Biomedical subjects

Jean-Louis Spadoni

Publications and source records attributed to Jean-Louis Spadoni.

6 recordsLinked to original sources

PubMed2006

Exhaustive genotyping of the interleukin-1 family genes and associations with AIDS progression in a French cohort.

Interleukin (IL)-1 family members are key players in inflammatory processes but have been the subject of few studies of acquired immunodeficiency syndrome (AIDS). To better evaluate the impact of the IL-1 family on AIDS development, we genotyped the IL1 alpha , IL1 beta , IL1Ra, and IL1R1 genes in 245 slow progressor (SP) and 82 rapid progressor (RP) human immunodeficiency virus type 1-seropositive patients as well as in 446 control subjects, all of whom were of white ethnicity. One hundred sixteen frequent polymorphisms were identified, of which 23 were newly characterized by our study. Many putative associations were found between single-nucleotide polymorphism (SNP) or haplotype alleles and the extreme profiles of progression. Most of them corresponded to weak associations (.01<P<.05); however, the SNP IL1Ra_2134 exhibited a consistent association, found at the level of the SNP, haplotypes, and haploblocks, when the SP and control populations were compared (P=.0002). The IL-1-dependent inflammatory response is, thus, likely to play a role in AIDS progression via the regulation of IL-1Ra expression. This association will need to be confirmed in other AIDS cohorts, and experiments will also have to be performed to unravel the biological mechanisms at work. The data presented here will be useful for future genomic studies of the IL-1 family members in other infectious and chronic inflammatory diseases.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Computation of haplotypes on SNPs subsets: advantage of the "global method".

BACKGROUND: Genetic association studies aim at finding correlations between a disease state and genetic variations such as SNPs or combinations of SNPs, termed haplotypes. Some haplotypes have a particular biological meaning such as the ones derived from SNPs located in the promoters, or the ones derived from non synonymous SNPs. All these haplotypes are "subhaplotypes" because they refer only to a part of the SNPs found in the gene. Until now, subhaplotypes were directly computed from the very SNPs chosen to constitute them, without taking into account the rest of the information corresponding to the other SNPs located in the gene. In the present work, we describe an alternative approach, called the "global method", which takes into account all the SNPs known in the region and compare the efficacy of the two "direct" and "global" methods. RESULTS: We used empirical haplotypes data sets from the GH1 promoter and the APOE gene, and 10 simulated datasets, and randomly introduced in them missing information (from 0% up to 20%) to compare the 2 methods. For each method, we used the PHASE haplotyping software since it was described to be the best. We showed that the use of the "global method" for subhaplotyping leads always to a better error rate than the classical direct haplotyping. The advantage provided by this alternative method increases with the percentage of missing genotyping data (diminution of the average error rate from 25% to less than 10%). We applied the global method software on the GRIV cohort for AIDS genetic associations and some associations previously identified through direct subhaplotyping were found to be erroneous. CONCLUSION: The global method for subhaplotyping can reduce, sometimes dramatically, the error rate on patient resolutions and haplotypes frequencies. One should thus use this method in order to minimise the risk of a false interpretation in genetic studies involving subhaplotypes. In practice the global method is always more efficient than the direct method, but a combination method taking into account the level of missing information in each subject appears to be even more interesting when the level of missing information becomes larger (>10%).

Apolipoproteins E↗

PubMed2006

Associations of the IL2Ralpha, IL4Ralpha, IL10Ralpha, and IFN (gamma) R1 cytokine receptor genes with AIDS progression in a French AIDS cohort.

We have performed an extensive analysis of Th1/Th2 cytokine receptors IL2Ralpha, IL4Ralpha, IL10Ralpha, and IFNgammaR1 gene polymorphisms to evaluate their impact on AIDS progression. The coding regions and promoters of these genes were sequenced in the genetics of resistance to immunodeficiency virus cohort, composed of 327 HIV-1-positive patients with extreme progression phenotypes, slow and rapid progressors, and of 446 healthy control subjects, all of them of Caucasian descent. Overall, 104 single nucleotide polymorphisms and four insertions/deletions with a minor allelic frequency higher than 1% were identified, 21 of them being newly characterized. We observed weak associations for 13 polymorphisms of IL2Ralpha, IL4Ralpha, IL10Ralpha, and IFNgammaR1, and 11 haplotypes of IL2Ralpha, IL4Ralpha, and IFNgammaR1. However, we could not relate these positive signals to any relevant biological information on the gene function. To affirm these putative associations in AIDS, further confirmation on other AIDS cohorts will be needed. This complete catalog of polymorphisms in IL2Ralpha, IL4Ralpha, IL10Ralpha, and IFNgammaR1 cytokine receptor genes should also be useful for investigating associations in other immune-related diseases.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Improvement of collagen-induced arthritis by active immunization against murine IL-1beta peptides designed by molecular modelling.

