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Sökning: WFRF:(Milani Lili) > (2006-2009)

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  • Dideberg, Vinciane, et al. (författare)
  • An insertion-deletion polymorphism in the Interferon Regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases
  • 2007
  • Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 16:24, s. 3008-3016
  • Tidskriftsartikel (refereegranskat)abstract
    • The interferon regulatory factor 5 (IRF5) gene encodes a transcriptionfactor that plays an important role in the innate as well asin the cell-mediated immune responses. The IRF5 gene has beenshown to be associated with systemic lupus erythematosus andrheumatoid arthritis. We studied whether the IRF5 gene is alsoassociated with inflammatory bowel diseases (IBD), Crohn disease(CD) and ulcerative colitis (UC). Twelve polymorphisms in theIRF5 gene were genotyped in a cohort of 1007 IBD patients (748CD and 241 UC) and 241 controls from Wallonia, Belgium. Thesame polymorphisms were genotyped in a confirmatory cohort of311 controls and 687 IBD patients (488 CD and 192 UC) from Leuven,Belgium. A strong signal of association (p = 1.9 x 10–5,OR: 1.81 (1.37-2.39)) with IBD was observed for a 5bp indel(CGGGG) polymorphism in the promoter region of the IRF5 gene.The association was detectable (p = 6.8 x 10–4) also inCD patients, and was particularly strong among the UC patients(p = 5.3 x 10–8, OR 2.42 (1.76 -3.34)). The associationof the CGGGG indel was confirmed in the second cohort (p = 3.2x 10–5, OR 1.59 (1.28 - 1.98)). The insertion of one CGGGGunit is predicted to create an additional binding site for thetranscription factor SP1. Using an electrophoretic mobilityshift assay we show allele-specific differences in protein bindingto this repetitive DNA-stretch, which suggest a potential functionrole for the CGGGG indel.
  • Ghotbi, Roza, et al. (författare)
  • Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human livers
  • 2009
  • Ingår i: The Pharmacogenomics Journal. - 1470-269X .- 1473-1150. ; 9:3, s. 208-217
  • Tidskriftsartikel (refereegranskat)abstract
    • The basis for interindividual variation in the CYP1A2 gene expression is not fully understood and the known genetic polymorphisms in the gene provide no explanation. We investigated whether the CYP1A2 gene expression is regulated by DNA methylation and displays allele-specific expression (ASE) using 65 human livers. Forty-eight percent of the livers displayed ASE not associated to the CYP1A2 mRNA levels. The extent of DNA methylation of a CpG island including 17 CpG sites, close to the translation start site, inversely correlated with hepatic CYP1A2 mRNA levels (P=0.018). The methylation of two separate core CpG sites was strongly associated with the CYP1A2 mRNA levels (P=0.005) and ASE phenotype (P=0.01), respectively. The CYP1A2 expression in hepatoma B16A2 cells was strongly induced by treatment with 5-aza-2'-deoxycytidine. In conclusion, the CYP1A2 gene expression is influenced by the extent of DNA methylation and displays ASE, mechanisms contributing to the large interindividual differences in CYP1A2 gene expression.
  • Gupta, Manu, et al. (författare)
  • Expression of BCR-ABL1 oncogene relative to ABL1 gene changes overtime in chronic myeloid leukemia
  • 2008
  • Ingår i: Biochemical and Biophysical Research Communications - BBRC. - 0006-291X .- 1090-2104. ; 366:3, s. 848-851
  • Tidskriftsartikel (populärvet., debatt m.m.)abstract
    • Using a quantitative single nucleotide polymorphism (SNP) assay we have investigated the changes in the expression of the BCR-ABL1 oncogene relative to the wild-type ABL1 and BCR alleles in cells from chronic myeloid leukemia (CML) patients not responding to therapy. The results show a progressive increase in the BCR-ABL1 oncogene expression at the expense of decreased expression of the ABL1 allele, not involved in the fusion. No relative changes in the expression of the two BCR alleles were found. These results demonstrate that allele-specific charities in gene expression, with selective, progressive silencing of the wild-type A BL1 allele in favor of the oncogenic BCR-ABL1 allele occur in CML patients with therapy-resistant disease.
