To see the other types of publications on this topic, follow the link: Malaria susceptibility.
Dissertations / Theses on the topic 'Malaria susceptibility'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Malaria susceptibility.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Cunnington, Aubrey Justin. "Malaria and susceptibility to other infections." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2012. http://researchonline.lshtm.ac.uk/901045/.
Full textAbstract:
Malaria is widely perceived as immunosuppressive. Despite extensive phenomenological description, the underlying mechanisms remain poorly described. The aim of this thesis was to identify possible mechanisms by which malaria modifies host defence, and to determine the importance of these mechanisms in a translational system moving from a mouse model to human malaria. The most frequently cited immunological consequences of malaria are: suppression of vaccine responses, susceptibility to bacterial infection, susceptibility to endemic Burkitt lymphoma, and increased HIV viral load. Of these, susceptibility to non-Typhoid Salmonella (NTS) bacteremia, associated with severe hemolysis, was the most consistent between animal and human studies. I hypothesized that hemolysis would induce the immunomodulatory enzyme heme oxygenase-l (HO-l), which is essential for survival in malaria infections in mice, but might impair host defence against NTS. I demonstrate in mice that malaria, chemically-induced hemolysis, or simply administration of heme, cause loss of resistance to NTS, allowing more rapid bacterial growth than in control animals. A new niche for bacterial replication is established within neutrophils, which have impaired oxidative burst and bacterial killing activity. Hemolysis and heme induce HO-1 in neutrophil progenitors in the bone marrow, and this reduces the oxidative burst capacity of maturing neutrophils whilst also causing their premature mobilization into the circulation. Inhibition of HO by the competitive inhibitor SnPP abrogates the impaired resistance to NTS infection. I observed a similar phenomenon in Gambian children with malaria, with prolonged impairment of neutrophil function, the severity of which is related to hemolysis and HO-l induction. In summary I have shown that hemolysis- and HO-l-mediated neutrophil dysfunction occurs in malaria and is important for susceptibility to NTS infection. HO-1 inhibition might offer a novel therapy to alleviate neutrophil dysfunction in malaria patients.
2
Khor, Chiea Chuen. "Host genetic susceptibility to malaria and bacteraemia." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534216.
Full text
3
Carpenter, Danielle. "Genetics of susceptibility to malaria and leishmaniasis." Thesis, University of Leeds, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396597.
Full text
4
Sikora, Martin. "Evolutionary genetics of malaria: genetic susceptibility and natural selection." Doctoral thesis, Universitat Pompeu Fabra, 2010. http://hdl.handle.net/10803/7220.
Full textAbstract:
Una de les forces selectives més fortes que han afectat a les poblacions humanes en la història més recent és el paràsit de la malària: Plasmodium falciparum, que és la causa de varis exemples d'adaptació induïda per patògens en els éssers humans. Una forma especial de malària és l'associada a l'embaràs, que es caracteritza per l'acumulació d'eritròcits infectats en la placenta, i que pot arribar a causar fins a 200.000 morts maternoinfantils cada any. L'objectiu d'aquest treball és descriure com aquesta forma peculiar de malària ha afectat la variació genètica humana. Amb aquesta finalitat, hem utilitzat mètodes tant de la genètica evolutiva com de l'epidemiologia molecular, resultant en la primera investigació a gran escala de la base genètica de la malària placentària. Els resultats ofereixen una nova visió sobre els gens que modulen el risc d'infecció, ,així com de la selecció natural actuant sobre les vies cel·lulars implicades en la patogènesi de la malaltia. Finalment, també aportem noves dades sobre l'estructura genètica de les poblacions sub-saharianes analitzades.One of the strongest selective forces affecting human populations in recent history is the malaria parasite Plasmodium falciparum, which is the cause of a variety of well-established examples of pathogen-induced adaptation in humans. A special form of malaria is pregnancy-associated malaria, which is characterised by the accumulation of infected erythrocytes in the placenta, and causes up to 200,000 maternal and infant deaths every year. The aim of this work is to characterise how this particular form of malaria has shaped human genetic variation. To that end we use methods of both evolutionary genetics and molecular epidemiology, reporting the first large-scale investigation of the genetic basis of placental infection. Our results provide new insights into genes modulating the risk of infection, as well as natural selection acting on cellular pathways involved in the pathogenesis of the disease. Finally, we also provide new data on the genetic structure of affected populations in Sub-Saharan Africa.
5
Ruwende, Cyril. "Host genetic factors in susceptibility to malaria and tuberculosis." Thesis, University of Oxford, 1996. http://ora.ox.ac.uk/objects/uuid:2accb6c6-8a70-4320-8b8b-16e6e595b5ed.
Full textAbstract:
Plasmodium falciparum and Mycobacterium tuberculosis infections collectively cause as many as five million deaths world-wide each year. In the most afflicted populations, currently available drugs and vaccines appear inadequate. By offering insight into the pathophysiology of diseases, genetic studies provide options for new therapeutic approaches to major health problems. The results of case-control studies of genetic factors associated with disease outcomes in malaria and tuberculosis in an African setting are presented in this thesis. Glucose-6-Phosphate dehydrogenase (G6PD) deficiency, the commonest enzymopathy of humans, affects over 400 million people. The geographical correlation of its distribution with the historical endemicity of malaria suggests that this disorder has risen in frequency through natural selection by malaria. However, attempts to confirm that G6PD deficiency is protective in case-control studies of malaria have yielded conflicting results. Hence, for this X-linked disorder, it is unclear whether both male hemizygotes and female heterozygotes are protected or, as frequently suggested, only females. Furthermore, how much protection may be afforded is unknown. In two large case-control studies of over 2000 African children, I found that the common African form of G6PD deficiency (G6PD A-) is associated with a 46-58% reduction in risk of severe malaria for both female heterozygotes and male hemizygotes. A mathematical model incorporating the measured selective advantage against malaria suggests that a counterbalancing selective disadvantage, associated with this enzyme deficiency, has retarded its rise in frequency in malaria-endemic regions. There is some evidence that two T helper cell subsets, Thl and Th2, regulate the immune response and thus influence the course of infections in mammalian hosts. These T cell subsets are reciprocal and associated with distinct cytokine profiles. Th2 T cell differentiation is promoted mainly by interleukin-4. Analysis of an IL-4 promoter polymorphism indicates that homozygosity for a putatively upregulatory IL-4 promoter variant is associated with a signficantly increased risk for severe malaria whilst heterozygotes are protected against this condition. Epidemiological evidence implicates host genetic factors as major determinants of variable susceptibility to tuberculosis. Most attempts to define the genetic factor(s) have focused on the HLA genes but only one result, an association of HLA-DR2 with increased susceptibility to disease in Asian populations, has been reported with any consistency. The genetic component in tuberculosis is likely to be determined by multiple genes and, therefore, in this study, the role of both HLA and non-HLA candidate genes was investigated. No association was found with variants of the macrophage gene, NRAMP1, the homologue of which has been implicated in the regulation of genetic resistance in the mouse model. Examination of certain class I and class II HLA alleles as well as the -590 interleukin-4 promoter polymorphism also did not show any association with disease. However, heterozygotes for a promoter polymorphism at position -238 of the tumour necrosis factor gene and homozygotes for dysfunctional variants of the gene encoding the collectin, mannose binding protein, were both at increased risk of developing pulmonary tuberculosis.
6
Sisay-Joof, Fatoumatta. "Immunogenetic studies on susceptibility of West Africans to malaria." Thesis, Open University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392869.
Full text
7
Ling, Edmund Y. S. "'Host genetic susceptibility to tuberculosis and malaria in Africa'." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491193.
Full textAbstract:
Humans have been afflicted with tuberculosis (TB) and malaria since antiquity. Although largely eradicated from the developed nations of Europe and North America, these diseases have remained a constant threat in the developing world, especially Asia and Africa. TB a~d malaria are multifactorial infectious diseases which have been shown to have a strong genetic component, through twin studies, genome-wide linkage studies and candidate gene association studies. A partial genome screen, utilising microsatellite markers from chromosomes 2, 5, 6, 15, 19,20,21 and 22, ofTB in Algerian affected sibling pair families was undertaken for this thesis. The marker D5S641 on chromosome 5 located 'a region (5qI4.2) suggestive of linkage in TB (LOD 1.48, P=0.005). This thesis also reports research on candidate genes for TB and malaria' in West Africa. The incidence of TB in West African males is more than twice that of females. Nevertheless, no association was found between TB and the Y chromosome polymorphisms studied. Analysis of Y chromosome SNP markers confirmed that case and control groups were adequately matched in the West African' TB study. The Y chromosome data ·also showed that the paternal gene pool of these West African populations were distinct from those of their geographical and linguistic neighbours. Conversely, the evidence from mitochondrial DNA supported a proposed migration of females into the study region, resulting in a greater similarity of the maternal gene pools among populations in West Africa. ' This thesis focussed particularly on candidate genes involved in pathogen pattern recognition receptor pathways, and identified several such genes that appeared to be associated with TB. Heterozygotes for the TIRAP SNP, rs8177374, were found to be protected against TB (OR=4.38, 95% C.1. 1.37 to 13.96, Pcorrected=O.013), supporting parallel work implicating this variant in protection against other infectious diseases. A non-synonymous coding SNP, rs1990760, of IFIHI, a gene which encodes a cytoplasmic receptor for certain pathogen-associated molecular patterns, also provided evidence of association with TB, with heterozygotes for the SNP being more susceptible (OR=1.83, 95% C.I. 1.27 to 2.62, PcorrecterO.OOl). TT homozygotes for the non-synonymous coding SNP, rs1884444, of IL23R also showed greater susceptibility to TB than individuals with the alternate allele, G (OR=1.50, 95% C.1. 1.05 to 2.14, PcorrecterO.026). There was no evidence for association of TLR9, TICAM2, IRF3, IRF5, IRF7 and MCPI with TB, nor PKLR and BTLA with malaria. ' . These findings ·add to our understanding of the multigenie basis of variable resistance to these· diseases and provide further evidence for the importance of innate immunity genes in affecting susceptibility.
8
Cockburn, Ian. "Complement receptor one polymorphisms and susceptibility to severe malaria." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/13435.
Full textAbstract:
Rosetting – the binding of parasitized red blood cells to uninfected red cells to form “rosettes” has been associated with severe disease in many studies in Africa. However, a study in Papua New Guinea found no association between resetting and severe disease. It remains unclear whether resetting is a cause or correlate of parasite virulence. Rosetting is mediated by the interaction of at least one parasite protein: Plasmodium falciparum erythrocyte membrane protein one (PfEMP1) on the infected erythrocyte surface and a variety of host red cell surface receptors including complement receptor one (CR1). We reasoned that if resetting were a cause of severe disease we would be able to identify protective polymorphisms in the CR1 gene. Here we show that CR1 deficiency is extremely common among individuals from malaria endemic populations in Papua New Guinea. This deficiency is associated with previously reported polymorphisms in the CR1 gene and unexpectedly with alpha-thalassaemia, a red cell disorder that occurs in up to 90% of Melanesians. We tested the hypothesis that CR1 polymorphisms protect against severe malaria by genotyping samples from a case control study for polymorphisms in the CR1. We found that both CR1 deficiency alleles and alpha-thalassaemia protect against severe malaria. We wished to test the hypothesis that resetting was not associated with severe disease in Papua New Guinea because of widespread CR1 deficiency preventing the formation of rosettes strong enough to withstand sheer forces in the circulation. Studies on field isolates from Papua New Guinea showed that resetting was unusual in this population, rarely mediated by binding to CR1 and not associated with disease severity. This suggests that CR1 is essential for physiologically significant resetting associated with severe malaria. We have therefore identified a new malaria resistance gene and provided compelling evidence that CR1 mediated resetting is an important virulence phenotype and a potential target for drug vaccine development.
9
Kimathi, Peter Opiyo. "Leveraging genotypes imputation and polygenic risk scores in malaria susceptibility." Master's thesis, Faculty of Health Sciences, 2020. http://hdl.handle.net/11427/32271.
