Abel

Information about Abel

Published on October 25, 2007

Author: Jolene

Source: authorstream.com

Content

Slide1:  Identification of human genes involved in the response to infectious agents. The example of mycobacterial diseases Slide2:  Human genetics in infectious diseases ? Experimental models Genetic epidemiology Epidemiological observations Mendelian genetics Proof of concept Concept Slide3:   Large individual variability in response to infection INFECTIOUS AGENT INFECTION DISEASE IMMUNE RESPONSE Infectious agent factors (virulence…) Host factors (age, GENES, …) Exposure factors Environmental factors Slide4:  Methods of investigation in humans Rare mutation Common polymorphism Slide5:  HYPOTHESIS-DRIVEN APPROACH MENDELIAN AND COMPLEX INHERITANCE ASSOCIATION STUDIES (Replications) VARIANT DETECTION FUNCTIONAL STUDIES ‘COMMON’ POLYMORPHISMS ‘RARE’ MUTATIONS GENOME-WIDE APPROACH ASSOCIATION STUDIES DIFFERENTIAL EXPRESSION CANDIDATE GENES ANIMAL MODELS HUMAN DATA LINKAGE STUDIES Slide6:  AB CD AC AC AD BC IBD=2 IBD=1 IBD=0 Based on number of parental alleles shared identical by descent (IBD) Expected IBD distribution for a sib-pair IBD = 2 : 0.25 IBD = 1 : 0.5 IBD = 0 : 0.25 LINKAGE ANALYSIS METHODS Classical approach: affected sib-pair method  Test whether affected sibs share more parental alleles than expected Linkage when excess of alleles IBD shared by affected sib-pairs To investigate the role of a chromosomal region (familial)  Study of highly polymorphic markers Slide7:    To test the role of a speficic allele  study of intragenic single nucleotide polymorphisms (SNP) with 2 alleles : (A, T) Population-based case/control studies compare A frequency between affected and unaffected subjects   ASSOCIATION STUDIES : DESIGNS Family-based studies: avoid population stratification and bias due to choice of controls Ex: Transmission Disequilibrium Test (Spielman et al, Am J Hum Genet, 1993) AT TT AT If A is the functional allele or is in linkage disequilibrium with it, it will be transmitted from AT parents to affected children with probability  0.5 AT TT TT Slide8:  Haplotype Map of the Human Genome Goals: Define patterns of genetic variation across human genome Guide selection of SNPs efficiently to “tag” common variants Genome-wide association studies Phase I: 1.3 M markers in 269 people Phase II: +2.8 M markers in 270 people Slide9:  MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL DISEASES (MSMD) Disseminated infections by environmental mycobacteria (EM), BCG No known primary or acquired immunodeficiency Very rare (10-5 – 10-6) but often familial (consanguinity) Mendelian transmission (5 identified genes so far) Slide10:  Macrophage/Dendritic cell T Lymphocyte/ NK Cell Mycobacteria IL12Rb1 IL12Rb2 IFNgR1 IL12 p35 p40 IFNg IFNgR2 STAT1 IFNgR1 IFNgR2 New specific antimycobacterial immunological pathway New therapeutic strategies Slide11:  IL12-Rb1 deficiency and tuberculosis (1) 18 yo Abdo TB BCG-itis Inherited IL12Rb1 deficiency : student from Casablanca No reaction to 3 live BCG No other unusual clinical infectious diseases Well without any prophylactic treatment IL12RB1 mutation: R213W No cellular response to IL12 Slide12:  Inherited IL12Rb1 deficiency : No BCG/NTM disease No IL12-Rb1 expression No cellular responses to IL-12 IL12RB1 mutation: 1721+2T->G                               IL12-Rb1 deficiency and tuberculosis (2) 17 yo 15 yo Pulm TB 8 yo Diss TB Slide13:  Mendelian disorders of the IL12-IFN axis are genetic etiologies for severe forms of tuberculosis: - What is the proportion of ‘Mendelian’ tuberculosis? (in children)?   