scholarly journals Competitive endogenous RNA network and pathway-based analysis of LncRNA single-nucleotide polymorphism in myasthenia gravis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tianfeng Wang ◽  
Si Xu ◽  
Huixue Zhang ◽  
Xiaoyu Lu ◽  
Shuang Li ◽  
...  
Keyword(s):  
Myasthenia Gravis ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Candidate Snps ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Risk Biomarkers ◽  
Regulatory Functions ◽  
Functional Analyses

AbstractMyasthenia gravis (MG) is a complex neurological autoimmune disease with a pathogenetic mechanism that has yet to be elucidated. Emerging evidence has revealed that genes, non-coding RNAs and genetic variants play significant roles in the pathogenesis of MG. However, the molecular mechanisms of single nucleotide polymorphisms (SNPs) located on lncRNAs could disturb lncRNA-mediated ceRNA regulatory functions still unclear in MG. In this study, we collated 276 experimentally confirmed MG risk genes and 192 MG risk miRNAs. We then constructed a lncRNA-mediated ceRNA network for MG based on multi-step computational strategies. Next, we systematically integrated risk pathways and identified candidate SNPs in lncRNAs for MG based on data acquired from public databases. In addition, we constructed a pathway-based lncRNA-SNP mediated network (LSPN) that contained 128 lncRNAs targeting 8 MG risk pathways. By analyzing network, we propose a latent mechanism for how the “lncRNA-SNP-mRNA-pathway” axis affects the pathogenesis of MG. Moreover, 25 lncRNAs and 51 SNPs on lncRNAs were extracted from the “lncRNA-SNP-mRNA-pathway” axis. Finally, functional analyses demonstrated lncRNA-SNPs mediated ceRNA regulation pairs associated with MG participated in the MAPK signaling pathway. In summary, we constructed MG-specific lncRNA-SNPs mediated ceRNA regulatory networks based on pathway in the present study, which was helpful to elucidate the roles of lncRNA-SNPs in the pathogenesis of MG and provide novel insights into mechanism of lncRNA-SNPs as potential genetic risk biomarkers of MG.

scholarly journals Multicenter Study on Differential Human Neutrophil Antigen 2 Expression and Underlying Molecular Mechanisms

2020 ◽  
Vol 47 (5) ◽  
pp. 385-395
Author(s):  
Brigitte K. Flesch ◽  
Angelika Reil ◽  
Núria Nogués ◽  
Carme Canals ◽  
Peter Bugert ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Human Neutrophil ◽  
Molecular Mechanisms ◽  
Normal Population ◽  
Regulatory Elements ◽  
Population Exposure ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Immune Neutropenia ◽  
The Impact

Background: The human neutrophil antigen 2 (HNA-2), which is expressed on CD177, is undetectable in 3–5% of the normal population. Exposure of these HNA-2null individuals to HNA-2-positive cells can cause immunization and pro­duction of HNA-2 antibodies, which can induce immune neutropenia and transfusion-related acute lung injury. In HNA-2-positive individuals, neutrophils are divided into a CD177pos. and a CD177neg. subpopulation. The molecular background of HNA-2 deficiency and the bimodal expression pattern, however, are not completely decoded. Study Design: An international collaboration was conducted on the genetic analysis of HNA-2-phenotyped blood samples, including HNA-2-deficient individuals, mothers, and the respective children with neonatal immune neutropenia and regular blood donors. Results: From a total of 54 HNA-2null individuals, 43 were homozygous for the CD177*787A>T substitution. Six carried the CD177*c.1291G>A single nucleotide polymorphism. All HNA-2-positive samples with >40% CD177pos. neutrophils carried the *787A wild-type allele, whereas a lower rate of CD177pos. neutrophils was preferentially associated with *c.787AT heterozygosity. Interestingly, only the *c.787A allele sequence was detected in complementary DNA (cDNA) sequence analysis carried out on all *c.787AT heterozygous individuals. However, cDNA analysis after sorting of CD177pos. and CD177neg. neutrophil subsets from HNA-2-positive individuals showed identical sequences, which makes regulatory elements within the promoter unlikely to affect CD177 gene transcription in different CD177 neutrophil subsets. Conclusion: This comprehensive study clearly demonstrates the impact of single nucleotide polymorphisms on the expression of HNA-2 on the neutrophil surface but challenges the hypothesis of regulatory epigenetic effects being implicated in the bimodal CD177 expression pattern.