Full textAbstract:
Background Over the past few years, Genome Wide Association Studies (GWAS) have identified thousands of genetic variants that are associated with a wide range of complex traits, and have provided valuable insights as far as their genetic architectures are concerned. In malaria studies too, GWAS has been successful and a number of genetic variants have been identified. Despite the success, the complete aetiology of malaria, and many complex traits in general, remains poorly understood. A key concern is that the missing heritability remains too large, with some of the variants identified in some populations failing to replicate using independent study populations. Indeed comparable sources have revealed that the statistical power of association studies can be improved either via genotypes imputation approaches or by treating the whole genome of an individual as a risk predictor using Polygenic Risk Scores (PRS). However, imputation remains at modest in Africa populations with few (or no) studies (study) have evaluated the potential of imputation tools in African populations. On the other hand, although the utility of PRS has been shown in other studies, it has neither been assessed in African population nor applied in an infectious disease, like malaria. Methodology We evaluated the performance of five popular genotypes imputation methods (IMPUTE4, minimac 4, IMPUTE2, minimac3 and BEAGLE4) using case control datasets that mimics African populations, European populations and the admixed populations simulated with FractalSIM. We assessed imputation performance based on internal imputation quality metrics and the genotypes concordance. We applied the best imputation tool based on the assessment results to impute raw genotypes data of severe malaria case control studies from MalariaGEN of three African populations: Kenya, The Gambia and Malawi. Similarly, we obtained summary statistics of the same datasets, and imputed the summary statistics with ImpG. We performed an association on the imputed raw genotypes, and compared the association results with that of ImpG based imputation. Additionally, we performed meta-analysis with METASOFT, and compared the meta-analysis result of ImpG based imputation and that from imputed raw genotypes associations. Finally, we assessed five PRS methods (PRSice, LDpred(p+t), PRSoS, PLINK and PRScS) in predicting genetic risk in African population, and applied the best PRS method to predict the genetic risk of severe malaria. Results IMPUTE2 recorded the best performance based on imputation accuracy and concordance for the African (accuracy=80.21% and concordance=99.2%) and the admixed samples (accuracy=69.46% and concordance=90.92%) for variants with MAF>0.05. Other tools recorded similar accuracy and concordance although BEAGLE 4 recorded the lowest concordance and accuracy across all the African and admixed datasets. For the real genotypes data, no SNP attained the genome wide significant threshold of 5.0 × 10−8 for Malawi and the Gambia datasets. However, for the Kenyan dataset, 9 SNPs on chromosome 11 were significantly associated with severe malaria. 3 of these SNPS were located on the HBG2 genes and the remaining 6 had not been reviewed. No SNP attained the genome wide threshold for the ImpG imputed summary statistics for all the populations. For IMPUTE2 based meta-analysis, only one SNP rs12295158 located on the HBB region was significant across all the meta-analysis model (with P-value of 2.88 × 10−12 for fixed (FE), 2.88 × 10−12 random (RE) and 9.64 × 10−12 binary effect (BE) respectively). On the other hand ImpG based meta-analysis, two SNPs were signicant across all the meta-analysis model (rs183731078 located on RFX3 with P-values of 8.40 × 10−9 , 8.40 × 10−9 , 4.47 × 10−8 for FE, RE and BE respectively, and rs8096513 located on DLGAP1 1.43 × 10−9 , 1.43 × 10−9 , 1.01 × 10−8 with P-value for FE, RE and BE respectively). Pathway enrichment and analysis of these genes revealed that both of these genes are associated with malaria. Finally, for the PRS, PRSoS recorded the best performance based on Nargalkerke's R 2 (0.01736) and area under curve (AUC) (0.511). Other PRS methods recorded slightly similar results with PLINK recording the least. The odds of having severe malaria was estimated as 2.869, and a unit change of PRS scores was associated with -5.143 change in odds of having severe malaria with P-value of 0.0193 at α = 0.05. However, the scores could only explain 1.28% of the phenotypic variance. Conclusion Our results provide foundation for future studies in genetics, especially in African population, where the best performing imputation tool remains a mystery. Moreover, our results have demonstrated the potential of application of PRS in infectious diseases.
10
Steiner, Kevin Lee. "Prenatal priming to malaria antigens increases susceptibility to HIV infection." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1321827400.
Full text
11
Coleman, Emma Elizabeth. "Individual variation in the TNF response to malaria." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337559.
Full text
12
Burgner, David Paul. "Genetic polymorphism of the inducible nitric oxide synthase locus and susceptibility to severe infection." Thesis, Open University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390809.
Full text
13
Mangano, Valentina D. "Dissecting the complexity of human susceptibility to Plasmodium falciparum malaria : genetic approaches /." Doctoral thesis, Stockholm : Wenner-Gren Institute for Experimental Biology, Stockholm University, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-8310.
Full text
14
Omar, Sabah Ahmed. "Drug-susceptibility and molecular characterization of epidemic and endemic malaria in Kenya." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288639.
Full text
15
Farouk, Salah Eldin. "T cell and antibody responses in Plasmodium falciparum malaria and their relation to disease susceptibility." Doctoral thesis, Stockholm : Wenner-Grens institut för experimentell biologi, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-320.
Full text
16
Fortin, Anny. "Identification and characterization of the genetic component of differential susceptibility to mouse malaria." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82874.
Full textAbstract:
Using strain distribution pattern in a series of recombinant inbred strains derived from malaria susceptible A/J and resistant C57BL/6J (B6) inbred strains of mice, it was established that the genetic control of infection with Plasmodium chabaudi AS is multigenic. Quantitative trait linkage analysis in backcross and F2 crosses derived from A/J and B6 mice identified a major locus on mouse chromosome 8 (Pchr/Char2) controlling the extend of blood-stage parasite replication. The Chr.8 interval contains several candidate genes, one of them being the macrophage scavenger (Scvr) locus encoding for the scavenger receptor type A (SR-AI/AII) expressed at the surface of monocytes and macrophages. The possible role of the SR-A in host defense, and particularly as a candidate for being Char2, was investigated. Sequencing of the coding region and immunoprecipitation of the receptors from A/J and B6 mice, as well as functional studies in transfected CHO cells showed that the B6 strain has a particular haplotype at the Scvr locus. Despite the fact that a link between differential function of SR-A and resistance/susceptibility to P. chabaudi AS was not established, results have shown that the conformation of B6 SR-A at the cell surface differ from one of the known haplotype. Novel loci regulating response to P. chabaudi AS infection were investigated using an alternative strategy based on a newly derived set of AcB/BcA recombinant congenic strains (RCS) bred from A/J and B6 strains. One of the AcB strains, AcB55, was shown to be highly resistant to infection despite having 83% susceptible A/J genomic composition, which includes susceptibility alleles at Char2. Linkage analysis in an informative (AcB55 X A) F2 population located a new resistance locus on chromosome 3 (Char4). Early onset of parasite clearance in AcB55 is associated with lower peak parasitemia and absence of mortality. Investigation of possible mechanisms mediating P. chabaudi AS resistanc
17
Diakite, Mahamadou. "Host genetic determinants of parasite clearance and susceptibility to severe malaria in Africa." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440146.
Full text
18
Israelsson, Elisabeth. "Host genetic factors and antibody responses with potential involvement in the susceptibility to malaria." Doctoral thesis, Stockholm : Department of Immunology, the Wenner-Gren Institute, Stockholm university, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-8301.
Full text
19
Traore, Karim. "Analyse anthropobiologique de la susceptibilité au paludisme chez l'homme." Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1016/document.
Full textAbstract:
Le paludisme reste la parasitose avec les taux de morbidité et mortalité les plus élevés et son impact socioéconomique constitue un frein au développement. Il y a eu une coévolution entre l'hôte humain, le vecteur et le Plasmodium avec parfois des adaptations spécifiques de résistance. Cela s'est traduit aujourd'hui par la résistance du Plasmodium aux produits antipaludiques et des difficultés de développement de vaccin efficace. L'exploration de nouveaux axes de recherche s'avère donc pertinent pour la compréhension de certaines adaptations pouvant jouer un rôle dans la susceptibilité au paludisme. Des différences de susceptibilités au paludisme ont été décrites chez les Peulh et Dogons symatriques au Mali. La plupart des études faites pour comprendre cette différence de susceptibilité ont porté sur l'immunité. Dans ce travail, nous avons fait une approche novatrice plus globale, en étudiant l'interaction entre l'environnement, le système immunitaire et la susceptibilité au paludisme. Nous nous sommes ainsi intéressés à la relation entre l'alimentation, le métabolisme et l'immunité qui est un exemple d'interaction entre l'environnement et la biologie. Nos travaux ont permis de décrire des différences entre Peulh et Dogons du Mali en termes de taux sanguins d'AGE et sRAGE, ainsi que dans expression et le polymorphisme du récepteur RAGE. Cela pourrait avoir des implications sur le plan immunitaire et donc dans la susceptibilité au paludisme. Ces résultats constituent d'importantes données de base pour soutenir une nouvelle voie de recherche sur le paludisme en combinant l'alimentation, le métabolisme, en associant le microbiote intestinal qui suscite aussi actuellement beaucoup d’intérêt dans le paludismeMalaria remains the parasitic disease with the highest rates of morbidity and mortality and its socio-economic impact is an obstacle to development.There has been a coevolution between human host, the vector and Plasmodium with sometimes specific adaptations of resistance, leading today into resistance of Plasmodium to antimalarial products and the difficulties to develop an effective vaccine. The exploration of new areas of research is therefore relevant for the understanding of some adaptations that may have implications in the susceptibility to malaria.Differences in susceptibility to malaria have been described in symmetric Fulani and Dogon in Mali. Most of the studies carried out to understand this difference in susceptibility have focused on immunity. In this work, we have implemented a more global and innovative approach, studying the inteplay between the environment, the immune system and susceptibility to malaria. We investigated the relationship between diet, metabolism and immunity, which is an example of interaction between environment and biology.In our study, we described differences between Fulani and Dogons of Mali in terms of blood levels of AGE and sRAGE, as well as in expression and polymorphism of the RAGE receptor. This could have implications for the immune system and therefore for susceptibility to malaria. These results provide important baseline data for supporting a new malaria research approach by combining diet, metabolism, and gut microbiota which is also currently of great interest in malaria
20
Maiga, Bakary. "Human candidate polymorphisms and malaria susceptibility in sympatric ethnic groups, The Fulani and The Dogon of Mali." Doctoral thesis, Stockholms universitet, Institutionen för molekylär biovetenskap, Wenner-Grens institut, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-99613.
Full textAbstract:
In malaria endemic regions, resistance to malaria constitutes a critical selective pressureon genetic polymorphisms that regulate immune defense and inflammatory pathways.Differences in malaria susceptibility between sympatric ethnic groups have been described inMali. The Fulani are less susceptible to malaria compared to the neighboring group the Dogon,in spite of similar socio-economic and environmental conditions. Paper I is focused on IL-4-590 T/C polymorphism and correlation with levels of malariaspecific IgG, IgG (1-4) subclasses as well as malaria specific and total IgE level in the two ethnicgroups. Our data show that the Fulani individual carrying the IL-4-590 T allele found to havehigher parasite carriage rate and had higher levels of malaria-specific IgG4 and IgE compared tothe individual carrying the C allele. No such differences were seen within the Dogon.Paper II investigated 166 SNPs in the human host in individuals belonging to the Fulani and theDogon ethnic groups. These SNPs were correlated with total IgG against AMA-1, MSP-1, MSP-2 and CSP antigens as well as total IgE level. All antibody levels were higher in the Fulanicompared to the Dogon and strengthens previous finding that antibodies might play a role in theprotection seen in the Fulani. We identified higher frequencies of the protective blood group O.Several allelic differences between the two ethnic groups were found in CD36, IL-4, RTN3 andADCY9. Moreover several polymorphisms in SLC22A4, IRF1, IL5, LTA and TNF have beenfound to be correlated with anti-MSP antibody level; TLR6, IL3, TNF, and IL22 found to becorrelated with anti-MSP-2 antibody level in the Fulani. Such association was not seen in theDogon. In Paper III, the same individuals, as in paper II, were investigated with a focus on the FcγRIIapolymorphism and correlation with levels of anti-AMA-1, MSP-1, MSP-2, CSP specificantibodies as well as total IgE level. The genotype distribution and allele frequency weresignificantly different between the Fulani and the Dogon with the Fulani being HH, H allele- andthe Dogon RR, R allele carriers. A correlation between the HH genotype and the H allele andprotection against mild malaria was seen in the Fulani but not in the DogonTaken together our study has found significant genetic differences between the Fulani and theDogon Ethnic groups, which suggest that ethnicity should be taken into account in monitoring ofimmunological studies and vaccines trials in malaria endemic areas.
21
Auburn, Sarah. "Host Genetic Components of the Erythrocyte Stimulatory G Protein Signal Pathway that Determine Susceptibility to Severe Malaria." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491304.
