The Experts below are selected from a list of 30 Experts worldwide ranked by ideXlab platform

J M Blackwell - One of the best experts on this subject based on the ideXlab platform.

  • Genetics of host resistance and susceptibility to intramacrophage pathogens: a study of multicase families of tuberculosis, leprosy and leishmaniasis in north-eastern Brazil
    International journal for parasitology, 1998
    Co-Authors: J M Blackwell
    Abstract:

    Abstract Genetic analysis of disease phenotypes segregating in recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively “scan” the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions were implicated which, because they show conserved synteny with regions of the Human genome, immediately provide candidate gene regions for Human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes (Nramp 1) was identified for its role in controlling a range of intramacrophage pathogens, including leishmanial, salmonella and mycobacterial infections. In recent studies, multicase families of visceral leishmaniasis, tuberculosis and leprosy, from north-eastern Brazil have been analysed to determine the role of these candidate genes/regions in Humans. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to these diseases in this population. Family-based linkage analyses (e.g., combined segregation and linkage analysis; sib-pair analyses) and transmission disequilibrium testing have been used to examine the role of four regions in disease susceptibility and/or immune response phenotypes. Results to date demonstrate: (1) the major histocompatibility complex (MHC: H-2 in mouse, HLA in Humans: mouse Chromosome 17/Human 6p; candidates class II and class III including tumour necrosis factor α β genes) shows both linkage to, and allelic association with, leprosy per se, but is only weakly associated with visceral leishmaniasis and shows neither linkage to, nor allelic association with, tuberculosis; (2) no evidence for linkage between NRAMP1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse Chromosome 1/Human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis; (3) the region of Human Chromosome 17q (candidates NOS2A, SCYA2-5) homologous with distal mouse Chromosome 11 is linked to tuberculosis susceptibility; and (4) the “T helper 2” cytokine gene cluster (proximal murine Chromosome 11/Human 5p; candidates IL4, IL5, IL9, IRF1, CD14) is not linked to Human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. The demonstration of an allelic association between IL4 and immune response to mycobacterial antigen may provide a genetic explanation for the inverse association recently demonstrated between delayed hypersensitivity T helper 1 responses to mycobacterial antigen and atopic disorder in Japanese children. These studies demonstrate that the “mouse-to-Human” strategy, refined by our knowledge of the Human immune response to infection, can lead to the identification of important candidate gene regions in Humans.

  • immunogenetics of leishmanial and mycobacterial infections the belem family study
    Philosophical Transactions of the Royal Society B, 1997
    Co-Authors: J M Blackwell, E N Miller, G F Black, C S Peacock, J J Shaw, D Sibthorpe, D Gnananandha, Fernando Tobias Silveira, Z Linslainson, F Ramos
    Abstract:

    In the 1970s and 1980s, analysis of recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively 'scan' the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions of the genome were implicated in the control of infections caused by different Leishmania species which, because they show conserved synteny with regions of the Human genome, immediately provides candidate gene regions for Human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes (Nramp1) was identified for its role in controlling a range of intramacrophage pathogens including leishmania, salmonella and mycobacterium infections. In recent studies, multicase family data on visceral leishmaniasis and the mycobacterial diseases, tuberculosis and leprosy, have been collected from north-eastern Brazil and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family-based linkage analyses (combined segregation and linkage analysis; sib-pair analysis), which have the power to detect linkage between marker loci in candidate gene regions and the putative disease susceptibility genes over 10-20 centimorgans, and transmission disequilibrium testing, which detects allelic associations over 1 centimorgan (ca. 1 megabase), have been used to examine the role of four regions in determining disease susceptibility and/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse Chromosome 17/Human 6p; candidates class II and class III including TNF alpha/beta genes) shows both linkage to, and allelic association with, leprosy per se, but is only weakly associated with visceral leishmaniasis and shows neither linkage to nor allelic association with tuberculosis; (ii) no evidence for linkage between NRAMP1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse Chromosome 1/Human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis could be demonstrated in this Brazilian population; (iii) the region of Human Chromosome 17q (candidates NOS2A, SCYA2-5) homologous with distal mouse Chromosome 11, originally identified as carrying the Scl1 gene controlling healing versus nonhealing responses to Leishmania major, is linked to tuberculosis susceptibility; and (iv) the 'T helper 2' cytokine gene cluster (proximal murine Chromosome 11/Human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. major infection, is not linked to Human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. These studies demonstrate that the 'mouse-to-man' strategy, refined by our knowledge of the Human immune response to infection, can lead to the identification of important candidate gene regions in man.

