12 cases of Alzheimer’s disease (AD) from Northern
France. We have found no novel changes but confirm the occurrence of a polymorphism in exon 6 of the gene (A216V). This polymorphism
is rare (2.8% of controls) and is in linkage equilibrium with previously reported polymorphisms. The V216 allele is negatively
associated with the disease in a large case-controlled series. These data suggest that the LRP receptor may be involved in
the pathobiology of AD, but the association that we report here cannot explain the previously reported genetic data implicating
the LRP gene in AD. If the LRP gene is a major site of genetic variability leading to AD, there must be other biologically
relevant variability in promoter or other regulatory elements of this large gene.
Received: 28 December 1998 / Accepted: 1 March 1999 相似文献
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《Cell》2023,186(4):690-692
7.
The present case–control study was conducted to investigate the relationship between smoking and rheumatoid arthritis, and
to investigate formally the interaction between sex, smoking, and risk for developing rheumatoid arthritis. The study was
performed in the Central District of Finland. Cases were patients with rheumatoid arthritis and the control group was a random
sample of the general population. Logistic regression models were used to evaluate the effect of smoking on risk for rheumatoid
arthritis, after adjusting for the effects of age, education, body mass index, and indices of general health and pain. Overall,
1095 patients with rheumatoid arthritis and 1530 control individuals were included. Patients were older, less well educated,
more disabled, and had poorer levels of general health as compared with control individuals (all P < 0.01). Preliminary analyses revealed the presence of substantial statistical interaction between smoking and sex (P < 0.001). In separate multivariable analyses, past history of smoking was associated with increased risk for rheumatoid arthritis
overall in men (odds ratio 2.0, 95% confidence interval 1.2–3.2) but not in women. Among men, this effect was seen only for
rheumatoid factor-positive rheumatoid arthritis. There were significant interactions between smoking and age among women but
not among men. We conclude that sex is a biologic effect modifier in the association between smoking and rheumatoid arthritis.
The role of menopause in the etiology of rheumatoid arthritis merits further research. 相似文献
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Cytosolic and mitochondrial Trypanosoma cruzi tryparedoxin peroxidases belong to the family of 2-Cys peroxiredoxins. These enzymes play an essential role as antioxidants by their peroxidase and peroxynitrite reductase activities. TXNPx are key components of the trypanosomatid peroxide detoxification pathways. The aim of this work was to determine the role of TXNPx as virulence factors in the parasite, and whether these enzymes are good candidates for drug design. We observed that peroxiredoxins are not highly abundant proteins expressed at similar levels throughout the T. cruzi life cycle. In order to study the role of c-TXNPx and m-TXNPx in invasion and infectivity, parasites overexpressing TXNPx were produced, and infection experiments were carried out using phagocytic and non-phagocytic cells. Parasites overexpressing peroxiredoxins showed a significant increase in infectivity with respect to the control ones. The results presented in this work point out that the T. cruzi peroxiredoxins are important in survival, replication and differentiation of T. cruzi and could constitute virulence factors. Moreover, their expression in the infective forms of the life cycle and their low intracellular concentration make them good candidates to become targets for drug design. 相似文献
10.
Giuseppe D. Ciccotosto Kevin J. Barnham Robert A. Cherny Colin L. Masters Ashley I. Bush Cyril C. Curtain Roberto Cappai Deborah Tew 《International journal of peptide research and therapeutics》2003,10(5-6):413-417
Summary The amyloid β-peptide, Aβ is toxic to neurons and this toxicity plays a central role in the progression of Alzheimer's disease.
The mechanism(s) by which Aβ exerts its toxicity has been hotly debated with several theories postulated. Here we discuss
the role of oxidation of the sulfur atom of Met35 in Aβ42 (Met(O)Aβ), a modification that has significant implications for
the mechanism of Aβ toxicity. Both Met(O)Aβ and its native form display toxicity to primary neuronal cells in culture which
can be rescued by catalase, a H2O2 inhibitor and clioquinol a mild copper chelator. However both native Aβ and Met(O)Aβ differ substantially in primary and
secondary structures, solubility, ability to penetrate lipid membranes, and oligomerization profiles. It is clearly evident
that metals play an important role in the oxidation of Aβ to Met(O)Aβ via Fenton chemistry and that regulation of this pathway
has a potential therapeutic application for the regulation of Alzheimer's disease. 相似文献
11.