Full textAbstract:
The host stimulatory G protein signal transduction pathway has been functionally implicated in the modulation of erythrocyte invasion by Pjalciparum, and putatively implicated in the establishment of new permeability pathways in Pjalciparum-infected erythrocytes. The objective of this thesis was to identify whether the G protein pathway has genetic determinants involved in severe malaria pathogenesis. I investigated eleven components of the G protein pathway; GNAS, f3-2-AR, ADORA2A, ADORA2B, ADRBKJ, RGS2, GNB3, ADCY9, CFTR and P2RYJ. GNAS SNPs were genotyped in 7 studies (family and population-based) while f3-2-AR and all other genes were genotyped in either a single population-based study or a single family-based study, respectively. The most compelling association was observed at the GNAS locus, encoding G-alpha-s. Meta-analysis across 7 studies revealed significant association between an intronic variant, rs2057291, and severe malaria (P=O.002). I used allele-specific transcript quantification mapping in the attempt to map putative cis-regulatory polymorphisms in G-alpha-s transcription that might explain the rs2057291 association. Using B cells from fifteen HapMap individuals, I found evidence of relative allelic transcription imbalance in two cell lines (ratio C to T allele -1.3). However, mapping analysis was limited by sample size and failed to identify a plausible candidate for this regulatory effect. Analysis of P-2-AR and P-I-AR was limited due to difficulties in genotyping several key SNPs and, therefore, the role of these genes in severe malaria remains unclear. However, genotyping in the other genes revealed a promising association with a non-synonymous SNP in the catalytic domain of the ADCY9 gene, rs2230739 (ile772met), which had previously been shown to be functional in the regulation of cAMP production and [3-2-AR stimulation (P=O.027). This association requires validation in further studies. In conclusion, the involvement of the G protein pathway in severe malaria deserves further investigation. Future studies should focus on characterizing and replicating significant associations identified here and elucidating other important components of the pathway.
22
Min-Oo, Gundula Ellen. "The genetic basis of malaria susceptibility: uncovering novel host factors in a mouse model of blood-stage infection." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=66739.
Full textAbstract:
This thesis examines the genetic factors controlling host response to malaria. Recombinant congenic strains AcB55 and AcB61 were identified as uniquely resistant to malaria despite a susceptible genetic background. These mice display splenomegaly, anemia, reticulocytosis and extra-medullary erythropoiesis. Genome wide mapping led to the identification of a mutation in pyruvate kinase (PklrI90N) that is associated with increased survival and decreased peak parasite levels. We found a significant malaria-protective effect with a second Pklr mutation (PklrG338D) on a distinct genetic background (CBA/N), thus validating our initial findings. The mechanism of protection was linked to increased erythrocyte uptake and compensatory erythropoiesis. Subsequently, we showed that PK-deficiency in humans was protective against P.falciparum replication in vitro. A second genetic locus in AcB55, Char9, was identified and localized to a 14Mb C57Bl/6-derived congenic segment. The Vnn1/Vnn3 genes map within the minimal interval and encode a pantetheinase enzyme; they show cis-regulated gene expression A/J-like alleles associated with an absence of mRNA. In addition, no enzymatic activity was detected in A/J tissues. Administration of cysteamine, the product of pantetheinase, to susceptible A/J mice resulted in increased survival and decreased parasite levels. The inhibition of parasite replication by cysteamine suggests a potential for this compound to be used as a novel anti-malarial monotherapy or in combination with current therapeutics. Finally, a third recombinant congenic strain, AcB62, shows rapid parasite replication with an early peak of infection, despite the presence of the PklrI90N mutation. AcB62 mice do display PK-deficiency associated anemia, erythropoiesis, tissue iron overload, and concomitant increases in iron-regulated proteins. We identified a novel locus controlling peak parasite levels in an [AcB6Cette thèse examine les facteurs génétiques contrôlant la réponse de l'hôte au paludisme. Les souches recombinantes congéniques (RCS) AcB55 et AcB61 ont été identifiées comme présentant une résistance unique au paludisme malgré un fond génétique de susceptibilité. Ces souris développent une splénomégalie, de l'anémie, de la réticulose et une érythropoïèse extra médullaire. Un génome scan a conduit à l'identification d'une mutation de la pyruvate kinase (PklrI90N), laquelle est associée à une survie accrue et à une diminution des niveaux de pic de parasitémie. Un effet protecteur significatif contre le paludisme, du à une seconde mutation de la pyruvate kinase (PklrG338D) sur un fond génétique différent (CBA/N), a également été mis en évidence, validant ainsi nos premiers résultats. Le mécanisme de protection est associé à une augmentation de la phagocytose érythrocytaire et de l'érythropoïèse compensatoire. Nous avons également montré, chez l'humain, qu'un déficit en pyruvate kinase protégeait contre la réplication de P. falciparum in vitro. Un second locus, Char9, a été identifié sur la RCS AcB55 et a été localisé sur un segment congénique de 14Mb dérivé de C57Bl/6. Les gènes Vnn1/Vnn3 sont situés à l'intérieur de l'intervalle minimum et codent pour une enzyme pantéthéinase. Leur expression est régulée en cis et les allèles de type A/J ne codent pour aucun ARNm. Par ailleurs, aucune activité enzymatique n'a été détectée dans les tissus A/J. L'administration de cystéamine (un produit de la pantéthéinase) à des souris susceptibles A/J est responsable d'une survie accrue et d'une diminution des niveaux de parasitémie. L'inhibition de la réplication du parasite par la cystéamine suggère que ce composé pourrait potentiellement être utilisé comme nouvel antipaludéen, en monothérapie ou en combinaison avec des drogues actue
23
Iriemenam, Nnaemeka C. "Antibody responses and Fc gamma receptor IIa polymorphism in relation to Plasmodium falciparum malaria." Doctoral thesis, Stockholms universitet, Wenner-Grens institut, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-27541.
Full textAbstract:
Immunity to asexual blood-stage of Plasmodium falciparum malaria is believed to be associated with protective antibodies of certain immunoglobulin classes and subclasses. This thesis addressed the importance of antibodies in relation to malaria infection and their effective interactions with Fc gamma receptor IIa (FcyRIIa) polymorphisms. Our data indicate that the frequency of FcyRIIa-R/R131 genotype was statistically significantly higher in Sudanese patients with severe malaria, while the FcyRIIa-H/H131 genotype showed a significant association with mild malaria. The levels of IgG1 and IgG3 subclass antibodies were statistically higher in the mild malaria patients. The Fulani ethnic group in West Africa has been shown to be relatively resistant to malaria. We investigated the possible impact of FcyRIIa polymorphisms in the Fulani and non-Fulani in Mali and Sudan, and analysed their malaria-reactive IgG subclass profiles. The FcyRIIa-H/H131 genotype and H131-allele were found to be prevalent in the Fulani while R131-allele was prevalent in non-Fulani. The Fulani had higher serum levels of IgG1-3, with higher proportion of IgG2 than the non-Fulani. Most clinico-epidemiology studies have been in areas with holo- and hyper-malaria endemicity. We have analysed antibody responses to a panel of six blood-stage antigens in relation to clinical malaria outcome in mesoendemic Sudan. Our results revealed a linear association with anti-AMA-1 IgG1 antibodies and reduced risk of severe malaria while a non-linear relationship with IgG3 antibodies was observed for MSP-2, MSP-3 and GLURP. In the combined final model, the highest levels of IgG1 subclass antibodies to AMA-1, GLURP-R0, and the highest levels of IgG3 subclass antibodies reactive to 3D7 MSP-2 were independently associated with a reduced risk of clinical malaria. Taken together, these data suggest a possible association between FcyRIIa-R/H131 and anti-malarial antibody responses in the clinical outcome of malaria.
24
Lima, Brena de Lourdes Aguiar. "Caracterização molecular das enzimas glutationa stransferase (genes gstt1, gstm1 e gstp1) em pacientes com malária por plasmodium vivax." Universidade Federal do Amazonas, 2013. http://tede.ufam.edu.br/handle/tede/2576.
Full textAbstract:
Made available in DSpace on 2015-04-11T13:54:30Z (GMT). No. of bitstreams: 1
Brena de Lourdes Aguiar Lima.pdf: 1248497 bytes, checksum: d14922a8c86943653012f0ea3e3818cf (MD5)
Previous issue date: 2013-04-08CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Plasmodium vivax threatens ~40% of the world s population, with a wide spectrum of asymptomatic to severe clinical manifestations. Glutathione S-transferase (GST) gene polymorphisms have been shown to influence their ability to reduce oxidative stress. Using molecular tools we identified and compared GSTM1, GSTT1 and GSTP1 gene polymorphism in 175 uncomplicated (n=118) and severe (n=57) vivax patients. There were no differences in the frequency of GST alleles between uncomplicated and severe malaria. Nevertheless, a comparison of biochemical and hematological parameters in severe malaria, we observed patients with GSTM1 double-deletion had more platelets (p<0.04) suggesting a decreased risk of thrombocytopenia. In addition, patients with single and/or double deletion of GSTT1 and GSTM1 also had a reduced risk for thrombocytopenia (p<0.045, p<0.026, respectively) compared to wild type allele. In contrast, individuals with GSTP1 heterozygous or homozygous A313G mutation had an increased risk of jaundice (p<0.034, p<0.022) and anemia as observed with decreased RBCs (p<0.008), hemoglobin (p<0.019) and hematocrit (p<0.008) levels in serum. Our results, not only indicate a direct influence of GST polymorphism on biochemical parameters but also its diagnostic potential in assessing disease progression during clinical malaria.
Plasmodium vivax acomete aproximadamente 40% da população mundial, com um amplo espectro de manifestações clínicas, desde formas assintomáticas a infecções graves. Polimorfismos nos genes da Glutationa S-transferase (GST) influenciam a capacidade das isoenzimas de reduzir o estresse oxidativo. Usando métodos moleculares nós identificamos e comparamos polimorfismos nos genes da GST em 175 pacientes com malária vivax não-grave (n=118) e grave (n=57). Não houve diferenças estatísticas nas freqüências alélicas das GSTs entre os pacientes com malária não grave e grave. No entanto, guando comparou-se os parâmetros bioquímicos e hematológicos no grupo com malária grave, observamos que pacientes com deleção no gene GSTM1 apresentaram maior contagem plaquetária (p˂0.04), sugerindo menor risco de trombocitopenia. Além disso, pacientes com deleção única e/ou dupla nos genes GSTT1 e GSTM1 demonstraram menor risco de desenvolverem trombocitopenia (p˂0.045, p˂0.026, respectivamente) em comparação com os pacientes portadores do genótipo selvagem. Em contraste, indivíduos com malária grave e portadores dos genótipos heterozigotos ou homozigotos para a mutação A313G no gene GSTP1 apresentaram maior risco de desenvolverem icterícia (p˂0.034, p˂0.022, respectivamente) e anemia, como demonstrado pelos menores níveis de hemácias (p˂0.008, p˂0.019, respectivamente) e hematócrito (p˂0.008). Nossos resultados não indicam apenas uma influência direta dos polimorfismos das GSTs nos parâmetros bioquímicos e hematológicos, mas também o seu potencial de avaliar a progressão da doença.
25
Oppenheimer, Stephen James. "Iron deficiency and susceptibility to infection : a prospective study of the effects of iron deficiency and iron prophylaxis in infants in Papua New Guinea." Thesis, University of Oxford, 1987. http://ora.ox.ac.uk/objects/uuid:1891d054-1564-47f5-b2e0-b6da5f60e996.
Full textAbstract:
Investigation of the relationship between iron deficiency, iron supplementation and susceptibility to infection, was suggested by the author's initial observations of an association of anaemia with serious bacterial infections in infancy in Papua New Guinea. The bulk of previous longitudinal clinical intervention studies in infancy showed beneficial effects of iron supplementation. However, defects of control and design and recording in these studies and contradictory anecdotal reports left the question unresolved. A prospective, placebo-controlled, randomised, double-blind trial of iron prophylaxis (3ml intramuscular iron dextran = 150mg Fe) to two month old infants was carried out on the North Coast of Papua New Guinea where there is high transmission of malaria. A literature review, pilot studies, protocol, demography, geography and laboratory methods developed are described. Findings indicate that the placebo control group became relatively iron deficient over the first year of life and that the iron dextran group had adequate, although not excessive iron stores and a higher mean haemoglobin; however, the prevalence and effects of malaria recorded in the field were higher in the iron dextran group. Analysis of field and hospital infectious morbidity in the trial indicated a deleterious association with iron dextran for all causes including respiratory infections (the main single reason for admission). Total duration of hospitalisation was significantly increased in the iron dextran group. Analysis of other factors showed (1) a higher admission rate associated with low weight-for-height recorded at the start of the trial; (2) a significant positive correlation between birth haemoglobin and hospital morbidity rates; (3) increased malaria rates in primiparous mothers of the cohort infants who received iron infusion during pregnancy; (4) lower relative risk of malaria associated with iron prophylaxis in individuals with alpha thalassaemia, which was found to be highly prevalent in this region. In conclusion, it is suggested that policies of iron supplementation, total dose iron injection and routine presumptive iron therapy for anaemia which are widely in practice in malaria endemic areas should be closely reviewed.