  • Genetic susceptibility to leishmanial infections: studies in mice and man.
    Parasitology, 1996
    Co-Authors: J M Blackwell
    Abstract:

    Two important recent advances in Leishmania immunology are: (i) the demonstration of a dramatic dichotomy in T helper 1 versus T helper 2 subset expansion leading to protection versus disease exacerbation; and (ii) analysis of the macrophage activation pathways leading to enhanced intracellular killing of parasites, in particular the tumour necrosis factor alpha (TNF alpha)-dependent sustained induction of the inducible nitric oxide synthase gene (Nos2) leading to the generation of large amounts of nitric oxide (NO). Given the broad spectrum of disease phenotypes in Human leishmaniasis, one might predict that a genetic defect at any key point in this macrophage activation pathway and/or in pathways leading to activation of different T cell subsets, and the latter may be a pleiotropic effect of the former, will contribute to disease susceptibility. By studying disease in genetically-defined inbred mouse strains, it has been possible to identify 5 regions of the murine genome carrying leishmanial susceptibility genes. The genes include: (i) Scl-2 (mouse Chromosome 4/Human Chromosome 9p; candidate Janus tyrosine kinase 1) controlling a unique no lesion growth resistance phenotype to Leishmania mexicana; (ii) Scl-1 (distal mouse Chromosome 11/Human 17q; candidates Nos2, Sigje, MIP1 alpha, MIP1 beta) controlling healing versus non-healing responses to L. major; (iii) the 'T helper 2' cytokine gene cluster (proximal murine Chromosome 11/Human 5p; candidates IL4,5,9) controlling later phases of L. major infection; (iv) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse Chromosome 17/Human 6p; candidates class II and class III including TNF alpha/beta genes); and (v) Nramp1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse Chromosome 1/Human 2q35). This review examines these 5 regions and the candidate genes within them, reflecting on their current status as candidates for Human disease susceptibility genes.

  • Genetic susceptibility to leishmanial infections: studies in mice and man
    Parasitology, 1996
    Co-Authors: J M Blackwell
    Abstract:

    Two important recent advances in Leishmania immunology are : (i) the demonstration of a dramatic dichotomy in T helper 1 versus T helper 2 subset expansion leading to protection versus disease exacerbation ; and (ii) analysis of the macrophage activation pathways leading to enhanced intracellular killing of parasites, in particular the tumour necrosis factor α (TNFα)-dependent sustained induction of the inducible nitric oxide synthase gene (Nos2) leading to the generation of large amounts of nitric oxide (NO). Given the broad spectrum of disease phenotypes in Human leishmaniasis, one might predict that a genetic defect at any key point in this macrophage activation pathway and/or in pathways leading to activation of different T cell subsets, and the latter may be a pleiotropic effect of the former, will contribute to disease susceptibility. By studying disease in genetically-defined inbred mouse strains, it has been possible to identify 5 regions of the murine genome carrying leishmanial susceptibility genes. The genes include : (i) Scl-2 (mouse chromosme 4/Human Chromosome 9p ; candidate Janus tyrosine kinase 1) controlling a unique no lesion growth resistance phenotype to Leishmania mexicana ; (ii) Scl-1 (distal mouse Chromosome 11/Human 17q ; candidates Nos2, Sigje, MIP1α, MIP1β controlling healing versus non-healing responses to L. major ; (iii) the 'T helper 2' cytokine gene cluster (proximal murine Chromosome 11/Human 5p ; candidates IL4,5,9) controlling later phases of L. major infection ; (iv) the major histocompatibility complex (MHC : H-2 in mouse, HLA in man : mouse Chromosome 17/Human 6p ; candidates class II and class III including TNFα/β genes) ; and (v) NrampI, the positionally cloned candidate for the murine macrophage resistance gene Yty/Lsh/Brg (mouse Chromosome 1/Human 2q35). This review examines these 5 regions and the candidate genes within them, reflecting on their current status as candidates for Human disease susceptibility genes.