Yiping Fei Ryan Webb Beth L Cobb Haner Direskeneli Güher Saruhan-Direskeneli Amr H Sawalha 《Arthritis research & therapy》2009,11(3):R66-7
Introduction
Behçet's disease is a chronic systemic inflammatory disease that remains incompletely understood. Herein, we perform the first genome-wide association study in Behçet's disease.Methods
Using DNA pooling technology and the Affymetrix 500K arrays, we identified possible candidate gene associations with Behçet's disease in a cohort of 152 Behçet's disease patients and 172 healthy ethnically matched controls. Genetic loci that were identified in the pooling study were genotyped in patients and controls using TaqMan genotyping technology.Results
We identified genetic associations between Behçet's disease and single-nucleotide polymorphisms (SNPs) in KIAA1529, CPVL, LOC100129342, UBASH3B, and UBAC2 (odds ratio = 2.04, 2.26, 1.84, 1.71, and 1.61, respectively; P value = 4.2 × 10-5, 1.0 × 10-4, 3.0 × 10-4, 1.5 × 10-3, and 5.8 × 10-3, respectively). Among the associated SNPs, the Behçet's disease-risk allele in rs2061634 leads to substitution of serine to cysteine at amino acid position 995 (S995C) in the KIAA1529 protein.Conclusions
Using an unbiased whole-genome genetic association approach, we identified novel candidate genetic loci that are associated with increased susceptibility for Behçet's disease. These findings will help to better understand the pathogenesis of Behçet's disease and identify novel targets for therapeutic intervention. 相似文献12.
Kowalska A Wender M Florczak J Pruchnik-Wolinska D Modestowicz R Szczech J Rossa G Kozubski W 《Journal of applied genetics》2003,44(2):231-234
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and personality changes. Pathological hallmarks of AD are: deposition of amyloid plaques and neurofibrillary tangles in the brain, accompanied by neuronal and synaptic loss. The genetic background of AD is heterogeneous and strongly depends on the form of the disease. In most of the families with early-onset AD (EOAD) (10% of the total population of patients), the disease segregates as an autosomal dominant fully penetrant trait. To date, some missense mutations in three genes encoding the amyloid precursor protein, presenilin 1 (PS1) and 2 (PS2) have been found to cause familial EOAD. We screened for mutations in the presenilin genes in a sample of 55 patients with familial or sporadic form of EOAD from the Poznan region. We found 4 missense mutations in the PS1 gene: A246E in exon 7, P267L in exon 8, E318G in exon 9, and L424R in exon 12 among 5 unrelated patients. The frequency of PS1 mutations was 11% (5 of 55) in the whole sample of the patients with EOAD or 50% (3 of 6) if the analysis was restricted to familial cases with a positive history of dementia in the patient's family. 相似文献
13.
M Marta C Castellano A Oliverio F Pavone P G Pagella M Brufani M Pomponi 《Life sciences》1988,43(23):1921-1928
The synthesis of a series of physostigmine analogs, in which the methylcarbamyl group has been substituted with monoalkylcarbamyl, dimethyl- and diethylcarbamyl groups, is reported. These compounds were prepared with the aim of investigating their possible therapeutic effects in the treatment of Alzheimer's type dementia. The new analogs of physostigmine are inhibitors of acetylcholinesterase from Electroforus electricus, with a value of the reactivation constant, k3 smaller than the one of physostigmine. The percentage of anticholinesterase activity in vitro and in vivo, the acute toxicity and some behavioural effects were also evaluated for selected derivatives. The reactivation constant, in vitro, supports the view that the derivatives described would be more suitable for therapeutic use than physostigmine. 相似文献
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Background
Emerging evidence from preclinical and clinical studies has shown that interleukin-12 (IL-12) has some effectiveness against endogenously arising carcinogenesis. Several potentially functional polymorphisms of IL-12 gene have been implicated in cancer risk, but individually published studies showed inconclusive results. The aim of this study was to investigate the association between IL-12 polymorphisms and cancer risk.Methods
The MEDLINE, EMBASE, Web of science and CBM databases were searched for all articles published up to June 10, 2012 that addressed IL-12 polymorphisms and cancer risk. Statistical analyses were performed using RevMan 5.1.6 and STATA 12.0 softwares.Results
Eighteen studies were included with a total of 6463 cancer cases and 7412 healthy controls. We found that the 3'UTR A > C (rs3212227) polymorphism of IL-12B gene was associated with significantly increased overall risk of cancers using random effects model (C vs A: odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.02-1.27; AC + CC vs AA: OR = 1.20, 95%CI: 1.01-1.43). However, the 3'UTR G > A (rs568408), IVS2 T > A (rs582054) and 5'UTR T > G (rs2243115) polymorphisms of IL-12A gene did not appear to have an influence on cancer susceptibility. Further subgroup analyses showed that the 3'UTR A > C (rs3212227) polymorphism was associated with increased cancer risks in the subgroups of Asians, cervical and nasopharyngeal cancers.Conclusions
Results from the current meta-analysis indicates that the 3'UTR A > C (rs3212227) polymorphism of IL-12B gene might be a potential biomarker for cancer risk among Asians, especially for cervical and nasopharyngeal cancers. 相似文献17.