26
Furlani, Natália Guelfi. "Pesquisa da ancestralidade genômica em população da Amazônia Ocidental Brasileira." Faculdade de Medicina de São José do Rio Preto, 2011. http://bdtd.famerp.br/handle/tede/105.
Full textAbstract:
Made available in DSpace on 2016-01-26T12:51:30Z (GMT). No. of bitstreams: 1
nataliaguelfifurlani_dissert.pdf: 2586696 bytes, checksum: c66f56a5e70e155d3ec22d8e0643f53a (MD5)
Previous issue date: 2011-07-27The Brazilian population is mainly composed of three parental populations: Native Americans, Europeans and Africans. Significant levels of tri-hybrid admixture have been detected in all regions and socioeconomic levels within the country. Recent statistical methods allied to the ability to genotype a large number of markers permit the estimate of the admixture at the individual level. In epidemiological studies with case-control design, ethnic heterogeneity between subgroups can produce false positive results. Therefore, for this type of study, it is important to evaluate individual admixture, as well as to measureits influence on the genetic structure of diverse subgroups within the Brazilian populations. Ancestry Informative Markers (AIMs), which frequencies show large differences between parental populations are suitable for tracking the effect of mixing, in order to avoid spurious associations in case control studies. This knowledge could help to further define the levels of population structure in groups and subgroups that constitute the subject of epidemiological studies, optimizing their designto avoid false positive results. Among these groups are particularly relevant studies addressing genetic factors that modulate susceptibility to malaria in regions where the population is exposed to endemic levels, for example, those residing in the municipality of Porto Velho (RO), Brazilian amazon region and surroundings. Objectives: a) to describe the Amerindian, European and African individual genomic ancestry in healthy individuals and patients with falciparum malaria in Porto Velho, RO (Western Amazonia) and assess its impact on the design of epidemiological studies and b) to determine, from the genotyped markers, the genetic structure of populations of falciparum malaria patients and healthy individuals from the same region, depending on the admixture levels .
A população brasileira é formada majoritariamente por três populações parentais: Nativos Americanos, Europeus e Africanos. Níveis significativos de miscigenação tri-híbrida já foram detectados em todas as regiões e níveis sócio-econômicos do País. Métodos estatísticos recentes aliados à possibilidade de genotipagem de um grande número de marcadores permitem estimar a miscigenação em nível individual. Em estudos epidemiológicos com desenho de caso-controle, a heterogeneidade étnica entre estas categorias pode produzir resultados falso-positivos. Por este motivo, para este tipo de estudo, é importante estudar a miscigenação individual, assim como avaliar como a miscigenação neste nível influencia a estrutura genética dos diferentes subgrupos das populações brasileiras. O controle do efeito da miscigenação, para evitar as associações espúrias em estudos do tipo caso-controle pode ser feito estudando Marcadores Informativos de Ancestralidade (MIAs), os quais apresentam grandes diferenças de freqüência entre as populações parentais. Este conhecimento poderá contribuir para a futura definição dos níveis de estruturação populacional em grupos e subgrupos que constituirão alvo de estudos epidemiológicos, permitindo a otimização dos mesmos, a fim de evitar resultados falso-positivos. Dentre estes grupos, são de particular relevância estudos que abordem os fatores genéticos que modulam a suscetibilidade à malária em regiões onde a população se encontra exposta em nível endêmico como, por exemplo, a que reside no município de Porto Velho (RO) e região. Objetivos: a) descrever a ancestralidade genômica individual Ameríndia, Européia e Africana em indivíduos sadios e portadores de malária por Plasmodium falciparum da cidade de Porto Velho, RO (Amazônia Ocidental), Brasil, e avaliar seu impacto no desenho de estudos epidemiológicos e b) determinar, a partir dos marcadores genotipados, a estrutura genética das populações de portadores de malária falciparum e indivíduos sadios da mesma região, em função dos níveis de miscigenação.
27
Martin-Peprah, Ruby. "The genetic susceptibility to hyperreactive malarial splenomegaly in Kumasi, Ghana." Thesis, University of Liverpool, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423934.
Full text
28
Goumidi, Araria Louisa. "Recherche de facteurs de susceptibilité génétique de la maladie d'Alzheimer." Lille 2, 2002. http://www.theses.fr/2002LIL2MT21.
Full text
29
Boulos-Owhadi, Areen. "Molecular evaluation of antibiotic susceptibility of fastidious bacteria." Aix-Marseille 2, 2004. http://www.theses.fr/2004AIX20672.
Full text
30
Pommier, Janine. "Etude de facteurs influençant la susceptibilité de l'hôte au paludisme : Effet de facteurs génétiques et de l' état inflammatoire." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM4003.
Full textAbstract:
Mon travail de thèse a porté sur l'étude des facteurs influençant le devenir de l'infection palustre. Une étude de liaison génétique basée sur des marqueurs répartis sur l'ensemble du génome nous a permis de mettre en évidence la liaison génétique de la région chromosomique 17p11-p13 avec la parasitémie. Nous avons étudié les variations génétiques des gènes HS3ST3A1 et HS3ST3B1 du chromosome 17p12 humain car ces gènes pourraient influencer l'infection de cellules humaines par le Plasmodium. Nous avons ainsi observé la liaison génétique de certain SNP de ces gènes avec la parasitémie. Les anticorps IgG dirigés contre le parasite P. falciparum sont connus pour jouer un rôle important dans la réponse immunitaire. Certain gènes associés à la résistance au paludisme pourraient également être associés au niveau de production d'IgG. Nous avons montré que certains polymorphismes situés dans les gènes HBB, FcRIIA, et du TNF influencent le niveau de production de différentes sous classes IgG. Ces résultats nous permettent de mieux comprendre le contrôle génétique de la réponse humorale contre la malaria.J'ai aussi caractérisé l'inflammation non infectieuse dans un modèle murin afin de tester l'influence de l'état inflammatoire lors de l'infection par le plasmodium. L'étude transcriptomique de trois organes réalisée sur un modèle de souris injectée avec de l'acide oléique, nous a permis de mettre en évidence une réponse inflammatoire principalement au niveau des poumons et du cerveau. Ces résultats vont nous permettre de tester l'hypothèse qu'une réponse inflammatoire pré-existante favoriserait la survenue de forme sévère du paludisme chez des souris infectées par PlasmodiumMy thesis focused on the study of factors influencing the future of malaria infection. A genetic linkage study based on markers distributed throughout the genome has allowed us to highlight the linkage of 17p11 - p13 chromosome region with parasitaemia. We investigated the genetic variation of genes and HS3ST3A1 HS3ST3B1 human chromosome 17p12 because these genes may influence the infection of human cells by Plasmodium . We observed genetic linkage of some SNPs in these genes with parasitaemia.IgG antibodies against the parasite P. falciparum are known to play an important role in the immune response . Certain genes associated with resistance to malaria could also be associated with the level of IgG production . We have shown that some polymorphisms located in genes HBB , Fc RIIA , and TNF influence the level of production of different IgG subclasses . These results allow us to better understand the genetic control of humoral response against malaria.I also characterized non- infectious inflammation in a mouse model to test the influence of the inflammatory condition during infection by Plasmodium . The transcriptomic study performed on three organs mouse model injected with oleic acid , has allowed us to demonstrate an inflammatory response mainly in the lungs and brain. These results will allow us to test the hypothesis that pre-existing inflammatory response favor the occurrence of severe malaria in mice infected with Plasmodium
31
Laugier, Laurie. "Identification de marqueurs de susceptibilité dans les formes chroniques de la maladie de Chagas." Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0226.
Full textAbstract:
La maladie de Chagas est une maladie parasitaire causée par le protozoaire Trypanosoma cruzi et transmise par des insectes hématophages . Elle est composée de 2 phases : la phase aiguë et la phase chronique. Parmi les individus infectés, 30 % développent la forme chronique de la maladie. Les patients présentent des atteintes cardiaques, digestives (œsophage, côlon) et cardiodigestives. Notre étude a été focalisée sur les patients atteints de cardiomyopathie chagasique (CCC). Notre objectif est d’identifier des gènes de susceptibilité pouvant être impliqués dans le développement des formes chroniques. Notre étude a permis de mettre en évidence une variation d’expression de certains gènes entre les CCC et les contrôles. Nous nous sommes également intéressés aux processus épigénétiques pouvant réguler l’expression des gènes. Une étude de la méthylation de l’ADN croisée avec l’étude du transcriptome nous ont permis d’identifier des gènes présentant à la fois des variations d’expression et de méthylation. Pour certains de ces gènes, nous avons démontré que la méthylation est responsable de la variation d’expression observée. Enfin, nous avons étudié un ARN long non-codant, MIAT. Nous avons démontré qu’il est surexprimé chez les CCC par rapport aux contrôles et dans un modèle murin infecté par T. cruzi. De plus, l’analyse de l’expression de micro-ARNs couplée à une analyse de transcriptome nous a permis d'identifier plusieurs micro-ARNs indispensables à la régulation de l’expression des gènes. Enfin, une étude protéomique nous a permis de mettre en évidence une augmentation de la production de protéine pour certains gènes, en lien avec l’augmentation de l’expression observéeChagas disease is a parasitic disease caused by the protozoan Trypanosoma cruzi and transmitted by the hematophagous insects. The disease is composed by acute and chronic phases. Among the infected individuals, 30 % develop chronic form. They suffer from heart, digestive (esophagus, colon) and cardiodigestives injury. Our study was focused on patients with dilated chagasic cardiomyopathy (CCC). Our goal is to identify susceptibility genes that may be involved in the development of chronic forms. Our study revealed a variation in the expression of certain genes between CCC group and controls. We are also interested in epigenetic processes that can regulate the expression of genes. A study of the DNA methylation crossed with the transcriptome allowed us to identify genes presenting both variations in expression and methylation. For some of these genes we demonstrated that methylation is responsible for the expression variation observed. Finally, we studied a long non-coding RNA called MIAT. Our study demonstrated that it is overexpressed in CCC compared to controls and in a murine model infected by T. cruzi. Furthermore, the analysis of the expression of micro-RNAs crossed with transcriptome analysis allowed us to identify several micro-RNAs whose functions are essential in the regulation of gene expression. Finally, a proteomic study allowed us to demonstrate an increase in the production of protein for certain genes, correlated with the increase in expression levels observed
32
Kagunda, Joséphine. "Mathematical analysis and dynamical systems : modeling Highland malaria in western Kenya." Thesis, Université de Lorraine, 2012. http://www.theses.fr/2012LORR0271/document.