J J Shaw - One of the best experts on this subject based on the ideXlab platform.

  • Evidence for a cluster of genes on Chromosome 17q11–q21 controlling susceptibility to tuberculosis and leprosy in Brazilians
    Genes & Immunity, 2004
    Co-Authors: S E Jamieson, E N Miller, G F Black, C S Peacock, H J Cordell, J M M Howson, M-a Shaw, D Burgner, Z Lins-lainson, J J Shaw
    Abstract:

    The region of conserved synteny on mouse Chromosome 11/Human 17q11–q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. The region is rich in candidates including NOS2A , CCL2/MCP-1 , CCL3/MIP-1α , CCL4/MIP-1β , CCL5/RANTES , CCR7 , STAT3 and STAT5A/5B . To examine the region in man, we studied 92 multicase tuberculosis (627 individuals) and 72 multicase leprosy (372 individuals) families from Brazil. Multipoint nonparametric analysis (ALLEGRO) using 16 microsatellites shows two peaks of linkage for leprosy at D17S250 ( Z _lr score 2.34; P =0.01) and D17S1795 ( Z _lr 2.67; P =0.004) and a single peak for tuberculosis at D17S250 ( Z _lr 2.04; P =0.02). Combined analysis shows significant linkage (peak Z _lr 3.38) at D17S250, equivalent to an allele sharing LOD score 2.48 ( P =0.0004). To determine whether one or multiple genes contribute, 49 informative single nucleotide polymorphisms were typed in candidate genes. Family-based allelic association testing that was robust to family clustering demonstrated significant associations with tuberculosis susceptibility at four loci separated by intervals ( NOS2A –8.4 Mb– CCL18 –32.3 kb– CCL4 –6.04 Mb– STAT5B ) up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control data set showed that the four genes contributed separate main effects, consistent with a cluster of susceptibility genes across 17q11.2.

  • immunogenetics of leishmanial and mycobacterial infections the belem family study
    Philosophical Transactions of the Royal Society B, 1997
    Co-Authors: J M Blackwell, E N Miller, G F Black, C S Peacock, J J Shaw, D Sibthorpe, D Gnananandha, Fernando Tobias Silveira, Z Linslainson, F Ramos
    Abstract:

    In the 1970s and 1980s, analysis of recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively 'scan' the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions of the genome were implicated in the control of infections caused by different Leishmania species which, because they show conserved synteny with regions of the Human genome, immediately provides candidate gene regions for Human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes (Nramp1) was identified for its role in controlling a range of intramacrophage pathogens including leishmania, salmonella and mycobacterium infections. In recent studies, multicase family data on visceral leishmaniasis and the mycobacterial diseases, tuberculosis and leprosy, have been collected from north-eastern Brazil and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family-based linkage analyses (combined segregation and linkage analysis; sib-pair analysis), which have the power to detect linkage between marker loci in candidate gene regions and the putative disease susceptibility genes over 10-20 centimorgans, and transmission disequilibrium testing, which detects allelic associations over 1 centimorgan (ca. 1 megabase), have been used to examine the role of four regions in determining disease susceptibility and/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse Chromosome 17/Human 6p; candidates class II and class III including TNF alpha/beta genes) shows both linkage to, and allelic association with, leprosy per se, but is only weakly associated with visceral leishmaniasis and shows neither linkage to nor allelic association with tuberculosis; (ii) no evidence for linkage between NRAMP1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse Chromosome 1/Human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis could be demonstrated in this Brazilian population; (iii) the region of Human Chromosome 17q (candidates NOS2A, SCYA2-5) homologous with distal mouse Chromosome 11, originally identified as carrying the Scl1 gene controlling healing versus nonhealing responses to Leishmania major, is linked to tuberculosis susceptibility; and (iv) the 'T helper 2' cytokine gene cluster (proximal murine Chromosome 11/Human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. major infection, is not linked to Human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. These studies demonstrate that the 'mouse-to-man' strategy, refined by our knowledge of the Human immune response to infection, can lead to the identification of important candidate gene regions in man.