Evaluation of Published Single-Nucleotide Polymorphisms (SNPs) Associated with Cytomegalovirus Infection and Disease after Hematopoietic Cell Transplantation in a Large Caucasian Cohort

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 182-182 ◽  
Author(s):  
Sachiko Seo ◽  
Wenhong Fan ◽  
John A. Hansen ◽  
Barry E. Storer ◽  
Steven A. Pergam ◽  
...  
Keyword(s):  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Preemptive Therapy ◽  
Candidate Snps ◽  
Nucleotide Polymorphisms ◽  
Cmv Infection ◽  
Single Nucleotide ◽  
Snp Association ◽  
Genome Wide ◽  
Cmv Disease

Abstract Background: Cytomegalovirus (CMV) infection is one of the most common complications after hematopoietic cell transplantation (HCT). Regardless of preemptive therapy for CMV infection, CMV disease still occurs in approximately 10% of seropositive HCT recipients, resulting in high mortality. A number of studies have reported the association between CMV infection or disease and single-nucleotide polymorphisms (SNPs), however the results have not been validated in independent cohorts. We performed a candidate gene validation study of previously reported SNPs using a large genome-wide association study (GWAS) cohort. Patients and methods: This GWAS cohort included donor-recipient (D/R) pairs who received the first allogeneic transplantation between 1990 and 2011 at the FHCRC. Of an overall cohort of 4855 D/R pairs, 2193 Caucasian CMV seropositive recipients and their donors (seropositve or seronegative) were analyzed. Two CMV phenotypes were analyzed: any infection within 100 days (only among 1585 recipients transplanted after 1995, antigenemia-based preemptive therapy administered) and CMV disease within 1 year after HCT. Published SNPs associated with CMV infection or disease were collected by a PubMed search using the keywords ‘cytomegalovirus' and ‘SNP' or ‘polymorphism.' A p-value of less than 0.05 was required for validation. Genomic DNA samples from donors and recipients were analyzed using the Affymetrix GeneChip Genome-Wide Human SNP Array 5.0 (for one third of subjects) and Ilummina OmniExpress Beadchip Array (for the remainder). When the candidate SNPs were not included in the arrays, we imputed genotypes using IMPUTE software. Among genotyped and imputed SNPs, only SNPs with a minor allele frequency ≥0.05, call rate ≥90%, and Hardy-Weinberg equilibrium ≥0.0001 were analyzed. Donor serostatus, age, year of transplantation, donor type, HLA disparity, and intensity of conditioning regimen were used as adjustment factors as appropriate. Results: Among the 2193 HCT recipients in our cohort, 1009/1585 (64%) had CMV infection and 354/2193 (16%) had CMV disease. We identified 52 SNPs in 31 publications that reported significant associations between SNPs and CMV infection or disease (median number of subjects in these studies, 215; range, 37-1770). A total of 32 SNPs were available for the analysis. For CMV infection, six SNPs in four genes (TLR9, MCP1, CCR5, and CD209) in recipient or donor met our validation criteria (Table). For all SNPs but one, however, the direction of the association was opposite to that reported in the previous studies. We validated one SNP association (TLR9/rs5743836) in the recipient exactly as originally reported (adjusted HR, 1.16; 95% CI, 1.00-1.34, p=0.043). The donor genotype at this SNP was also significantly associated with CMV infection (adjusted HR, 1.47; 95% CI, 1.02-2.14, p=0.041) (Table), but an association with donor genotype was not assessed in the original publication. As for CMV disease, a different TLR9 SNP (rs352140) in donors was identified as significant (adjusted HR, 0.74; 95% CI, 1.02-2.14, p=0.029), although the ethnicity is different from the reported cohort (Table). None of the candidate SNPs in the recipient genome were associated with CMV disease. Conclusions: Of 32 SNPs that were previously reported to be associated with either CMV infection or disease, we were only able to validate two, both in TLR9. Most of the previously reported SNP associations for CMV infection or disease were not replicated in this large GWAS cohort. The inability to replicate these SNP associations does not necessarily negate the original discoveries, since many factors, including the sample size, could account for the different results. Our findings suggest that results of SNP association studies should be confirmed in multiple independent large cohorts and the biological mechanisms underlying the associations should be examined before clinical application. Unbiased discovery approaches are needed to determine the genetic associations of CMV infection and disease. Table 1 Table 1. Disclosures Boeckh: Chimerix Inc.: Consultancy, Research Funding; Viropharma Inc.: Research Funding; Genentech/Roche: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Clinigen: Consultancy.

scholarly journals Third-generation sequencing-based mapping and visualization of single nucleotide polymorphism, meiotic recombination, illegitimate mutation and repeat-induced point mutation

2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Wan-Chen Li ◽  
Hou-Cheng Liu ◽  
Ying-Jyun Lin ◽  
Shu-Yun Tung ◽  
Ting-Fang Wang
Keyword(s):  
Point Mutation ◽  
Meiotic Recombination ◽  
Molecular Mechanisms ◽  
Cytosine Methylation ◽  
Defense Mechanism ◽  
Nucleotide Polymorphisms ◽  
Tetrad Analysis ◽  
Single Nucleotide ◽  
A Genome ◽  
Repeat Induced Point Mutation