Full textAbstract:
L'objectif de cette thèse est de modéliser la transmission du paludisme dans la région montagneuse de l'ouest du Kenya, en se servant des outils de systèmes dynamiques. Nous considérons deux modèles mathématiques. Le premier prend en compte une susceptibilité et une infectivité différentielle dans les métapopulations, et le second un taux de saturation des repas sanguins dans la population des moustiques. Dans le premier modèle, nous considérons plusieurs écosystèmes identifiés comme zones sensibles dans la région montagneuse de l'ouest du Kenya. Dans ce modèle, ces zones sensibles sont considérées comme nos différents patchs. Les populations de chaque patch sont divisées en deux : les enfants et les adultes. Le modèle nous permet d'évaluer le rôle de l'hétérogénéité de l'écosystème et la persistance de l'épidémie dans la région, due à la structuration d'âge. Nous prenons en compte la susceptibilité et l'infectivité différentielle afin d'étendre le modèle d'un patch en un modèle à plusieurs patchs. Après avoir subdivisé la région en n zones sensibles, nous faisons une analyse mathématique du modèle obtenu. Pour effectuer cette analyse, nous utilisons la théorie des systèmes triangulaires, des systèmes dynamiques monotones, des systèmes dynamiques non linéaires anti-monotones et le principe d'invariance de LaSalle. Un des éléments très utilisés dans notre analyse qui est un concept clé en épidémiologie, est le taux de reproduction de base, très souvent noté Ro. Cette quantité, sans dimension, est le nombre moyen de cas secondaires, engendré par un individu infectieux typique durant sa période d'infectiosité, quand il est introduit dans une population constituée entièrement de susceptibles. L'existence et la stabilité du point d'équilibre sans maladie (DFE) sont établies et nous prouvons que le DFE est globalement asymptotiquement stable lorsque Ro<1. Lorsque Ro>1, le modèle admet un point d'équilibre endémique qui est globalement asymptotiquement stable. L'analyse de notre modèle montre que la structuration d'âge réduit l'ampleur de l'infection. En utilisant les données relevées, nous faisons quelques simulations numériques afin de montrer l'impact de la métapopulation et de la structuration d'âge sur le taux de reproduction de base. Dans la seconde partie, nous formulons un modèle de paludisme avec saturation du taux d'alimentation des moustiques qui nous conduit à une incidence non linéaire. Nous démontrons que DFE est globalement asymptotiquement stable si Ro<1. Lorsque Ro>1, il existe un unique point d'équilibre endémique qui est globalement asymptotiquement stable. Des simulations numériques sont faites afin d'illustrer l'impact de la saturation d'alimentation sur le taux de reproduction de baseThe objective of this thesis is to model highland malaria in western Kenya using dynamical systems. Two mathematical models are formulated ; one, on differentiated susceptibility and differentiated infectivity in a metapopulation setting with age structure, the other, a saturated vector feeding rate model with disease induced deaths and varying host and vector populations. In the first model, we consider the different ecosystems identified as malaria hotspots in the western Kenya highlands and consider the ecosystems as different patches. The population in each patch is classified as, either child or, adult. The model will aid in examining the role of ecosystem heterogeneity and age structure to the persistent malaria epidemics in the highlands. We formulate the differentiated susceptibility and infectivity model that extend to multiple patches the well known epidemiological models in one patch. Classifying the hot spots as n patches, we give its mathematical analysis using the theory of triangular system, monotone non-linear dynamical systems, and Lyapunov-Lasalle invariance principle techniques. Key to our analysis is the definition of a reproductive number, Ro, the number of new infections caused by one individual in an otherwise fully susceptible population throughout the duration of the infectious period. The existence and stability of disease-free and endemic equilibrium is established. We prove that the disease free state of the systems is globally asymptotically stable when the basic reproduction number Ro<1, and when Ro>1 an endemic equilibrium is established which is locally and globally asymptotically stable. The model shows that the age structuring reduces the magnitude of infection. Using relevant data we did some simulation, to demonstrate the role played by metapopulation and age structuring on the incidence and Ro. In the second part we formulate a model for malaria with saturation on the vector feeding rates that lead to a nonlinear function in the infection term. The vector feeding rate is assumed, as in the predator prey models, to rise linearly as a function of the host-vector ratio until it reaches a threshold Qv, after which the vector feeds freely at its desired rate. The two populations are variable and drive malaria transmission, such that when the vectors are fewer than hosts, the rate of feeding is determined by the vectors feeding desire, whereas, when the hosts are more than the vectors, the feeding rate is limited by host availability and other feeding sources may have to be sought by the vector. Malaria induced deaths are introduced in the host population, while the vector is assumed to survive with the parasite till its death. We prove that the Disease Free Equilibrium is locally and globally asymptotically stable if Ro<1 and when Ro>1, an endemic equilibrium emerges, which is unique, locally and globally asymptotically stable. The role of the saturated mosquito feeding rate is explored with simulation showing the crucial role it plays especially on the basic reproduction number
33
Fleury, Agnès. "Neurocysticercose : facteurs impliqués dans la modulation de la susceptibilité à l'infection et à la maladie." Limoges, 2002. http://www.theses.fr/2002LIMO104D.
Full textAbstract:
La neurocysticerose est endémique dans la plupart des pays d'Amérique latine et d'Afrique sub-saharienne. Elle est secondaire à la présence de la forme larvaire du Tœnia solium dans le système nerveux central. Son épidémiologie est peu connue ainsi que les facteurs impliqués dans la variabilité de la susceptibilité à l'infection et dans la variabilité de son évolution. Pour améliorer nos connaissances dans ces domaines, deux études principales ont été menées. La première dans une petite communauté rurale endémique du Mexique, et la seconde à l'Institut National de Neurologie de Mexico. Dans la première étude, 10% de l'échantillon des sujets étudiés présentait une NCC. Tous les cas étaient calcifiés et asymptomatiques. Aucun des facteurs d'expositions évalués n'étaient associés à la parasitose, et ni le sexe ni l'âge ne paraissaient moduler la susceptibilité à l'infection. Certaines données suggéraient que celle-ci pouvait être influencée par le statut génétique des hôtes. Cette étude a également confirmé que dans la majorité des cas cette maladie est bénigne et que chez seulement une infime proportion des patients, le parasite peut se développer et causer une maladie grave. Par ailleurs, elle démontre que bien que l'exposition est bien sur nécessaire pour qu'il existe une infection, d'autres facteurs sont impliqués dans la survenue de la maladie. La seconde étude, hospitalière, concernait justement seulement des patients symptomatiques. Il y est apparu que l'âge est lié à une augmentation de la susceptibilité et à une diminution de la capacité de détruire la parasite alors que la réaction inflammatoire est exacerbée chez la femme. Ces résultats, pour la première fois, établissent le rôle de facteurs propres à l'hôte et le rôle de l'exposition dans la modulation de la susceptiblité à l'infection et à la maladie.
34
Roslan, Norsyafina. "The potential susceptibility of urban hardrock aquifers to hydraulic and contaminant stresses : the case of Shah Alam, Malaysia." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7270/.
Full textAbstract:
Urban groundwater needs proper management since it is potentially susceptible to both hydraulic and chemical stresses. To manage an aquifer well, an understanding is needed of how the aquifer works. Much research has been done on urban aquifers but relatively little on hard-rock metasediment aquifers especially in equatorial climates such as Peninsular Malaysia. Therefore, research aim is to understand equatorial climate hard rock metasediment urban aquifers and their susceptibility to hydraulic and chemical impacts using data likely to be available to regulatory authorities. Shah Alam, a city developed over the last 50 years is investigated. Borehole log, meteorological, pumping test, and water quality data were used. The meta sandstone-shale sequence is fractured to at least 100m and covered by a weathering zone that is more clay rich where finer metasediments occur. Permeabilities ranged from 0.01 to 1 m/day. Results show that the abstraction activity has induced recharge into aquifer; which CO2 contents indicate that it had been through a soil zone. Some weathering reactions had occurred. Water quality samples with very low salinity barely above precipitation concentrations. Many of the water samples were polluted by one or more species, and sewer influences were common. It can be concluded that aquifer very susceptible to quality stress with a very limited pollution attenuation capacity. It is quite flashy system when pumping.
35
Lamontagne, Maxime. "Marqueurs génétiques influençant l'expression des gènes dans les poumons et susceptibilité à la maladie pulmonaire obstructive chronique." Thesis, Université Laval, 2013. http://www.theses.ulaval.ca/2013/29782/29782.pdf.
Full textAbstract:
La maladie pulmonaire obstructive chronique (MPOC) se caractérise par une obstruction non complètement réversible des voies aériennes. De récentes études de criblage génomique par association ont identifié quatre régions chromosomiques associées à la MPOC. Par contre, les mécanismes moléculaires responsables de ces associations génétiques demeurent inconnus. Dans le cadre de cette étude, nous avons obtenu les profils d'expression des gènes de tissus pulmonaires non-tumoraux et les génotypes de 1,2 million de variations génétiques pour ces mêmes patients. Les analyses furent effectuées sur 1111 sujets provenant de trois cohortes. Des marqueurs génétiques influençant l'expression des gènes dans les poumons, c.-à-d. « expression Quantitative Trait Loci » (eQTLs) pulmonaires, furent identifiés dans les régions chromosomiques d'intérêts. Les résultats de ce mémoire démontrent que HHIP serait le gène causal dans la région 4q31, alors que les évidences pointent vers les gènes FAM13A et EGLN2 pour les régions 4q22 et 19q13, respectivement.Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that is not fully reversible. Recent genome-wide association studies have identified four susceptibility loci robustly associated with COPD. However, the genetic mechanisms mediating the risk within these loci remain to be found. In this study, genome-wide gene expression profiles of non-tumor lung specimens and blood-DNA from the same patients were genotyped for 1,2 million SNPs. The analyses were performed on 1111 subjects from three cohorts. Genetics variations influencing gene expression levels in lung samples, i.e. lung expression quantitative trait loci (eQTLs), were identified in the COPD susceptibility regions (4q22, 4q31, 19q13). The results of this thesis demonstrated that HHIP is the most likely causal gene at 4q31, while the evidences supported the contribution of the FAM13A and EGLN2 genes at 4q22 and 19q13, respectively.
36
Labreche, Karim. "Genetic Susceptibility and Molecular Characterization of Glioma." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS161/document.
Full textAbstract:
Les gliomes constituent les plus fréquentes des tumeurs malignes primaires du système nerveux central. Les liens qui existent entre ces tumeurs et un certain nombre de cancers rares héréditaires, comme les Neurofibromatoses I et II ou les syndromes de Turcot et de Li-Fraumeni, attestent d’une prédisposition génétique aux gliomes. L’observation d’un risque deux fois plus élevé de développer un gliome chez les parents de premier degré de patients atteints suggère aussi une possible prédisposition génétique dans les gliomes sporadiques. Par ailleurs, l’analyse à haut débit permet de préciser le profil somatique des gliomes et d’identifier des biomarqueurs pronostiques voire prédictifs et s’inscrire dans une démarche de traitement personnalisé du patient. Durant ma thèse, je me suis focalisé sur deux axes de recherches complémentaires; l’identification de gènes de susceptibilité et la découverte de nouveaux gènes fréquemment mutés dans les gliomes, afin de déterminer les voies de signalisation contribuant à la gliomagenèse. Dans leur ensemble, les résultats obtenus dans cette thèse apportent non seulement des informations importantes sur la nature de la prédisposition génétique aux gliomes mais également de son association spécifique pour les différents sous-types de tumeurs. La découverte d’un nouveau gène muté, offre la perspective à plus long terme d’un traitement personnalisé pour chaque patient sur la base du profil génétique de sa tumeurGliomas are the most common adult malignant primary tumour of the central nervous system. Thus far, no environmental exposures has been linked to risk except for ionizing radiation, which only accounts for a very small number of cases. Direct evidence for inherited predisposition to glioma is provided by a number of rare inherited cancer syndromes, such as Turcot's and Li–Fraumeni syndromes, and neurofibromatosis. Even collectively, these diseases however account for little of the twofold increased risk of glioma seen in first-degree relatives of glioma patients. My research was centred on two complementary research activities: Identifying susceptibility genes for glioma to delineate key biological pathways contributing to disease pathogenesis and to identify new recurrent mutated genes for glioma to provide for further insights into glial oncogenesis and suggesting targets for novel therapeutic strategies. Collectively the findings in this thesis provide increased insight into the nature of genetic predisposition to glioma and substantiate the often distinct associations between susceptibility variants and glioma molecular groups. In addition the discovery of a new mutated gene in glioma offers the potential to support drug development and advance precision medicine for this tumours
37
Adamou, Rafiou. "Etude du rôle fonctionnel des IgG dans la susceptibilité au paludisme chez de jeunes enfants béninois." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB026.