E N Miller - One of the best experts on this subject based on the ideXlab platform.

  • Evidence for a cluster of genes on Chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians
    Genes and immunity, 2004
    Co-Authors: S E Jamieson, E N Miller, G F Black, C S Peacock, H J Cordell, J M M Howson, M-a Shaw, D Burgner, Z Lins-lainson
    Abstract:

    The region of conserved synteny on mouse Chromosome 11/Human 17q11-q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. The region is rich in candidates including NOS2A, CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL5/RANTES, CCR7, STAT3 and STAT5A/5B. To examine the region in man, we studied 92 multicase tuberculosis (627 individuals) and 72 multicase leprosy (372 individuals) families from Brazil. Multipoint nonparametric analysis (ALLEGRO) using 16 microsatellites shows two peaks of linkage for leprosy at D17S250 (Z(lr) score 2.34; P=0.01) and D17S1795 (Z(lr) 2.67; P=0.004) and a single peak for tuberculosis at D17S250 (Z(lr) 2.04; P=0.02). Combined analysis shows significant linkage (peak Z(lr) 3.38) at D17S250, equivalent to an allele sharing LOD score 2.48 (P=0.0004). To determine whether one or multiple genes contribute, 49 informative single nucleotide polymorphisms were typed in candidate genes. Family-based allelic association testing that was robust to family clustering demonstrated significant associations with tuberculosis susceptibility at four loci separated by intervals (NOS2A-8.4 Mb-CCL18-32.3 kb-CCL4-6.04 Mb-STAT5B) up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control data set showed that the four genes contributed separate main effects, consistent with a cluster of susceptibility genes across 17q11.2.

  • Evidence for a cluster of genes on Chromosome 17q11–q21 controlling susceptibility to tuberculosis and leprosy in Brazilians
    Genes & Immunity, 2004
    Co-Authors: S E Jamieson, E N Miller, G F Black, C S Peacock, H J Cordell, J M M Howson, M-a Shaw, D Burgner, Z Lins-lainson, J J Shaw
    Abstract:

    The region of conserved synteny on mouse Chromosome 11/Human 17q11–q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. The region is rich in candidates including NOS2A , CCL2/MCP-1 , CCL3/MIP-1α , CCL4/MIP-1β , CCL5/RANTES , CCR7 , STAT3 and STAT5A/5B . To examine the region in man, we studied 92 multicase tuberculosis (627 individuals) and 72 multicase leprosy (372 individuals) families from Brazil. Multipoint nonparametric analysis (ALLEGRO) using 16 microsatellites shows two peaks of linkage for leprosy at D17S250 ( Z _lr score 2.34; P =0.01) and D17S1795 ( Z _lr 2.67; P =0.004) and a single peak for tuberculosis at D17S250 ( Z _lr 2.04; P =0.02). Combined analysis shows significant linkage (peak Z _lr 3.38) at D17S250, equivalent to an allele sharing LOD score 2.48 ( P =0.0004). To determine whether one or multiple genes contribute, 49 informative single nucleotide polymorphisms were typed in candidate genes. Family-based allelic association testing that was robust to family clustering demonstrated significant associations with tuberculosis susceptibility at four loci separated by intervals ( NOS2A –8.4 Mb– CCL18 –32.3 kb– CCL4 –6.04 Mb– STAT5B ) up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control data set showed that the four genes contributed separate main effects, consistent with a cluster of susceptibility genes across 17q11.2.

  • immunogenetics of leishmanial and mycobacterial infections the belem family study
    Philosophical Transactions of the Royal Society B, 1997
    Co-Authors: J M Blackwell, E N Miller, G F Black, C S Peacock, J J Shaw, D Sibthorpe, D Gnananandha, Fernando Tobias Silveira, Z Linslainson, F Ramos
    Abstract:

    In the 1970s and 1980s, analysis of recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively 'scan' the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions of the genome were implicated in the control of infections caused by different Leishmania species which, because they show conserved synteny with regions of the Human genome, immediately provides candidate gene regions for Human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes (Nramp1) was identified for its role in controlling a range of intramacrophage pathogens including leishmania, salmonella and mycobacterium infections. In recent studies, multicase family data on visceral leishmaniasis and the mycobacterial diseases, tuberculosis and leprosy, have been collected from north-eastern Brazil and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family-based linkage analyses (combined segregation and linkage analysis; sib-pair analysis), which have the power to detect linkage between marker loci in candidate gene regions and the putative disease susceptibility genes over 10-20 centimorgans, and transmission disequilibrium testing, which detects allelic associations over 1 centimorgan (ca. 1 megabase), have been used to examine the role of four regions in determining disease susceptibility and/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse Chromosome 17/Human 6p; candidates class II and class III including TNF alpha/beta genes) shows both linkage to, and allelic association with, leprosy per se, but is only weakly associated with visceral leishmaniasis and shows neither linkage to nor allelic association with tuberculosis; (ii) no evidence for linkage between NRAMP1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse Chromosome 1/Human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis could be demonstrated in this Brazilian population; (iii) the region of Human Chromosome 17q (candidates NOS2A, SCYA2-5) homologous with distal mouse Chromosome 11, originally identified as carrying the Scl1 gene controlling healing versus nonhealing responses to Leishmania major, is linked to tuberculosis susceptibility; and (iv) the 'T helper 2' cytokine gene cluster (proximal murine Chromosome 11/Human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. major infection, is not linked to Human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. These studies demonstrate that the 'mouse-to-man' strategy, refined by our knowledge of the Human immune response to infection, can lead to the identification of important candidate gene regions in man.

G F Black - One of the best experts on this subject based on the ideXlab platform.

  • Evidence for a cluster of genes on Chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians
    Genes and immunity, 2004
    Co-Authors: S E Jamieson, E N Miller, G F Black, C S Peacock, H J Cordell, J M M Howson, M-a Shaw, D Burgner, Z Lins-lainson
    Abstract:

    The region of conserved synteny on mouse Chromosome 11/Human 17q11-q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. The region is rich in candidates including NOS2A, CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL5/RANTES, CCR7, STAT3 and STAT5A/5B. To examine the region in man, we studied 92 multicase tuberculosis (627 individuals) and 72 multicase leprosy (372 individuals) families from Brazil. Multipoint nonparametric analysis (ALLEGRO) using 16 microsatellites shows two peaks of linkage for leprosy at D17S250 (Z(lr) score 2.34; P=0.01) and D17S1795 (Z(lr) 2.67; P=0.004) and a single peak for tuberculosis at D17S250 (Z(lr) 2.04; P=0.02). Combined analysis shows significant linkage (peak Z(lr) 3.38) at D17S250, equivalent to an allele sharing LOD score 2.48 (P=0.0004). To determine whether one or multiple genes contribute, 49 informative single nucleotide polymorphisms were typed in candidate genes. Family-based allelic association testing that was robust to family clustering demonstrated significant associations with tuberculosis susceptibility at four loci separated by intervals (NOS2A-8.4 Mb-CCL18-32.3 kb-CCL4-6.04 Mb-STAT5B) up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control data set showed that the four genes contributed separate main effects, consistent with a cluster of susceptibility genes across 17q11.2.

  • Evidence for a cluster of genes on Chromosome 17q11–q21 controlling susceptibility to tuberculosis and leprosy in Brazilians
    Genes & Immunity, 2004
    Co-Authors: S E Jamieson, E N Miller, G F Black, C S Peacock, H J Cordell, J M M Howson, M-a Shaw, D Burgner, Z Lins-lainson, J J Shaw
    Abstract:

    The region of conserved synteny on mouse Chromosome 11/Human 17q11–q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. The region is rich in candidates including NOS2A , CCL2/MCP-1 , CCL3/MIP-1α , CCL4/MIP-1β , CCL5/RANTES , CCR7 , STAT3 and STAT5A/5B . To examine the region in man, we studied 92 multicase tuberculosis (627 individuals) and 72 multicase leprosy (372 individuals) families from Brazil. Multipoint nonparametric analysis (ALLEGRO) using 16 microsatellites shows two peaks of linkage for leprosy at D17S250 ( Z _lr score 2.34; P =0.01) and D17S1795 ( Z _lr 2.67; P =0.004) and a single peak for tuberculosis at D17S250 ( Z _lr 2.04; P =0.02). Combined analysis shows significant linkage (peak Z _lr 3.38) at D17S250, equivalent to an allele sharing LOD score 2.48 ( P =0.0004). To determine whether one or multiple genes contribute, 49 informative single nucleotide polymorphisms were typed in candidate genes. Family-based allelic association testing that was robust to family clustering demonstrated significant associations with tuberculosis susceptibility at four loci separated by intervals ( NOS2A –8.4 Mb– CCL18 –32.3 kb– CCL4 –6.04 Mb– STAT5B ) up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control data set showed that the four genes contributed separate main effects, consistent with a cluster of susceptibility genes across 17q11.2.