Abstract Generation of new genetic diversity by crossover (CO) and non-crossover (NCO) is a fundamental process in eukaryotes. Fungi have played critical roles in studying this process because they permit tetrad analysis, which has been used by geneticists for several decades to determine meiotic recombination products. New genetic variations can also be generated in zygotes via illegitimate mutation (IM) and repeat-induced point mutation (RIP). RIP is a genome defense mechanism for preventing harmful expansion of transposable elements or duplicated sequences in filamentous fungi. Although the exact mechanism of RIP is unknown, the C:G to T:A mutations might result from DNA cytosine methylation. A comprehensive approach for understanding the molecular mechanisms underlying these important processes is to perform high-throughput mapping of CO, NCO, RIP and IM in zygotes bearing large numbers of heterozygous variant markers. To this aim, we developed ‘TSETA’, a versatile and user-friendly pipeline that utilizes high-quality and chromosome-level genome sequences involved in a single meiotic event of the industrial workhorse fungus Trichoderma reesei. TSETA not only can be applied to most sexual eukaryotes for genome-wide tetrad analysis, it also outcompetes most currently used methods for calling out single nucleotide polymorphisms between two or more intraspecies strains or isolates.

scholarly journals Transposable elements contribute to the genomic response to insecticides in Drosophila melanogaster

2020 ◽  
Vol 375 (1795) ◽  
pp. 20190341 ◽  
Author(s):  
Judit Salces-Ortiz ◽  
Carlos Vargas-Chavez ◽  
Lain Guio ◽  
Gabriel E. Rech ◽  
Josefa González
Keyword(s):  
Gene Expression ◽  
Drosophila Melanogaster ◽  
Regulatory Networks ◽  
Regulation Of Gene Expression ◽  
Nucleotide Polymorphisms ◽  
Rna Seq ◽  
Organophosphate Insecticide ◽  
Single Nucleotide ◽  
Insecticide Exposure ◽  
Genomic Response

Most of the genotype–phenotype analyses to date have largely centred attention on single nucleotide polymorphisms. However, transposable element (TE) insertions have arisen as a plausible addition to the study of the genotypic–phenotypic link because of to their role in genome function and evolution. In this work, we investigate the contribution of TE insertions to the regulation of gene expression in response to insecticides. We exposed four Drosophila melanogaster strains to malathion, a commonly used organophosphate insecticide. By combining information from different approaches, including RNA-seq and ATAC-seq, we found that TEs can contribute to the regulation of gene expression under insecticide exposure by rewiring cis -regulatory networks. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

scholarly journals CDS1 and promoter single nucleotide polymorphisms of the CTLA-4 gene in human myasthenia gravis

2002 ◽  
Vol 3 (1) ◽  
pp. 46-49 ◽  
Author(s):  
X B Wang ◽  
M Kakoulidou ◽  
Q Qiu ◽  
R Giscombe ◽  
DeRen Huang ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Myasthenia Gravis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

scholarly journals Candidate SNPs for carcass and meat traits in Nelore animals and in their crosses with Bos taurus

2012 ◽  
Vol 47 (2) ◽  
pp. 294-301 ◽  
Author(s):  
Rogério Abdallah Curi ◽  
Monique Marcondes Krauskopf ◽  
Janaína Conte Hadlich ◽  
Marina Rufino Salinas Fortes ◽  
Dianne Margaret Vankan ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Multiple Testing ◽  
Bos Taurus ◽  
Bos Indicus ◽  
Total Sample ◽  
Candidate Snps ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Fragmentation Index ◽  
Allele Substitution

The objective of this work was to evaluate the effects of single-nucleotide polymorphisms (SNPs) in the genes IGF1 (AF_017143.1:g.198C>T), MSTN (AF_320998.1:g.433C>A), MYOD1 (NC_007313:g.1274A>G) and MYF5 (NC_007303:g.1911A>G) on carcass and meat traits in Nelore (Bos indicus) and Nelore x B. taurus. A total of 300 animals were genotyped and phenotyped for rib eye area (REA), backfat thickness (BT), intramuscular fat (IF), shear force (SF) and myofibrillar fragmentation index (MFI). The effects of allele substitution for each SNP were estimated by regression of the evaluated phenotypes on the number of copies of a particular allele using the general linear model. The polymorphism at IGF1 was non-informative in Nelore animals. In crossbred animals, the IGF1 C allele was associated with greater REA. However, this relation was not significant after Bonferroni correction for multiple testing. The A allele of the MSTN polymorphism was absent in Nelore cattle and was only found in two crossbred animals. The polymorphisms of MYOD1 and MYF5 were little informative in Nelore animals with G allele frequency of 0.097 and A allele frequency of 0.031, respectively. These markers show no association with the analyzed traits in the total sample of evaluated animals.