Full textAbstract:
L'objectif général de cette thèse était d'étudier le rôle des anticorps dans la susceptibilité ou la résistance au paludisme chez de jeunes enfants béninois exposés naturellement aux infections palustres durant leurs deux premières années de vie. Deux projets complémentaires (PALNOUGENENV et TOLIMMUNPAL) ont été mises en place au Bénin et consistaient à suivre des mères et leurs enfants. Dans le cadre du projet PALNOUGENENV, l'étude incluait 600 mères à l'accouchement et a suivi leurs enfants pendant les dix-huit premiers mois de vie dans le but d’étudier les conséquences de l’infection placentaire palustre chez les mères sur la survenue des premières infections palustres chez les nouveau-nés. Suite au projet PALNOUGENENV, il semblait important de connaitre le statut palustre de la mère pendant la grossesse et pas seulement à l’accouchement. Le projet TOLIMMUNPAL a donc été mis en place et incluait 400 mères et leurs enfants. Les mères ont été inclues à la première consultation prénatale et suivies au niveau parasitologique et clinique jusqu'à l'accouchement et leurs enfants ont été suivis de la naissance jusqu'à 24 mois dans le but d'étudier des déterminants environnementaux, biologiques et génétiques impliqués dans le développement de la tolérance immunitaire associée au paludisme et ses conséquences sur la protection de la femme enceinte et du jeune enfant. Plus spécifiquement, nous avons étudié chez ces enfants les relations entre l'infection palustre et les niveaux d'anticorps spécifiquement dirigés contre les antigènes candidats vaccins les plus avancés du stade érythrocytaire d'une part et la capacité des anticorps à inhiber le développement in vitro de P. falciparum d'autre part. Nos résultats mettent en évidence une association dans la cohorte PALNOUGENENV entre les niveaux élevés des sous-classes cytophiles IgG1 dirigées contre les antigènes candidats vaccins MSP1 (p<0,001, OR=0,90) et IgG3 anti-MSP2 (p<0,001, OR=0,89) et la protection contre l'infection palustre. Dans la cohorte TOLIMMUNPAL, les hauts niveaux d'IgG2 anti-GLURP R2 (p=0.05, OR=2.10) ont plutôt été associés au risque d'infection palustre. L'analyse fonctionnelle des IgG en utilisant le test GIA a révélé que l'infection par P. falciparum au moment du prélèvement affectait la capacité des IgG à inhiber la croissance parasitaire in vitro. Les IgG purifiées à partir d'échantillons collectés chez des individus infectés par P. falciparum avaient une capacité moyenne d'inhibition de la croissance parasitaire inférieure (p=0.003, Wilcoxon matched pairs test) de 19 % à celles purifiées à partir de plasmas d'enfants non infectés. Une corrélation inverse a été observée entre l'âge et la capacité des anticorps à inhiber l'invasion des globules rouges par le parasite. Aucune association entre les niveaux d'anticorps et leur capacité à inhiber le développement du parasite in vitro n'a été mis en évidence. Dans le cadre du développement du test Antibody-Dependent Respiratory Burst (ADRB), les cellules promyélocytaires de la lignée PLB 985W ont été utilisées. Ces cellules ont la capacité de se différencier en neutrophiles sous l'action du DMSO. Nos résultats ont montré que cette lignée a une faible capacité à produire les espèces réactives d'oxygène (ROS) comparés aux neutrophiles humains et les niveaux de ROS produits par cette lignée cellulaire sont insuffisants pour être utilisés dans le test ADRB. Nos résultats confortent le rôle important des antigènes candidats vaccins MSP1 et MSP2 dans la protection contre le paludisme. Cette relation est essentiellement établie au regard des quantités d’anticorps spécifiques produits, l’étude de fonctionnalité des anticorps employant le test GIA n’ayant pas permis de mettre en évidence de relation claire à la protection. (...)The aim of this thesis was to study the role of antibodies in susceptibility or resistance to malaria in young Beninese children naturally exposed to malaria infections during their first two years of life. Two complementary projects (PALNOUGENENV and TOLIMMUNPAL) were implemented in Benin to identify individual factors of malaria susceptibility. The PALNOUGENENV cohort included 600 mothers at delivery and their children from birth to 18 months of age in order to study the effects of placental malaria infection in mothers on first occurrence of malaria infections in newborns. In the TOLIMMUNPAL cohort 400 mothers were included at the first antenatal visit and followed until delivery while their infants were followed from birth to 24 months in order to study environmental determinants, biological and genetic involved in the development of immune tolerance associated with malaria and its impact on the protection of pregnant women and infants. Specifically, the association between malaria infection and the level of antibodies specifically directed against the most advanced vaccine candidate antigens of the erythrocyte stage on one hand and the ability of antibodies to inhibit in vitro the development of P. falciparum on the other hand were investigated. Our results show an association in the cohort PALNOUGENENV between high levels of IgG1 to MSP1 19 vaccine candidate antigens (p <0.001, OR = 0.90) and IgG3 to MSP2 3D7 (p <0.001, OR = 0.89) and protection against malaria infection. In the TOLIMMUNPAL cohort, high levels of IgG2 to GLURP R2 (p = 0.05, OR = 2.10) were instead associated with an increased risk of malaria infection. Functional analysis of IgG using the GIA test revealed that the infection with P. falciparum at the sampling time affected the ability of IgG to inhibit parasite growth in vitro. The purified IgG from individuals infected with P. falciparum when the sample was collected had an average 19% lower capacity of inhibition of parasite growth (p = 0.003, Wilcoxon matched pairs test) than those that were uninfected at the time of sampling. An inverse correlation was found between age and the ability of antibodies to inhibit in vitro invasion of red blood cells by the parasite. There was no association between antibody levels and ability to inhibit the in vitro parasite development. In the development of the Antibody-Dependent Respiratory Burst (ADRB) assay, the promyelocytic cell line PLB 985W was used. These cells have the capacity to differentiate into neutrophils after exposure to DMSO. Our results showed a low ability of this cell line to produce reactive oxygen species (ROS) compared to human neutrophils and ROS levels produced by this cell line are insufficient to be used in the test ADRB. Our results confirm the important role of MSP1 19 and MSP2 3D7 vaccine candidate antigens in malaria protection. Although the levels of antibodies to MSP1 19 and MSP2 3D7 were associated with decrease risk of P. falciparum infection, the functional study of antibody using the GIA assay did not allow demonstrating the relationship to protection. Investigation on the functional role of antibodies is complex as IgG could act through multiple direct or indirect mechanisms. We will continue to investigate the functional role of antibody, particularly in plasma samples from our two birth cohorts by using the ADRB assay. Results will aid in providing new information to the existing knowledge gap and will help in malaria vaccine development
38
Smati-Grangeon, Sarra. "Influence du sexe dans la susceptibilité aux hépatopathies métaboliques." Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30213.
Full textAbstract:
Les hépatopathies non alcooliques (NAFLD) sont aujourd'hui la première cause de maladies hépatiques, et constituent désormais un véritable enjeu de santé publique. Elles sont composées de différents stades d'atteintes, allant de la simple stéatose à la stéato-hépatite (NASH) définie par la présence d'une inflammation hépatique accompagnée ou non de fibrose. Chez l'humain, il existe un fort dimorphisme sexuel dans cette maladie, les femmes sont protégées de cette atteinte, et cette protection disparaît après la ménopause. Les mécanismes liés à cette protection, médiée en partie par les œstrogènes, sont mal connus et il est nécessaire de disposer de modèles précliniques pertinents pour pouvoir les élucider. Nous avons d'abord cherché à identifier un modèle préclinique permettant d'étudier le dimorphisme sexuel dans le contexte de NAFLD. Pour cela, différents régimes hypercaloriques ont été testé (High Fat diet, High Fat diet déficient en choline, Western diet (WD) avec ou sans ajout de glucose et fructose dans l'eau de boisson) sur des souris mâles et femelles C57BL/6J pendant 15 semaines. Des analyses histologiques, biochimiques, transcriptomiques et métabolomiques ont été réalisées. Le régime WD a permis d'obtenir un fort dimorphisme dans la survenue de la NASH. Les mâles ont développé une stéatose sévère associée à une inflammation et un début de fibrose alors que les femelles ont uniquement développé une faible stéatose. Les analyses transcriptomiques ont mis en évidence des réponses géniques très contrastées selon le sexe. L'analyse des réseaux de gènes suggère que les récepteurs nucléaires ont une influence sur le dimorphisme sexuel observé dans notre étude. Parmi les récepteurs nucléaires, ERalpha est le récepteur principalement impliqué dans les effets des œstrogènes dans le foie. Des souris mâles et femelles porteuses de la délétion hépatocytaire d'ERalpha ont reçu le régime WD. L'absence d'ERalpha hépatocytaire n'a pas provoqué de modifications majeures du phénotype hépatique observé en réponse au régime WD dans les deux sexes, suggérant que les œstrogènes sont capables d'agir par l'intermédiaire d'une voie différente. Un autre récepteur nucléaire, PPARalpha, joue un rôle majeur dans le métabolisme des lipides et est protecteur vis-à-vis de la stéatose. Chez le mâle, il est montré que l'absence de PPARalpha provoque un défaut du catabolisme des lipides durant le jeûne. [...]Non Alcoholic Fatty Liver Disease (NAFLD), ranging from steatosis to steatohepatitis (NASH), is the most common liver disease and a major public health issue worldwide. There are strong clinical and preclinical evidence for sexual dimorphism. The establishment of reliable animal models is essential to understand the mechanisms underlying such gender specific susceptibility to the disease. We aimed at identifying a mouse model of NAFLD that replicates at best the sexual dimorphism observed in humans. We tested different hypercaloric diets: High-Fat Diet (HFD), Choline Deficient HFD, Western Diet enriched with cholesterol and co-administered or not with drinking water containing glucose and fructose in male and female C57BL/6J mice (n=12/group). Histological, biochemical, transcriptomic and metabolomic analyses were performed. The Western Diet induces a strong dimorphic phenotype for the onset of NASH. Males develop major steatosis associated with severe inflammation and fibrosis whereas females show much less steatosis. Both sexes develop obesity and have impaired glucose tolerance. In contrast, insulin resistance is more severe in males than in females. Finally, liver transcriptome analysis highlights contrasted gene expression profiles between males and females in response to the different diets. Gene network analysis suggest that nuclear receptors are influential in this sexual dimorphic response to dietary challenges. Among nuclear receptors, ERalpha is the major effector of estrogen signaling in the liver. We tested the western diet in male and female mice in absence of ERalpha in hepatocytes. This deletion did not cause significant changes in hepatic phenotype in response to western diet in males and females. Another nuclear receptor has been studied, PPARalpha plays a central role in lipid metabolism and is protective against NAFLD. In the absence of PPARalpha in hepatocytes, fatty acid catabolism is defective during fasting in male mice. Therefore, to investigate whether hepatocyte PPARalpha activity shows sexual dimorphism, we tested the effect of fasting in female mice. In vivo experiments in mice with a hepatocyte specific knock-out of PPARalpha reveal that fasting induces similar PPARalpha-dependent ketogenesis in mice from both sexes.[...]
39
Heresbach, Denis. "Contribution des etudes d'association cas-temoins a l'identification d'une susceptibilite genetique au cours des maladies inflammatoires chroniques de l'intestin." Rennes 1, 1998. http://www.theses.fr/1998REN1B026.
Full text
40
Kotti, Salma. "Etude des effets individuels et de l'effet interactif de deux gènes dans la susceptibilité à une maladie multifactorielle." Paris 11, 2008. http://www.theses.fr/2008PA11T006.
Full text
41
Grange, Laura. "Epistasis in genetic susceptibility to infectious diseases : comparison and development of methods application to severe dengue in Asia." Paris 7, 2014. http://www.theses.fr/2014PA077088.
Full textAbstract:
Ce travail est dédié à l'étude de l'épistasie dans la prédisposition génétique aux maladies complexes. Il existe de nombreuses méthodes dédiées à la détection de telles interactions. Le plus souvent, l'évaluation de ces méthodes utilise différentes procédures ce qui empêche la comparaison des études entre elles. Nous avons réalisé une étude comparative des performances de quelques méthodes de recherches d'interaction sur génome entier (GWIS), en particulier BOOST, MBMDR, PLINK et EPIBLASTER. Dans un deuxième projet, nous avons développé et évalué une méthode de détection de l'épistasie basée sur les odds ratio d'interaction. FORCE permet de réaliser un premier examen exhaustif des paires d'un GWIS. Pour les meilleurs candidats, une p-value exacte peut ensuite être calculée. Les performances de FORCE ont été comparées à celles de PUNK et MBMDR. Nous avons ensuite utilisé FORCE et PLINK pour analyser un jeu de données du WTCCC, concernant psoriasis. Enfin, nous avons réalisé un GWIS sur une base de données issue d'une cohorte de cas de dengue sévère et de contrôles provenant du Vietnam. Deux gènes ont été mis en évidence via leur contribution répétée à des p-values suggestives : CNTNAP5 sur le chromosome 2 en interaction avec SKAP2 sur le chromosome 7. Après enrichissement de ces deux régions par imputation, nous avons obtenu plusieurs paires satisfaisant le seuil de significativité corrigé pour un GWIS (p < ⁻¹³). L'analyse d'un jeu de données provenant d'une cohorte de cas de dengue hémorragique sévère originaires de Thaïlande, avant et après imputation, n'a pas permis la réplication du signal obtenu mais a révélé d'autres paires significatives entre CNTNAP5 et SKAP2This work is dedicated to the study of epistasis in genetic susceptibility to complex diseases. To date, there are numerous tools that rely on many different statistical methods aiming to detect such interactions. Most of the time, performance assessments are based on different procedures and are thus difficult to compare throughout all the studies. We ran a comprehensive study to compare the power and false positive performance of a selection of Genome-Wide Interaction Search (GWIS) methods, in particular BOOST, MBMDR, PLINK and EPIBLASTER. In a second project, we developed and evaluated a very simple epistasis detection method relying on interaction odds ratios. Thanks to smart algorithm coding, FORCE allows the completion of the first exhaustive screening step of a GWIS on a regular desktop in a reasonable amount of time and further significance assessment on the most relevant candidates. We compared FORCE's performances to those obtained with existing methods including MBMDR and PUNK. We then applied FORCE and PLINK on psoriasis case-control data from the WTCCC. Thirdly, we performed a GWIS on a case-control severe dengue cohort from Vietnam. Two genes repeatedly contributed to genome-wide suggestive p-values: CNTNAP5 on chromosome 2 in interaction with SKAP2 on chromosome 7. Epistasis exploration after imputation-based enrichment of there 2 regions led to GWIS significant signais of interaction between SKAP2 and CNTNAP5 (p < ⁻¹³). Analysing a Thai dengue hemorrhagic fever case-only cohort before and after imputation did not allow the replication of the signal obtained on the SNPs mentioned above but revealed significant hits involving SNPs in the same SKAP2 and CNTNAP5 genes
42
Llordés, Llordés Montserrat. "Estudi de susceptibilitat per la Malaltia Pulmonar Obstructiva Crònica d’una població fumadora. Lluita contra l’infradiagnòstic des de l’Atenció Primària." Doctoral thesis, Universitat Autònoma de Barcelona, 2011. http://hdl.handle.net/10803/51009.
