Genetic variations in genes involved in heparan sulphate biosynthesis are associated with Plasmodium falciparum parasitaemia: a familial study in Burkina Faso

<p>Abstract</p> <p>Background</p> <p>There is accumulating evidence that host heparan sulphate proteoglycans play an important role in the life cycle of <it>Plasmodium </it>through their heparan sulphate chains, suggesting that genetic variations in genes involved in heparan sulphate biosynthesis may influence parasitaemia. Interestingly, <it>Hs3st3a1 </it>and <it>Hs3st3b1 </it>encoding enzymes involved in the biosynthesis of heparan sulphate are located within a chromosomal region linked to <it>Plasmodium chabaudi </it>parasitaemia in mice. This suggests that <it>HS3ST3A1 </it>and <it>HS3ST3B1 </it>may influence <it>P. falciparum </it>parasitaemia in humans.</p> <p>Methods</p> <p>Polymorphisms within <it>HS3ST3A1 </it>and <it>HS3ST3B1 </it>were identified in 270 individuals belonging to 44 pedigrees and living in Burkina Faso. Linkage and association between parasitaemia and the polymorphisms were assessed with MERLIN and FBAT. A genetic interaction analysis was also conducted based on the PGMDR approach.</p> <p>Results</p> <p>Linkage between <it>P. falciparum </it>parasitaemia and the chromosomal region containing <it>HS3ST3A1 </it>and <it>HS3ST3B1 </it>was detected on the basis of the 20 SNPs identified. In addition, rs28470223 located within the promoter of HS3ST3A1 was associated with <it>P. falciparum </it>parasitaemia, whereas the PGMDR analysis revealed a genetic interaction between <it>HS3ST3A1 </it>and <it>HS3ST3B1</it>. Seventy-three significant multi-locus models were identified after correcting for multiple tests; 37 significant multi-locus models included rs28470223, whereas 38 multi-locus models contained at least one mis-sense mutation within HS3ST3B1.</p> <p>Conclusion</p> <p>Genetic variants of <it>HS3ST3A1 </it>and <it>HS3ST3B1 </it>are associated with <it>P. falciparum </it>parasitaemia. This suggests that those variants alter both the function of heparan sulphate proteoglycans and <it>P. falciparum </it>parasitaemia.</p

Striatal molecular signature of subchronic subthalamic nucleus high frequency stimulation in parkinsonian rat

International audienceThis study addresses the molecular mechanisms underlying the action of subthalamic nucleus high frequency stimulation (STN-HFS) in the treatment of Parkinson's disease and its interaction with levodopa (L-DOPA), focusing on the striatum. Striatal gene expression profile was assessed in rats with nigral dopamine neuron lesion, either treated or not, using agilent microarrays and qPCR verification. The treatments consisted in anti-akinetic STN-HFS (5 days), chronic L-DOPA treatment inducing dyskinesia (LIDs) or the combination of the two treatments that exacerbated LIDs. STN-HFS modulated 71 striatal genes. The main biological processes associated with the differentially expressed gene products include regulation of growth, of apoptosis and of synaptic transmission, and extracellular region is a major cellular component implicated. In particular, several of these genes have been shown to support survival or differentiation of striatal or of dopaminergic neurons. These results indicate that STN HFS may induce widespread anatomo-functional rearrangements in the striatum and create a molecular environment favorable for neuroprotection and neuroplasticity. STN-HFS and L-DOPA treatment share very few common gene regulation features indicating that the molecular substrates underlying their striatal action are mostly different; among the common effects is the down-regulation of Adrb1, which encodes the adrenergic beta-1-receptor, supporting a major role of this receptor in Parkinson's disease. In addition to genes already reported to be associated with LIDs (preprodynorphin, thyrotropin-releasing hormone, metabotropic glutamate receptor 4, cannabinoid receptor 1), the comparison between DOPA and DOPA/HFS identifies immunity-related genes as potential players in L-DOPA side effects

Gene expression profiling in blood from cerebral malaria patients and mild malaria patients living in Senegal