Mitochondrial DNA polymorphisms as risk factors for Parkinson’s disease and Parkinson’s disease dementia 总被引:8,自引:0,他引:8
Autere J Moilanen JS Finnilä S Soininen H Mannermaa A Hartikainen P Hallikainen M Majamaa K 《Human genetics》2004,115(1):29-35
The activity of complex I of the mitochondrial respiratory chain has been found to be decreased in patients with Parkinsons disease (PD), but no mutations have been identified in genes encoding complex I subunits. Recent studies have suggested that polymorphisms in mitochondrial DNA (mtDNA)-encoded complex I genes (MTND) modify susceptibility to PD. We hypothesize that the risk of PD is conveyed by the total number of nonsynonymous substitutions in the MTND genes in various mtDNA lineages rather than by single mutations. To test this possibility, we determined the number of nonsynonymous substitutions of the seven MTND genes from 183 Finns. The differences in the total number of nonsynonymous substitutions and the nonsynonymous to synonymous substitution rate ratio (Ka/Ks) of MTND genes between the European mtDNA haplogroup clusters (HV, JT, KU, IWX) were analysed by using a statistical approach. Patients with PD (n=238) underwent clinical examination together with mtDNA haplogroup analysis and the clinical features between patient groups defined by the number of nonsynonymous substitutions were compared. Our analysis revealed that the haplogroup clusters HV and KU had a lower average number of amino acid replacements and a lower Ka/Ks ratio in the MTND genes than clusters JT and IWX. Supercluster JTIWX with the highest number of amino acid replacements was more frequent among PD patients and even more frequent among patients with PD who developed dementia. Our results suggest that a relative excess of nonsynonymous mutations in MTND genes in supercluster JTWIX is associated with an increased risk of PD and the disease progression to dementia. 相似文献
18.
Luca Miele Valentina Dall’Armi Consuelo Cefalo Bojan Nedovic Dario Arzani Rosarita Amore Gianlodovico Rapaccini Antonio Gasbarrini Walter Ricciardi Antonio Grieco Stefania Boccia 《Genes & nutrition》2014,9(2):1-10
The oxidative stress is a key issue in the etiology of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to evaluate the effect of metabolic gene polymorphisms involved in the oxidative stress (GSTT1, GSTM1, SULT1A1, CYP2E1, and 1A1), lifestyle and nutrition aspects, and their interaction, on the risk of NAFLD. We enrolled 294 cases and 359 controls, and collected demographics, anthropometric, lifestyle, and nutrition data. A subgroup of NAFLD provided additional data on nutrients and on physical activity engagement. Each patient provided a blood sample for DNA extraction and genotyping. Clinical and laboratory data were collected from cases. Multivariable analysis shows a significant protective effect of age, gender, and moderate drinking habits on the risk of NAFLD, while an increased risk for greater consumption of fruit and grilled meat or fish. Significant interactions were reported between alcohol consumption, fruit intake, grilled meat and fish, and selected genetic variants. From the subgroup analysis, a moderate/high consumption of fat and/or grilled meat/fish, and a high consumption of white meat increase the risk of NAFLD. Engaging any physical activity at least 1 time/week halves the risk of NAFLD. Besides confirming the beneficial effect of moderate alcohol intake and regular physical activity, and the increased risk associated with high fruit and fat intake, for the first time, we report a detrimental effect of grilled food on NAFLD risk. An effect modification by selected gene variants increases the risk in combination with fruit and grilled food intake. 相似文献
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正Dear Editor,Here,we report the risk factors for severe hand-foot-mouth disease(HFMD)determined by our case-controlstudy.Our findings could help disease prevention and in-tervention initiatives.Patients with severe HFMD displayfatal clinical manifestations with sequelae,requiring≥7days of hospitalization.A tota1 of 249 severe cases treat-ed at Yuxi Children’s Hospital were included in the case 相似文献