Full textAbstract:
La malaltia pulmonar obstructiva crònica ( MPOC ) caracteritzada per la presència d’ obstrucció crònica i poc reversible del flux aeri, és una malaltia prevenible i tractable. L’ etiologia més freqüent en el nostre medi és el tabac. És causa freqüent de morbi mortalitat i una important causa de ingrés hospitalari en la nostra àrea, sent en la fase final quan la malaltia genera més despesa al sistema sanitari.
No totes les persones fumadores acaben desenvolupant MPOC, cal una susceptibilitat genètica i la concurrència d’ una sèrie de factors afavoridors ( paquets-any acumulats, envelliment, exposició laboral o ambiental a tòxics respiratoris...)
Es coneguda en la literatura l’ existència d’ un infradiagnòstic de la malaltia, en part per la desconeixença de la importància de determinats símptomes per part de la població i en part perquè els professionals no busquem prou la malaltia. Una base important en la lluita contra la malaltia és la detecció precoç.
Per tal de tenir ben estudiada a la nostra població i mirar de frenar el creixement de la MPOC, vam decidir fer un estudi de cribratge, en l’ àmbit de l’ atenció primària , en la població més susceptible de tenir la malaltia , realitzant una enquesta validada de símptomes respiratoris i exposició laboral i una espirometria a totes les persones del CAP majors o iguals a 45 anys ( en l’ any 2006) que en la seva història informatitzada constaven com a fumadors i exfumadors.
El fet de fer l’ espirometria en el CAP va facilitar la participació dels pacients, per la proximitat, en especial en adaptar-nos als seus horaris. La realització de les espirometries per personal del servei de Neumologia en el CAP, habituat a fer les proves, va assegurar un alt percentatge d’ espirometries correctament realitzades.
L’ estudi va permetre detectar errors diagnòstics, corroborar diagnòstics de MPOC existents i diagnosticar de MPOC a persones que fins ara no es coneixien afectades de la malaltia, evitant el sobrediagnòstic d’ asmàtics fumadors com a pacients amb MPOC gràcies a la utilització de tractament amb beta-2 i corticoides inhalats durant 4 setmanes.
Vam poder conèixer la susceptibilitat de la nostra població fumadora a patir la malaltia. En el treball utilitzarem com a sinònims susceptibilitat per desenvolupar MPOC i prevalença en exposats a tabac. També el grau d’ infradiagnòstic, determinar altres factors de risc per la MPOC diferents de l’ edat i els paquets-any , com són l’ exposició laboral, el dèficit d’ alfa-1 antitripsina i la presència de patologia cardiovascular.
Vam determinar quins eren els símptomes respiratoris que s’ associaven amb més freqüència amb el patró d’ obstrucció parcialment irreversible.
L’ estudi va demostrar que la patologia cardiovascular era més prevalent en els pacients amb MPOC i que la seva presència orientava a pensar que el pacient estava afectat de MPOC ( tenir PCV augmentava 1,7 vegades la susceptibilitat).
També es va concloure que la MPOC era un factor de risc independent per l’ existència de patologia cardiovascular, com ho són el tabac, la hipertensió, la dislipèmia...
L’ estudi ens va permetre fer una validació externa d’ un qüestionari de cribratge per MPOC en exposats a tabac, en l’ àmbit de l’ Atenció Primària , basat en l’ edat, els paquets-any, el IMC i uns pocs símptomes, realitzat per Price i col·laboradors, que ens va semblar d’ una gran utilitat per la seva simplicitat i sensibilitat.
En analitzar els resultats del nostre estudi, per establir l’ associació entre la MPOC i els diferents paràmetres avaluats i evitar variables confusores, vam identificar variables molt similars a les que contenia el qüestionari de Price, als que vam incorporar l’ existència d’ antecedent d’ exposició laboral de risc i de tenir patologia cardiovascular. Amb aquest nou model de qüestionari afinàvem molt més en el cribratge de la MPOC en els nostres pacients exposats al tabac, permetent-nos detectar a aquells que tenen més susceptibilitat per desenvolupar la malaltia.Chronic obstructive pulmonary disease (COPD) characterized by the presence of chronic, poorly reversible obstruction of airflow is a preventable and treatable disease. The most frequent etiology in our area is tobacco. It is a common cause of morbidity and mortality and a major cause of hospitalization in our area, being the final stage when the disease leads to greater spending on healthcare. Not all smokers develop COPD, there must be a genetic susceptibility and the occurrence of a number of favouring factors (packs-year cumulative, age, occupational or environmental exposure to toxic breathing ...) It is known in the literature the existence of an under diagnosing of the disease, partly due to the ignorance of the population about the importance of certain symptoms and partly because professionals do not look for the disease systematically enough. An important foundation in the fight against the disease is early detection. In order to study our population and try to stop the growth of COPD, we decided to make a study of screening in the field of primary care in the more likely population to have the disease. To do so, we made a validated survey of occupational exposure and respiratory symptoms and a spirometry to every smoker or former smoker, who was aged 45 years or more in 2006. The fact of making the spirometry in the PCC (Primary Care Center) facilitated the participation of patients, because of the closeness, in order to adapt to their schedules. The execution of spirometry by trained technician from the service Pneumology in the PCC assured a high percentage of correctly performed spirometry. The study allowed detecting diagnostic errors, confirming existing diagnoses of COPD and diagnosing new COPD patients, avoiding the over diagnosing of asthmatic smokers as if they were COPD patients, through the use of treatment inhaled corticosteroids and beta-2 for 4 weeks. We could find the susceptibility of our smoking population to suffer the disease. The work used as synonyms susceptibility to develop COPD and prevalence in people exposed to tobacco, the degree of under diagnosing, determine risk factors for COPD apart form age and year-packages, such as the occupational exposure, the deficit of alpha-1 antitrypsin and the presence of cardiovascular disease. We determined which respiratory symptoms were more often associated with the pattern of obstruction partially irreversible. The study showed that cardiovascular disease was more prevalent in patients with COPD and that their presence led to think that the patient was suffering from COPD (PCV had increased 1.7 times the susceptibility). We also conclude that COPD was an independent risk factor for the existence of cardiovascular disease, as smoking, hypertension, dyslipidemia ... The study allowed us to have an external validation of a screening questionnaire for COPD patients exposed to tobacco in the field of primary care based on age, package-year, BMI and few symptoms conducted by Price and colleagues, which we find it has a great utility for its simplicity and sensitivity. In analyzing the results of our study to establish the association between COPD and the different evaluated parameters and to avoid confusing variables, we identify variables similar to those contained in the questionnaire of Price. We incorporated the existence of antecedent of occupational risk exposure and the fact of having cardiovascular disease. With this new questionnaire we improved a lot in the screening of COPD in our patients exposed to tobacco, allowing us to detect those who are more susceptible to developing the disease.
43
Buisson, Anthony. "Etude du comportement des macrophages vis-à-vis des Escherichia Coli adhérents et invasifs islés de patients atteints de maladie de Crohn en fonction des facteurs de susceptibilité de l'hôte." Thesis, Clermont-Ferrand 1, 2016. http://www.theses.fr/2016CLF1MM16.
Full textAbstract:
La maladie de Crohn (MC) est une maladie inflammatoire chronique de l’intestin (MICI), dont la physiopathologie résulterait d’une interaction anormale entre le microbiote intestinal et le système immunitaire de l’hôte sous l’influence de facteurs génétiques et environnementaux. Au sein de ce microbiote, les E. coli adhérents et invasifs (AIEC) colonisent la muqueuse iléale des patients atteints de la MC et sont capables de survivre et se multiplier à l’intérieur des macrophages. Par ailleurs, les objectifs thérapeutiques de la MC et notamment la cicatrisation muqueuse endoscopique nécessitent des endoscopies répétées, peu acceptables du point de vue des patients. Parmi les moyens alternatifs, la calprotectine fécale est le marqueur fécal de référence même si ses performances semblent diminuées dans certaines situations comme la maladie iléale pure. Le premier objectif de ces travaux étaient de comparer la capacité des macrophages dérivés de monocytes (MDM) issus de patients atteints de MC, de rectocolite hémorragique (RCH) ou de sujets sains à contrôler l’infection par les AIEC et d’identifier les facteurs associés à cette multiplication des AIEC et notamment le rôle des polymorphismes génétiques associés à la MC en lien avec l’autophagie. Les AIEC se multipliaient de manière plus importante que la souche non pathogène K12 dans les macrophages quel que soit leur origine. L’entrée des AIEC (1h post- infection) ne variait pas en fonction de la provenance des macrophages. La survie des AIEC était augmentée dans les MDM issus de patients MC comparés à ceux issus de RCH ou de sujets contrôles. En analyse multivariée, cette survie était positivement corrélée à la sécrétion d’IL1β mais était diminuée en présence des variants à risque pour ULK1 (p=0,046) et XBP1 (p=0,014). Les MDM issus de patients MC étaient incapable de contrôler la multiplication des AIEC contrairement à ceux issus de RCH ou de sujets contrôles d’autant plus en présence du variant à risque pour IRGM (p=0,045). L’infection des MDM de patients MC par les bactéries AIEC induit un profil de sécrétion cytokinique pro-inflammatoire. La deuxième partie de ces travaux avait pour but de comparer les performances de la chitinase 3-like 1 fécale (CHI3L1), une protéine de l’hôte interagissant avec un facteur de virulence des AIEC, et la métalloprotéase matricielle 9 (MMP-9) pour détecter l’activité inflammatoire endoscopique de la MC en comparaison du marqueur fécal de référence, la calprotectine. Les taux de CHI3L1, de MMP-9 et de calprotectine fécales étaient corrélés au ‘Crohn’s Disease Endoscopic Index of Severity’ (CDEIS) et étaient significativement augmentés en présence d’ulcérations endoscopiques. En cas d’atteinte iléale pure, la CHI3L1 fécale semblait mieux corrélée au CDEIS que la calprotectine fécale. Le seuil de CHI3L1 fécale de 15 ng/g présentait de meilleures performances que la calprotectine fécale pour détecter la présence d’ulcérations endoscopiques. La MMP-9 étaient un marqueur performant pour détecter la présence de lésions endoscopiques dans les MICI. En conclusion, nous avons montré qu’il existe un défaut des macrophages à contrôler l’infection par les bactéries AIEC chez les patients atteints de MC en rapport avec les variants à risque impliqués dans l’autophagie conduisant à un phénotype de macrophages pro-inflammatoires. La CHI3L1 fécale, connue comme une protéine de l’hôte interagissant avec un facteur de virulence des AIEC, tout comme la MMP-9 semblent être de bons marqueurs d’activité endoscopique dans les MICICrohn's disease (CD) is a chronic inflammatory bowel disease (IBD) whose pathophysiology results from an abnormal interaction between the gut microbiota and the host's immune system under the influence of genetic and environmental factors. . Within this microbiota, adherent and invasive E. coli (AIEC) colonize the ileal mucosa of patients with CD and are able to survive and multiply within macrophages. Moreover, the therapeutic objectives of CD, and especially endoscopic mucosal healing, require repeated endoscopies, which are not acceptable from the patients' point of view. Among alternative means, fecal calprotectin is the fecal marker of reference even if its performance seems to be diminished in certain situations like pure ileal disease. The primary objective of this work was to compare the ability of monocyte-derived macrophages (MDM) from patients with CD, ulcerative colitis (UC) or healthy subjects to control AIEC infection and to identify associated with this multiplication of AIEC and in particular the role of genetic polymorphisms associated with CD in connection with autophagy. AIEC multiplied more than non-pathogenic strain K12 in macrophages irrespective of their origin. The entry of the AIEC (1h post-infection) did not vary according to the origin of the macrophages. The survival of AIEC was increased in MDM from MC patients compared to those from HCR or control subjects. In multivariate analysis, this survival was positively correlated with the secretion of IL1β but was decreased in the presence of the variants at risk for ULK1 (p = 0.046) and XBP1 (p = 0.014). MDM from MC patients were unable to control the multiplication of AIEC, unlike those from HCR or control subjects, especially in the presence of the variant at risk for IRGM (p = 0.045). Infection of MDM from MC patients by AIEC bacteria induces a pro-inflammatory cytokine secretion pattern. The second part of this work aimed to compare the performance of faecal chitinase 3-like 1 (CHI3L1), a host protein interacting with AIEC virulence factor, and matrix metalloprotease 9 (MMP-9). to detect the endoscopic inflammatory activity of MC in comparison with the standard fecal marker, calprotectin. Fecal CHI3L1, MMP-9 and calprotectin levels were correlated with Crohn's Disease Endoscopic Index of Severity (CDEIS) and were significantly increased in the presence of endoscopic ulcerations. In case of pure ileal involvement, fecal CHI3L1 seemed better correlated with CDEIS than fecal calprotectin. The fecal CHI3L1 threshold of 15 ng / g showed better performance than faecal calprotectin in detecting the presence of endoscopic ulcerations. MMP-9 was a powerful marker for detecting the presence of endoscopic lesions in IBD. In conclusion, we have shown that there is a macrophage defect to control infection by AIEC bacteria in patients with CD related to atopic risk variants involved in autophagy leading to a pro-inflammatory macrophage phenotype . Fecal CHI3L1, known as a host protein interacting with AIEC virulence factor, as well as MMP-9 appear to be good markers of endoscopic activity in IBD
44
Clot, Fabienne. "Etude de la composante génétique de la maladie coeliaque : analyse des gènes HLA de susceptibilité et recherche d'autres facteurs de risque génétique." Paris 11, 2000. http://www.theses.fr/2000PA11T010.