  • immunogenetics of leishmanial and mycobacterial infections the belem family study
    Philosophical Transactions of the Royal Society B, 1997
    Co-Authors: J M Blackwell, E N Miller, G F Black, C S Peacock, J J Shaw, D Sibthorpe, D Gnananandha, Fernando Tobias Silveira, Z Linslainson, F Ramos
    Abstract:

    In the 1970s and 1980s, analysis of recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively 'scan' the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions of the genome were implicated in the control of infections caused by different Leishmania species which, because they show conserved synteny with regions of the Human genome, immediately provides candidate gene regions for Human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes (Nramp1) was identified for its role in controlling a range of intramacrophage pathogens including leishmania, salmonella and mycobacterium infections. In recent studies, multicase family data on visceral leishmaniasis and the mycobacterial diseases, tuberculosis and leprosy, have been collected from north-eastern Brazil and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family-based linkage analyses (combined segregation and linkage analysis; sib-pair analysis), which have the power to detect linkage between marker loci in candidate gene regions and the putative disease susceptibility genes over 10-20 centimorgans, and transmission disequilibrium testing, which detects allelic associations over 1 centimorgan (ca. 1 megabase), have been used to examine the role of four regions in determining disease susceptibility and/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse Chromosome 17/Human 6p; candidates class II and class III including TNF alpha/beta genes) shows both linkage to, and allelic association with, leprosy per se, but is only weakly associated with visceral leishmaniasis and shows neither linkage to nor allelic association with tuberculosis; (ii) no evidence for linkage between NRAMP1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse Chromosome 1/Human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis could be demonstrated in this Brazilian population; (iii) the region of Human Chromosome 17q (candidates NOS2A, SCYA2-5) homologous with distal mouse Chromosome 11, originally identified as carrying the Scl1 gene controlling healing versus nonhealing responses to Leishmania major, is linked to tuberculosis susceptibility; and (iv) the 'T helper 2' cytokine gene cluster (proximal murine Chromosome 11/Human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. major infection, is not linked to Human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. These studies demonstrate that the 'mouse-to-man' strategy, refined by our knowledge of the Human immune response to infection, can lead to the identification of important candidate gene regions in man.

C S Peacock - One of the best experts on this subject based on the ideXlab platform.

  • Evidence for a cluster of genes on Chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians
    Genes and immunity, 2004
    Co-Authors: S E Jamieson, E N Miller, G F Black, C S Peacock, H J Cordell, J M M Howson, M-a Shaw, D Burgner, Z Lins-lainson
    Abstract:

    The region of conserved synteny on mouse Chromosome 11/Human 17q11-q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. The region is rich in candidates including NOS2A, CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL5/RANTES, CCR7, STAT3 and STAT5A/5B. To examine the region in man, we studied 92 multicase tuberculosis (627 individuals) and 72 multicase leprosy (372 individuals) families from Brazil. Multipoint nonparametric analysis (ALLEGRO) using 16 microsatellites shows two peaks of linkage for leprosy at D17S250 (Z(lr) score 2.34; P=0.01) and D17S1795 (Z(lr) 2.67; P=0.004) and a single peak for tuberculosis at D17S250 (Z(lr) 2.04; P=0.02). Combined analysis shows significant linkage (peak Z(lr) 3.38) at D17S250, equivalent to an allele sharing LOD score 2.48 (P=0.0004). To determine whether one or multiple genes contribute, 49 informative single nucleotide polymorphisms were typed in candidate genes. Family-based allelic association testing that was robust to family clustering demonstrated significant associations with tuberculosis susceptibility at four loci separated by intervals (NOS2A-8.4 Mb-CCL18-32.3 kb-CCL4-6.04 Mb-STAT5B) up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control data set showed that the four genes contributed separate main effects, consistent with a cluster of susceptibility genes across 17q11.2.