International audienceBACKGROUND:Plasmodium falciparum malaria remains a major health problem in Africa. The mechanisms of pathogenesis are not fully understood. Transcriptomic studies may provide new insights into molecular pathways involved in the severe form of the disease.METHODS:Blood transcriptional levels were assessed in patients with cerebral malaria, non-cerebral malaria, or mild malaria by using microarray technology to look for gene expression profiles associated with clinical status. Multi-way ANOVA was used to extract differentially expressed genes. Network and pathways analyses were used to detect enrichment for biological pathways.RESULTS:We identified a set of 443 genes that were differentially expressed in the three patient groups after applying a false discovery rate of 10%. Since the cerebral patients displayed a particular transcriptional pattern, we focused our analysis on the differences between cerebral malaria patients and mild malaria patients. We further found 842 differentially expressed genes after applying a false discovery rate of 10%. Unsupervised hierarchical clustering of cerebral malaria-informative genes led to clustering of the cerebral malaria patients. The support vector machine method allowed us to correctly classify five out of six cerebral malaria patients and six of six mild malaria patients. Furthermore, the products of the differentially expressed genes were mapped onto a human protein-protein network. This led to the identification of the proteins with the highest number of interactions, including GSK3B, RELA, and APP. The enrichment analysis of the gene functional annotation indicates that genes involved in immune signalling pathways play a role in the occurrence of cerebral malaria. These include BCR-, TCR-, TLR-, cytokine-, FcεRI-, and FCGR- signalling pathways and natural killer cell cytotoxicity pathways, which are involved in the activation of immune cells. In addition, our results revealed an enrichment of genes involved in Alzheimer's disease.CONCLUSIONS:In the present study, we examine a set of genes whose expression differed in cerebral malaria patients and mild malaria patients. Moreover, our results provide new insights into the potential effect of the dysregulation of gene expression in immune pathways. Host genetic variation may partly explain such alteration of gene expression. Further studies are required to investigate this in African populations

Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.

Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia

NCR3 polymorphism, haematological parameters, and severe malaria in Senegalese patients

Background Host factors, including host genetic variation, have been shown to influence the outcome of Plasmodium falciparum infection. Genome-wide linkage studies have mapped mild malaria resistance genes on chromosome 6p21, whereas NCR3-412 polymorphism (rs2736191) lying within this region was found to be associated with mild malaria. Methods Blood samples were taken from 188 Plasmodium falciparum malaria patients (76 mild malaria patients, 85 cerebral malaria patients, and 27 severe non-cerebral malaria patients). NCR3-412 (rs2736191) was analysed by sequencing, and haematological parameters were measured. Finally, their association with clinical phenotypes was assessed. Results We evidenced an association of thrombocytopenia with both cerebral malaria and severe non-cerebral malaria, and of an association of high leukocyte count with cerebral malaria. Additionally, we found no association of NCR3-412 with either cerebral malaria, severe non-cerebral malaria, or severe malaria after grouping cerebral malaria and severe non-cerebral malaria patients. Conclusions Our results suggest that NCR3 genetic variation has no effect, or only a small effect on the occurrence of severe malaria, although it has been strongly associated with mild malaria. We discuss the biological meaning of these results. Besides, we confirmed the association of thrombocytopenia and high leukocyte count with severe malaria phenotypes

Platelets Alter Gene Expression Profile in Human Brain Endothelial Cells in an In Vitro Model of Cerebral Malaria

Platelet adhesion to the brain microvasculature has been associated with cerebral malaria (CM) in humans, suggesting that platelets play a role in the pathogenesis of this syndrome. In vitro co-cultures have shown that platelets can act as a bridge between Plasmodium falciparum-infected red blood cells (pRBC) and human brain microvascular endothelial cells (HBEC) and potentiate HBEC apoptosis. Using cDNA microarray technology, we analyzed transcriptional changes of HBEC in response to platelets in the presence or the absence of tumor necrosis factor (TNF) and pRBC, which have been reported to alter gene expression in endothelial cells. Using a rigorous statistical approach with multiple test corrections, we showed a significant effect of platelets on gene expression in HBEC. We also detected a strong effect of TNF, whereas there was no transcriptional change induced specifically by pRBC. Nevertheless, a global ANOVA and a two-way ANOVA suggested that pRBC acted in interaction with platelets and TNF to alter gene expression in HBEC. The expression of selected genes was validated by RT-qPCR. The analysis of gene functional annotation indicated that platelets induce the expression of genes involved in inflammation and apoptosis, such as genes involved in chemokine-, TREM1-, cytokine-, IL10-, TGFβ-, death-receptor-, and apoptosis-signaling. Overall, our results support the hypothesis that platelets play a pathogenic role in CM

Association des IgE avec la resistance humaine a Schistosoma mansoni en region endemique. Effet antagoniste des IgG4

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : T 83916 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Immunologie génétique de la résistance humaine au paludisme à P. Falciparum (Rôle des sous-classes d'IgG dans la protection. Contrôle génétique de la charge parasitaire sanguine et de la réponse immune spécifique)

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Contrôle génétique de la résistance au paludisme chez l'homme (des études familiales d'association génétique à l'analyse de l'expression des gènes dans des modèles expérimentaux du paludisme humain)