Full textAbstract:
La maladie cœliaque (MC) de l'enfant est une des causes principales de malabsorption intestinale due à une intolérance permanente aux protéines du gluten, contenues dans certaines céréales. Son déterminisme est multifactoriel impliquant des facteurs de risque génétique et environnementaux. La région HLA est étroitement associée à la MC par certains allèles des gènes HLA-DR et DQ, mais n'explique pas toute la susceptibilité génétique. Partant de ce constat, nous avons cherché à affiner la composante immunogénétique, à localiser d'autres facteurs de risque génétique et à tester plusieurs gènes candidats. Dans la région HLA, nous avons mis en évidence l'implication de l'hétérodimère DR53 dans la susceptibilité à la MC. Nous avons montré, d'une part que les patients porteurs des hétérodimères DR53 et DQ2 représentent les patients les plus à risque de développer la MC et d'autre part que les peptides de la gliadine sont capables de se fixer avec une bonne affinité à l'hétérodimère DR53. Concernant la localisation de facteurs de risque génétique autres queHLA, nous avons recherché une liaison génétique entre la MC et des marqueurs polymorphes répartis sur l'ensemble du génome, par la méthode des paires de germains atteints. Nous avons mis en évidence une région candidate, en 5qter, dans la susceptibilité génétique à la MC, au sein de la population italienne. Parallèlement à la localisation de facteurs de risque génétique par cartographie de liaison, il est possible de définir a priori des gènes candidats qui, de par leur fonction, pourraient être impliqués dans la physiopathologie de la MC. Cette approche utilise un polymorphisme du gène candidat, ou d'un marqueur proche, dans une analyse statistique : le Transmission Disequilibrium Test, qui permet de tester simultanément l'association et la liaison génétique. Nous avons entrepris une telle approche pour trois gènes : le gène Cytotoxic T Lymphocyte Associated-4 (CTLA-4) codant pour une protéine membranaire, qui se comporte comme un régulateur négatif de l'activation lymphocytaire T et les gènes dipeptidylpeptidase IV (DPPIV) et aminopeptidase N (APN) codant pour des peptidases intervenant dans la digestion intestinale de peptides et dans le système immunitaire. La recherche de polymorphismes a permis l'identification de 2 polymorphismes dans l'intron 8 du gène DPPIV. Les données statistiques suggèrent que ces trois gènes ne semblent pas être impliqués dans la susceptibilité à la MC, du moins au sein de la population italienne.
45
Richard, Florence. "Predispositions a la baisse des fonctions cognitives et aux demences : impact des facteurs de susceptibilite genetique associes au risque vasculaire (doctorat)." Lille 2, 1999. http://www.theses.fr/1999LIL2T005.
Full text
46
Stingelin, Sibylle. "Analyse des HLA de classe II dans la polyarthrite rhumatoïde (PR) : rôles dans la susceptibilité et la sévérité de la maladie /." Genève : [s.n.], 2003. http://www.unige.ch/cyberdocuments/theses2003/StingelinS/these.pdf.
Full text
47
Chia, Tio-Huat. "Growth, distribution and susceptibility of major rat species to anticoagulant rodenticides and the inheritance of resistance to warfarin in Rattus tiomanicus in oil palm plantations in peninsular Malaysia." Thesis, University of Reading, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342461.
Full text
48
Toussirot, Éric. "Epitope partage, reponse cellulaire specifique de la glycoproteine gp 110 du virus d'epstein-barr et polyarthrite rhumatoide : relation avec la susceptibilite et la severite de la maladie et implications physiopathologiques." Besançon, 1999. http://www.theses.fr/1999BESA3710.
Full text
49
Delahaye-Sourdeix, Manon. "Moving beyond Genome-Wide Association Studies." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10238.
Full textAbstract:
Les études d'association à grande échelle consistent à étudier la corrélation de plusieurs millions de polymorphismes nucléotidiques avec un risque de cancer chez des milliers d'individus, sans avoir besoin de connaissances préalables sur la fonction biologique de ces variants. Ces études ont été utiles pour établir des hypothèses étiologiques et comprendre l'architecture génétique sous-jacente de plusieurs maladies humaines. Cependant, la plupart des facteurs héréditaires de ces maladies restent inexpliqués. Une partie de cette variation pourrait venir de variants rares qui ne sont pas ciblés par les puces de génotypage actuelles ou encore de variants avec un effet plus modéré voire faible pour lesquels une détection par les études d'association actuelles n'est pas envisageable. Dans ce contexte et comme illustré dans cette thèse, les récentes études d'association peuvent maintenant servir de point de départ pour de nouvelles découvertes, en mettant en place des stratégies innovantes pour étudier à la fois les variants rares et les maladies rares. Nous avons plus particulièrement exploré ces techniques dans le cadre du cancer du poumon, des voies aérodigestives et du lymphome de Hodgkins. L'utilisation de la bioinformatique pour combiner les résultats des études avec d'autres sources d'information, l'intégration de différents types de données génomiques ainsi que l'investigation de la relation entre altérations germinales et somatiques représentent les principales opportunités poursuivies dans ce travail de thèseGenome-wide association (GWA) studies consist in testing up to one million (or more) single nucleotide polymorphisms (SNPs) for their association with cancer risk in thousands of individuals, without requiring any prior knowledge on the functional significance of these variants. These studies have been valuable for establishing etiological hypotheses and understanding the underlying genetic architecture of human diseases. However, most of the heritable factors of these traits remain unexplained. Part of this variation may come from rarer variants that are not targeted by current genotyping arrays or variants with moderate to low effects for which detection by current GWA studies is impractical. In this context and as illustrated in this thesis, GWA studies can now serve as starting points towards further discoveries, looking for new strategies to study both rarer variants and rarer diseases. We have specifically explored these approaches in the context of lung cancer, head and neck cancer and Hodgkin's lymphoma. The use of bioinformatics to combine recent GWA study results with other sources of information, the integration of different types of genomic data as well as the investigation of the interrelationship between germline and somatic alterations represent the main opportunities pursued in this thesis work
50
Renault, Anne-Laure. "Identification de facteurs génétiques modifiant le risque de cancer chez les porteuses d'une mutation constitutionnelle d'ATM & profil tumoral des tumeurs du sein associées à une perte de fonction d'ATM." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS389/document.
Full textAbstract:
L’ataxie-télangiectasie (A-T) est une maladie génétique récessive rare de l’enfant, caractérisée par un syndrome neurodégénératif, un déficit immunitaire et des télangiectasies cutanées. La maladie est causée par des mutations bialléliques inactivatrices dans le gène ATM (Ataxia-Telangiectasia Mutated). La maladie implique aussi un risque élevé de développer des cancers, en particulier des leucémies et des lymphomes. Les sujets atteints d’A-T ont également une radiosensibilité accrue. Les femmes de plus de 50 ans apparentées à un enfant atteint d'A-T, porteuses d’une seule copie mutée d’ATM (HetAT), ont un risque plus élevé de cancer du sein que les femmes de la population générale (RR 4,94, 95%CI 1,90 - 12,09). Des études épidémiologiques confirment l’implication d’ATM dans la prédisposition au cancer du sein et montrent que 0,5% à 1% de la population porte une mutation délétère dans ce gène mais le risque de cancer pour les individus HetAT sont encore mal estimés. Dans le premier volet de ma thèse, j’ai recherché des facteurs génétiques constitutionnels pouvant modifier le risque de cancer chez les femmes de la cohorte CoF-AT (cohorte de femmes apparentées à un enfant atteint d’A-T). J’ai ensuite décrit les caractéristiques histologiques et génomiques des tumeurs du sein de sujets HetAT afin d’identifier des biomarqueurs permettant de discriminer les tumeurs ATM des autres tumeurs.Les résultats obtenus dans la première partie de mes travaux menés sur un échantillon de 284 individus HetAT et 174 individus non-HetAT issus de 103 familles A-T montrent que les individus HetAT ont des télomères plus longs que leurs apparentés non-HetAT (p=0.0008). En revanche, la longueur des télomères n’est pas associée au risque de cancer dans cette population. De plus, le SNP rs9257445 (ZNF311) qui est associé à la longueur des télomères chez les individus HetAT n’est pas lui non plus associé au risque de cancer. En revanche les SNPs rs6060627 (BCL2L1) et rs2380205 (ANKRD16) modifient le risque de cancer chez les femmes HetAT et non-HetAT.Les résultats obtenus dans la deuxième partie de la thèse à partir de la description morphologique de 41 tumeurs mammaires montrent que les tumeurs des porteurs d’une mutation dans ATM sont majoritairement de sous-type luminal B. D’un point de vue moléculaire, les 23 tumeurs ATM étudiées ne présentent pas la signature BRCAness associée à de grandes pertes chromosomiques. En revanche, nous avons montré que la majorité des tumeurs ATM sont tétraploïdes et présentent une perte d’hétérozygotie au locus 11q22-23 entrainant une inactivation de l’allèle normal d’ATM dans les tumeurs. De plus, l’analyse du nombre de copies réalisée sur ces tumeurs montre une signature ATM impliquant des pertes des loci 13q14.11-q14.3, 21p11.2-p11.1 et 22q11.23.L’ensemble de ces travaux aura permis de mieux caractériser les caractéristiques génétiques des femmes de la cohorte CoF-AT et de mettre en évidence des bio-marqueurs des tumeurs ATMInherited biallelic mutations in the ATM gene cause Ataxia Telangiectasia (A-T), a multisystemic disorder characterized by neurological, cutaneous and immunological abnormalities. The disease is associated with an elevated risk of malignancies, particularly of lymphoma or leukemia, and a high radiosensitivity. Epidemiological studies have shown that female heterozygote carriers (HetAT) younger than 50 years are at increased risk of breast cancer, as compared to women from the general population (RR 4,94, 95%CI 1,90 - 12,09). Despite the rarity of A-T disease, 0.5 to 1% of the population is estimated to be HetAT. Epidemiological studies have confirmed that some specific truncating or missense variants in ATM are associated with increased breast cancer risk but this risk is not yet well estimated. The first part of my thesis project has consisted in characterizing inherited genetic factors modifying cancer risk in women participating in the prospective cohort CoF-AT (“cohorte de femmes apparentées à un enfant atteint d’A-T). In the second part of my work, I described the morphological and molecular features of ATM breast tumours with the aim to identify biomarkers allowing to distinguished ATM-associated tumours from sporadic tumours.Assessment of the contribution of inherited factors such as SNPs of telomere length on the risk of cancer was performed on 284 HetAT individuals and 174 non-HetAT individuals belonging to 103 A-T families. We showed that HetAT individuals have longer telomeres than their non-HetAT counterparts (p=0.0008). However, we found that telomere length was not associated with cancer risk in our study population. The SNP rs9257445 (ZNF311), which is associated with telomere length in HetAT participants, was not associated with cancer risk. Conversely, SNPs rs6060627 (BCL2L1) and rs2380205 (ANKRD16) modified cancer risk in HetAT and non-HetAT women.Pathology review of 41 ATM-associated breast tumours revealed that these tumours mostly belonged to luminal B molecular subtype. The molecular characterization of 23 ATM-associated tumours did not revealed the BRCAness profile associated with Large-Scale State Transitions. However, we found that ATM tumours were mostly tetraploïd and observed loss of heterozygosity at 11q22-23 in the majority of the tumours and loss of ATM wild type allele. Moreover, copy number losses at loci 13q14.11-q14.3, 21p11.2-p11.1 and 22q11.23 appeared to be specific of ATM tumours.Altogether, this project allowed to better characterize the genetic background of the CoF-AT participants and to highlight biomarkers of ATM breast tumours