  • Evidence for a cluster of genes on Chromosome 17q11–q21 controlling susceptibility to tuberculosis and leprosy in Brazilians
    Genes & Immunity, 2004
    Co-Authors: S E Jamieson, E N Miller, G F Black, C S Peacock, H J Cordell, J M M Howson, M-a Shaw, D Burgner, Z Lins-lainson, J J Shaw
    Abstract:

    The region of conserved synteny on mouse Chromosome 11/Human 17q11–q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. The region is rich in candidates including NOS2A , CCL2/MCP-1 , CCL3/MIP-1α , CCL4/MIP-1β , CCL5/RANTES , CCR7 , STAT3 and STAT5A/5B . To examine the region in man, we studied 92 multicase tuberculosis (627 individuals) and 72 multicase leprosy (372 individuals) families from Brazil. Multipoint nonparametric analysis (ALLEGRO) using 16 microsatellites shows two peaks of linkage for leprosy at D17S250 ( Z _lr score 2.34; P =0.01) and D17S1795 ( Z _lr 2.67; P =0.004) and a single peak for tuberculosis at D17S250 ( Z _lr 2.04; P =0.02). Combined analysis shows significant linkage (peak Z _lr 3.38) at D17S250, equivalent to an allele sharing LOD score 2.48 ( P =0.0004). To determine whether one or multiple genes contribute, 49 informative single nucleotide polymorphisms were typed in candidate genes. Family-based allelic association testing that was robust to family clustering demonstrated significant associations with tuberculosis susceptibility at four loci separated by intervals ( NOS2A –8.4 Mb– CCL18 –32.3 kb– CCL4 –6.04 Mb– STAT5B ) up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control data set showed that the four genes contributed separate main effects, consistent with a cluster of susceptibility genes across 17q11.2.

  • immunogenetics of leishmanial and mycobacterial infections the belem family study
    Philosophical Transactions of the Royal Society B, 1997
    Co-Authors: J M Blackwell, E N Miller, G F Black, C S Peacock, J J Shaw, D Sibthorpe, D Gnananandha, Fernando Tobias Silveira, Z Linslainson, F Ramos
    Abstract:

    In the 1970s and 1980s, analysis of recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively 'scan' the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions of the genome were implicated in the control of infections caused by different Leishmania species which, because they show conserved synteny with regions of the Human genome, immediately provides candidate gene regions for Human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes (Nramp1) was identified for its role in controlling a range of intramacrophage pathogens including leishmania, salmonella and mycobacterium infections. In recent studies, multicase family data on visceral leishmaniasis and the mycobacterial diseases, tuberculosis and leprosy, have been collected from north-eastern Brazil and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family-based linkage analyses (combined segregation and linkage analysis; sib-pair analysis), which have the power to detect linkage between marker loci in candidate gene regions and the putative disease susceptibility genes over 10-20 centimorgans, and transmission disequilibrium testing, which detects allelic associations over 1 centimorgan (ca. 1 megabase), have been used to examine the role of four regions in determining disease susceptibility and/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse Chromosome 17/Human 6p; candidates class II and class III including TNF alpha/beta genes) shows both linkage to, and allelic association with, leprosy per se, but is only weakly associated with visceral leishmaniasis and shows neither linkage to nor allelic association with tuberculosis; (ii) no evidence for linkage between NRAMP1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse Chromosome 1/Human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis could be demonstrated in this Brazilian population; (iii) the region of Human Chromosome 17q (candidates NOS2A, SCYA2-5) homologous with distal mouse Chromosome 11, originally identified as carrying the Scl1 gene controlling healing versus nonhealing responses to Leishmania major, is linked to tuberculosis susceptibility; and (iv) the 'T helper 2' cytokine gene cluster (proximal murine Chromosome 11/Human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. major infection, is not linked to Human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. These studies demonstrate that the 'mouse-to-man' strategy, refined by our knowledge of the Human immune response to infection, can lead to the identification of important candidate gene regions in man.