  • Kristjansdottir, Gudlaug, et al. (författare)
  • Interferon Regulatory Factor 5 (IRF5) Gene Variants are Associated with Multiple Sclerosis in Three Distinct Populations
  • 2008
  • Ingår i: Journal of Medical Genetics. - 0022-2593 .- 1468-6244. ; 45:6, s. 362-369
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). METHODS: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. RESULTS: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. CONCLUSION: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.
  • Milani, Lili, et al. (författare)
  • Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation
  • 2009
  • Ingår i: Genome Research. - 1088-9051 .- 1549-5469. ; 19:1, s. 1-11
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify genes that are regulated by cis-acting functional elements in acute lymphoblastic leukemia (ALL) we determined the allele-specific expression (ASE) levels of 2, 529 genes by genotyping a genome-wide panel of single nucleotide polymorphisms in RNA and DNA from bone marrow and blood samples of 197 children with ALL. Using a reproducible, quantitative genotyping method and stringent criteria for scoring ASE, we found that 16% of the analyzed genes display ASE in multiple ALL cell samples. For most of the genes, the level of ASE varied largely between the samples, from 1.4-fold overexpression of one allele to apparent monoallelic expression. For genes exhibiting ASE, 55% displayed bidirectional ASE in which overexpression of either of the two SNP alleles occurred. For bidirectional ASE we also observed overall higher levels of ASE and correlation with the methylation level of these sites. Our results demonstrate that CpG site methylation is one of the factors that regulates gene expression in ALL cells.
  • Milani, Lili, et al. (författare)
  • Allelic imbalance in gene expression as a guide to cis-acting regulatory single nucleotide polymorphisms in cancer cells
  • 2007
  • Ingår i: Nucleic Acids Research. - 0305-1048 .- 1362-4962. ; 35:5, s. e34
  • Tidskriftsartikel (refereegranskat)abstract
    • Using the relative expression levels of two SNP alleles of a gene in the same sample is an effective approach for identifying cis-acting regulatory SNPs (rSNPs). In the current study, we established a process for systematic screening for cis-acting rSNPs using experimental detection of AI as an initial approach. We selected 160 expressed candidate genes that are involved in cancer and anticancer drug resistance for analysis of AI in a panel of cell lines that represent different types of cancers and have been well characterized for their response patterns against anticancer drugs. Of these genes, 60 contained heterozygous SNPs in their coding regions, and 41 of the genes displayed imbalanced expression of the two cSNP alleles. Genes that displayed AI were subjected to bioinformatics-assisted identification of rSNPs that alter the strength of transcription factor binding. rSNPs in 15 genes were subjected to electrophoretic mobility shift assay, and in eight of these genes (APC, BCL2, CCND2, MLH1, PARP1, SLIT2, YES1, XRCC1) we identified differential protein binding from a nuclear extract between the SNP alleles. The screening process allowed us to zoom in from 160 candidate genes to eight genes that may contain functional rSNPs in their promoter regions.