Interleukin-1beta (IL-1beta) is a crucial cytokine in inflammation processes and has been implicated in the pathogenesis of several chronic inflammatory diseases. Strategies designed to blocking IL-1beta by passive administration of inhibitors (mAbs, IL-1 receptor antagonist) have previously demonstrated efficacy in rheumatoid arthritis (RA). Using molecular modelling, we have defined three murine IL-1beta peptide regions characterized by their close proximity to the receptor. Synthetic peptides corresponding to these regions, in cyclic and linear form, were delivered as immunogens in Swiss mice, resulting in significant levels of autoantibodies directed against the native murine IL-1beta cytokine as determined by ELISA and by an assay for neutralization of IL-1beta biological activity. More importantly, one of the cyclic peptides showed a protective effect against inflammation and articular destruction in DBA/1 mouse collagen-induced arthritis, a model of RA. The high rate of success observed for active immunization against cytokine peptides in vivo suggests that the in silico approach to autoantigen design may be a promising avenue for the development of anti-cytokine immunotherapeutics.

Animals↗

PubMed2005

Genomic approach of AIDS pathogenesis: exhaustive genotyping of the TNFR1 gene in a French AIDS cohort.

Large-scale genomic studies in cohorts have been made possible for the last few years thanks to the progress of molecular biology and bioinformatics. This systematic approach allows a better understanding of the molecular mechanisms of disease development and as a consequence can contribute to the rational design of new diagnostic and therapeutic tools. We present here the exhaustive genotyping of a candidate gene, tumor necrosis factor receptor 1 (TNFR1), in the genetic of resistance to immunodeficiency virus (GRIV) AIDS cohort. This gene was chosen because it is likely to be involved in the apoptosis pathways of CD4+ and CD8+ T-cells during human immunodeficiency virus 1 (HIV-1) infection. Seven frequent polymorphisms were characterized in 319 HIV-1 seropositive patients from the GRIV cohort with extreme disease progression phenotypes, slow progression or rapid progression, and in 427 healthy controls. The TNFR1 gene locus does not appear to be part of any haploblock and contains only a small haploblock of two successive SNPs. One promoter SNP (TNFR1_17444594, position -581) and one intronic SNP (TNFR1_27223241, position +11511) gave weak positive signals of association (resp. P=0.03 and P=0.04) as well as two haplotypes. To our knowledge, this is the first genetic association study dealing with the TNFR1 gene in AIDS and the putative associations identified will need to be validated through other AIDS cohort analyses or by further biological experimentation.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Filtering redundancies for sequence similarity search programs.

Database scanning programs such as BLAST and FASTA are used nowadays by most biologists for the post-genomic processing of DNA or protein sequence information (in particular to retrieve the structure/function of uncharacterized proteins). Unfortunately, their results can be polluted by identical alignments (called redundancies) coming from the same protein or DNA sequences present in different entries of the database. This makes the efficient use of the listed alignments difficult. Pretreatment of databases has been proposed to suppress strictly identical entries. However, there still remain many identical alignments since redundancies may occur locally for entries corresponding to various fragments of the same sequence or for entries corresponding to very homologous sequences but differing at the level of a few residues such as ortholog proteins. In the present work, we show that redundant alignments can be indeed numerous even when working with a pretreated non-redundant data bank, going as high as 60% of the output results according to the query and the bank. Therefore the accuracy and the efficiency of the post-genomic work will be greatly increased if these redundancies are removed. To solve this up to now unaddressed problem, we have developed an algorithm that allows for the efficient and safe suppression of all the redundancies with no loss of information. This algorithm is based on various filtering steps that we describe here in the context of the Automat similarity search program, and such an algorithm should also be added to the other similarity search programs (BLAST, FASTA, etc...).

Algorithms↗