May common polymorphisms in these genes also predispose to tuberculosis? Conclusion and questions Slide15:  ~ 8 millions new cases per year ~ 90% of infected subjects do not develop the disease ~ 700,000 new cases per year ~ 95% of infected subjects do not develop the disease Tuberculosis (M. tuberculosis) Leprosy (M. leprae) Complex predisposition to common mycobacterial diseases Very large spectrum of clinical manifestations Slide16:  From Gentilini & Duflo, Médecine Tropicale, Flammarion Médecine-Sciences Clinical threshold LEPROSY: Response to M. leprae Slide17:  HYPOTHESIS-DRIVEN APPROACH LEPROSY INHERITANCE ASSOCIATION STUDIES Replication VARIANT DETECTION FUNCTIONAL STUDIES ‘COMMON’ POLYMORPHISMS ‘RARE’ MUTATIONS GENOME-WIDE APPROACH ASSOCIATION STUDIES DIFFERENTIAL EXPRESSION CANDIDATE REGIONS ANIMAL MODELS HUMAN DATA LINKAGE STUDIES Slide18:  LEPROSY: Genome-wide screen Leprosy subtype 86 multiplex families Mira et al, Nat Genet, 2003 Slide19:  Genome-scan - fine mapping 6q25 Slide20:  LD mapping 197 simplex families 2 parents + 1 affected offspring Mira et al, Nature, 2004 64 informative SNPs ( 1 / known gene) Slide24:  PACRG intron 1 PARK2 intron 1 PARK2 exon 1 PACRG exon 1 Bloc B Slide25:  PACRG intron 1 PARK2 intron 1 PARK2 exon 1 PACRG exon 1 Bloc B SNP2 Multivariate analysis SNP1 Slide26:  Snp 1 Snp 2 C T C T T T C T T T T C T T T C C T 1.00 3.2 5.3 [1.3 -7.8] [2.1 -13.5] OR* CI 95% - 0.009 0.0005 P-value - * Estimated by conditional logistic regression C C Slide27:  Replication study in Brazil 587 cases – 388 controls Leprosy subtype 13 significant SNPs (genomic controls) Slide29:  PARK2 / PACRG Slide30:  Ubiquitin-mediated proteolysis Giasson and Lee, Neuron, 2001 New pathway involved in response to mycobacteria: E3 ligase involved in Toll like receptors degradation (Chuang et al, Nat Immunol, 2004) -Parkin involved in regulation of cellular oxidative stress  Functional studies ongoing Slide31:  Variant effect in terms of Relative Risk RR: 1 2 5 10 100 Moderate effect Major effect Mendelian effect Mendelian control in rare phenotypes Rare mutations with causal role demonstrated direct clinical and therapeutic implications information on immunological pathways ( candidate genes) may be involved in more common phenotypes (TB) Genetic predisposition to mycobacterial infections  continuous spectrum Slide32:  Genetic control of more common phenotypes  Common polymorphisms with moderate effect - molecular basis difficult to validate - identification of relevant pathways - may have strong attributable risk (in large populations)  Importance of searching for major gene effects - in specific populations, phenotypes … - implications ~ Mendelian The genetic dissection of infectious diseases needs to combine different strategies and approaches Slide33:  Génétique Humaine des Maladies Infectieuses, INSERM U550, Paris, France Alexandre Alcaïs Guillemette Antoni Jacinta Bustamante Ludovic de Beaucoudrey Ariane Chapgier Orchidée dos Santos Stéphanie Dupuis Claire Fieschi Emmanuelle Jouanguy Daniel Nolan Capucine Picard Brigitte Ranque Natascha Remus Claire Soudais Guillaume Vogt Laurent Abel Jean-Laurent Casanova McGill University, Montreal, Canada Marcelo Mira Tom Hudson Erwin Schurr Laboratoire d’Immunologie, Hôpital Militaire de Rabat, Maroc Jamila El Baghdadi Abdellah Benslimane Hospital of Dermato-Veneorology, Ho Chi Minh City, Vietnam Nguyen Thuc Minh Phuong Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil Milton Moraes

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