  • Milani, Lili, 1981- (författare)
  • Gene Expression in Cancer Cells Detection of Splice Variants, Allele-specific Expression and DNA Methylation
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The human genome sequencing project has provided a wealth of information on sequence variation between individuals. The surprisingly low number of genes in the human genome is compensated for by a complex regulation of gene expression. New methods are now being developed for the discovery and analysis of the regulatory regions of the genome to elucidate factors that affect both normal and disease-associated human genetic variation. In parallel with identification of DNA sequence variation, efforts are being made to unravel the next layer of information - epigenetic modifications of the genome. The studies in this thesis describe the application of methods for genotyping single nucleotide polymorphisms (SNPs) in DNA for the analysis of gene transcripts in cancer cells. We performed quantitative analysis of splice variants and screened for allele-specific gene expression (ASE) in cancer cells using the tag-microarray based minisequencing system. This analysis revealed transcript isoforms that were differentially spliced in leukemia cell lines and normal endothelial cell lines. We detected wide-spread allele-specific gene expression in cancer cells that were sensitive or resistant to anti-cancer drugs. In regulatory regions of the genes with ASE we identified putative regulatory SNPs. Using technology developed for large-scale SNP genotyping, we screened for ASE in an internationally unique collection of childhood acute lymphoblastic leukemia (ALL) samples. Analysis of DNA methylation in promoter regions of genes displaying ASE revealed genes, whose expression is regulated by allele-specific DNA methylation. For a subset of these genes we found a correlation between DNA methylation levels and probability of disease-free survival in ALL patients with different chromosomal aberrations. The methylation patterns that we identified constitute excellent candidate markers for subtyping of ALL patients and for stratification of ALL patients based on their probability of disease-free survival and response to drug treatment. The results of this study have increased our understanding of epigenetic changes in ALL cells and will hopefully help to design better treatment plans for the patients to avoid over-treatment and unnecessary side effects.
  • Mukonzo, K, et al. (författare)
  • A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans.
  • 2009
  • Ingår i: British journal of clinical pharmacology. - 1365-2125. ; 68:5, s. 690-9
  • Tidskriftsartikel (refereegranskat)abstract
    • center dot Efavirenz is metabolized by highly polymorphic enzymes, CYP2B6 and CYP3A. The effect of the different variant alleles on efavirenz population pharmacokinetics has not yet been fully explored. center dot CYP2B6*6 influences efavirenz steady-state pharmacokinetics. Together with sex it explains 11% of the between-subject variability in apparent oral clearance, but predictions could potentially be improved if additional alleles causing reduced drug metabolism were identified. center dot ABCB1 (3435C -> T) may have effect on efavirenz single-dose and steady-state pharmacokinetics. WHAT THIS STUDY ADDS center dot A new polymorphism in ABCB1 gene (rs3842) and CYP2B6*11 in addition to sex and CYP2B6*6 genotype predict efavirenz single-dose pharmacokinetics. center dot A combined population pharmacogenetic/pharmacokinetic modelling approach allows determination and simulation of determinant factors for efavirenz single-dose pharmacokinetics based on data on gender, biochemical variables and genetic factors in relevant genes (a total of 30 SNPs in CYP2B6, ABCB1 and CYP3A4 genes) in Ugandan population. AIMS Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using nonmem. METHODS Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero- followed by first-order absorption. RESULTS Apparent oral clearance (95% confidence interval) was 4 l h l-1 (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONS The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.
  • Schnorrer, Frank, et al. (författare)
  • Positional cloning by fast-track SNP-mapping in Drosophila melanogaster
  • 2008
  • Ingår i: Nature Protocols. - 1754-2189 .- 1750-2799. ; 3:11, s. 1751-1765
  • Tidskriftsartikel (refereegranskat)abstract
    • Positional cloning of chemically induced mutations is the rate-limiting step in forward genetic screens in Drosophila. Single-nucleotide polymorphisms (SNPs) are useful markers to locate a mutated region in the genome. Here, we provide a protocol for high-throughput, high-resolution SNP mapping that enables rapid and cost-effective positional cloning in Drosophila. In stage 1 of the protocol, we use highly multiplexed tag-array mini-sequencing assays to map mutations to an interval of 1-2 Mb. In these assays, SNPs are genotyped by primer extension using fluorescently labeled dideoxy-nucleotides. Fluorescent primers are captured and detected on a microarray. In stage 2, we selectively isolate recombinants within the identified 1-2 Mb interval for fine mapping of mutations to about 50 kb. We have previously demonstrated the applicability of this protocol by mapping 14 muscle morphogenesis mutants within 4 months, which represents a significant acceleration compared with other commonly used mapping strategies that may take years.
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