Le paludisme est une maladie multifactorielle complexe. Il existe de plus en plus d arguments en faveur d un contrôle génétique de l infection, mais de nombreux gènes impliqués restent à découvrir. Ce travail regroupe des résultats provenant d analyses familiales d association génétique et d analyses génomiques issus de modèles expérimentaux du neuropaludisme afin de mieux comprendre le contrôle génétique et la pathogénèse du paludisme. Des polymorphismes de 3 gènes (IL12B, NCR3, LTA) situés dans les régions chromosomiques 5q31.33 et 6p21.23 liées au paludisme ont été analysés au sein de populations d étude vivant au Burkina faso en zone d endémie palustre. Cette approche a permis de détecter les associations de polymorphismes situés dans le promoteur des gènes codant pour Nkp30 et la lymphotoxine a avec respectivement les accès palustres et la parasitémie : le niveau d expression de ces gènes pourrait être impliqué dans le contrôle et le devenir de l infection. Une étude exhaustive de l expression des gènes a d ailleurs permis de détecter une signature transcriptionnelle du tissu cérébral à l infection par P. berghei ANKA discriminant les souris sensibles et résistantes au neuropaludisme. Le rôle de l endothélium cérébral qui est au coeur de cette pathologie a été étudié à travers un modèle in vitro de neuropaludisme. L analyse du transcriptome de cellules endothéliales cérébrales humaines a ainsi permis de mettre en évidence le rôle potentiellement actif des cellules endothéliales dans la pathogénèse en précisant l influence du TNFa, des plaquettes et des érythrocytes parasités par P. falciparum dans ce modèle. Les données concernant ces 2 modèles expérimentaux permettent de proposer de nouveaux gènes et voies physiologiques impliqués dans le neuropaludisme humain. Ce travail montre l intérêt d utiliser des approches génétiques et génomiques dans la découverte de nouveaux gènes impliqués dans la pathogénèse et le contrôle génétique du paludisme chez l homme.Malaria is a complex multifactorial disease. There is a growing body of evidence in favor of a genetic control of the infection, but many genes involved remain to be discovered. This work includes the results of family-based association analyses and genomic analyses from experimental models of cerebral malaria in order to better understand the genetic control and pathogenesis of malaria. Polymorphisms of 3 genes (IL12B, NCR3 and LTA) located in the genetic regions 5q31.33 and 6p21.23 previously linked to malaria were analyzed in study populations living in Burkina faso in malaria endemic area. This approach provided evidence for the association of polymorphisms in the promoter of genes coding for Nkp30 and lymphotoxin a with mild malaria attack and parasitemia respectively. The expression level of these 2 genes could be involved to explain the observed associations and also could be involved in the control of the disease. Besides, the use of microarray analyses allowed us to detect an early transcriptional response of brain tissue of mice infected by P. berghei ANKA, discriminating susceptible and resistant mice in this experimental model of cerebral malaria. Brain endothelium plays a central role in this pathology. Thus, the study of human brain endothelial cells transcriptome in an in vitro model of cerebral malaria has highlighted the potential active role of the cerebral endothelium in the pathogenesis. Statistical and functional analyses clarified the influence of TNFa, platelets and parasitized red blood cells by P. falciparum used in this model. Synthesis of the results coming from these 2 experimental models allowed us to propose new genes and physiological pathways potentially involved in human cerebral malaria. This work highlights the benefits of using familial genetic approaches and genomic analyses in order to discover new genes and polymorphisms involved in the genetic control of human malaria.AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

TAGOOS: genome-wide supervised learning of non-coding loci associated to complex phenotypes

International audienceGenome-wide association studies (GWAS) associate single nucleotide polymorphisms (SNPs) to complex phenotypes. Most human SNPs fall in non-coding regions and are likely regulatory SNPs, but linkage disequilibrium (LD) blocks make it difficult to distinguish functional SNPs. Therefore, putative functional SNPs are usually annotated with molecular markers of gene regulatory regions and prioritized with dedicated prediction tools. We integrated associated SNPs, LD blocks and regulatory features into a supervised model called TAGOOS (TAG SNP bOOSting) and computed scores genome-wide. The TAGOOS scores enriched and prioritized unseen associated SNPs with an odds ratio of 4.3 and 3.5 and an area under the curve (AUC) of 0.65 and 0.6 for intronic and intergenic regions, respectively. The TAGOOS score was correlated with the maximal significance of associated SNPs and expression quantitative trait loci (eQTLs) and with the number of biological samples annotated for key regulatory features. Analysis of loci and regions associated to cleft lip and human adult height phenotypes recovered known functional loci and predicted new functional loci enriched in transcriptions factors related to the phenotypes. In conclusion, we trained a supervised model based on associated SNPs to prioritize putative functional regions. The TAGOOS scores, annotations and UCSC genome tracks are available here: https: //tagoos.readthedocs.io