scholarly journals Selection in the dopamine receptor 2 gene: New candidate SNPs for disease-related studies

2015 ◽  
Author(s):  
Tobias Göllner ◽  
Martin Fieder
Keyword(s):  
Dopamine Receptor ◽  
Balancing Selection ◽  
Candidate Snps ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
1000 Genomes ◽  
Selection Processes ◽  
Flanking Region ◽  
A Minor

Dopamine is a major neurotransmitter in the human brain and is associated with various diseases. Schizophrenia, for example, is treated by blocking the dopamine receptors type 2. In 2009, Shaner, Miller and Mintz stated that schizophrenia was the low fitness variant of a highly variable mental trait. We therefore explore whether the dopamine receptor 2 gene (DRD2) underwent any selection processes. We acquired genotype data of the 1000 Genomes project (phase I), which contains 1093 individuals from 14 populations. We included only single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) of over 0.05 in the analysis. This is equivalent to 151 SNPs for DRD2. We used two different approaches (an outlier approach and a Bayesian approach) to detect loci under selection. The combined results of both approaches yielded nine candidate SNPs under balancing selection. While directional selection strongly favours one allele over all others, balancing selection favours more than one allele. All candidates are in the intronic region of the gene and only one (rs12574471) has been mentioned in the literature. Two of our candidate SNPs are located in specific regions of the gene: rs80215768 lies within a promoter flanking region and rs74751335 lies within a transcription factor binding site. We strongly encourage research on our candidate SNPs and their possible phenotypic effects.

Prediction of Disease-associated Single Nucleotide Polymorphisms Using Virtual Genomes Constructed from a Public Haplotype Database

2008 ◽  
Vol 47 (06) ◽  
pp. 522-528 ◽  
Author(s):  
A. Miyashita ◽  
N. Kitamura ◽  
R. Kuwano ◽  
K. Akazawa ◽  
S. Toyabe
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Association Studies ◽  
Case Control ◽  
Candidate Snps ◽  
International Hapmap Project ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Tag Snps ◽  
Control Association

Summary Objectives: Simultaneous dealing of hundreds of thousands of single nucleotide polymorphisms (SNPs) in genome-wide association studies is laborious. The aim of our study is to develop a method to decrease the number of candidate SNPs prior to the genotyping of study subjects. Methods: We created virtual genotype data on case and control subjects from data of the International HapMap Project by using haplotype-based simulation method. We repeated virtual case-control association studies and selected candidate SNPs. We applied the selected SNPs to previously published genetic casecontrol studies. Sensitivity to detect association with causative genes using our method was compared to the original studies and results using tag SNPs. Results: We found a discrete distribution pattern of SNPs, which was able to produce significant results in case-control association studies. The number of candidate SNPs that we selected was 24.7% of the number of the original set of SNPs. We applied this method to previously published genetic case-control studies and found that the use of candidate SNPs improved the sensitivity for detecting significant alleles, both compared to the original studies and to the use of tag SNPs. The results were not affected by the difference of the diseases and genes involved. Conclusions: Our simulation-based approach has advantages of reducing costs and improving performance to detect significant alleles. This method can be used without considering the specific disease and genes involved.

Variation in TRMT11 gene as a prognostic marker in advanced-stage castrate-resistant prostate cancer (CRPC) patients.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 255-255
Author(s):  
Ben Yiming Zhang ◽  
Shaun M. Riska ◽  
Douglas W. Mahoney ◽  
Ricardo Jorge Teixeira Ribeiro ◽  
Rui Medeiros ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cox Regression ◽  
Statistical Significance ◽  
Candidate Snps ◽  
Nucleotide Polymorphisms ◽  
Castration Resistance ◽  
Single Nucleotide ◽  
Hazard Ratios ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

255 Background: In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with overall survival (OS) in CRPC stage in a North American cohort of 519 subjects. We attempt to replicate these findings in an independent cohort of Portuguese patients. Methods: A hundred and forty CRPC stage patients in the new cohort were genotyped fort he candidate SNPs. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. For SNP level results we estimated hazard ratios (HR) and 95% confidence intervals (CI) under the dominant allele model using Cox regression and adjusted for age and Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 53-84). The GS distribution was 48% subjects with GS≥8; 35% with GS=7 and 17% with GS<7. Median time from castration resistance to death for the cohort was 2.2 years (IQ range: 0.8-3.4, 93 deaths). One of the 3 SNPs (rs2295005; C>G; MAF = 0.16) in the TRMT11gene was associated with OS after adjustment for age and GS: (dominant model p=0.05, HR=0.56; 95 CI=0.31-1.00). No other SNP was observed to have statistical significance with OS (Table 1). Conclusions: Variation in the TRMT11 gene is significantly associated with overall survival in patients with CRPC and warrants further validation as a potential prognostic biomarker. [Table: see text]

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