RESUMO
Leprosy is a chronic disease caused by infection with Mycobacterium leprae, which is manifested across a wide clinical spectrum. There is evidence that susceptibility both to leprosy per se and to the clinical type of leprosy is influenced by host genetic factors. This paper describes the application of an identity by descent regression search for genetic determinants of leprosy type among families from Karonga District, Northern Malawi. Suggestive evidence was found for linkage to leprosy type on chr 21q22 (P<0.001). The methodological implications of the approach and the findings are discussed.
Assuntos
Cromossomos Humanos Par 21/genética , Ligação Genética/genética , Predisposição Genética para Doença , Hanseníase/epidemiologia , Feminino , Humanos , Hanseníase/diagnóstico , Hanseníase/genética , Malaui/epidemiologia , Masculino , Linhagem , Análise de RegressãoRESUMO
The ancient disease of leprosy can cause severe disability and disfigurement and is still a major health concern in many parts of the world. Only a subset of those individuals exposed to the pathogen will go on to develop clinical disease and there is a broad clinical spectrum amongst leprosy sufferers. The outcome of infection is in part due to host genes that influence control of the initial infection and the host's immune response to that infection. Identification of the host genes that influence host susceptibility/resistance will enable a greater understanding of disease pathogenesis. In turn, this should facilitate development of more effective therapeutics and vaccines. So far at least a dozen genes have been implicated in leprosy susceptibility and a genome-wide linkage study has lead to the identification of at least one positional candidate. These findings are reviewed here.
Assuntos
Predisposição Genética para Doença/genética , Hanseníase/genética , Animais , Ligação Genética/genética , Ligação Genética/imunologia , Humanos , Hanseníase/imunologia , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologiaRESUMO
The ancient disease of leprosy can cause severe disability and disfigurement and is still a major health concern in many parts of the world. Only a subset of those individuals exposed to the pathogen will go on to develop clinical disease and there is a broad clinical spectrum amongst leprosy sufferers. The outcome of infection is in part due to host genes that influence control of the initial infection and the host's immune response to that infection. Identification of the host genes that influence host susceptibility/resistance will enable a greater understanding of disease pathogenesis. In turn, this should facilitate development of more effective therapeutics and vaccines. So far at least a dozen genes have been implicated in leprosy susceptibility and a genome-wide linkage study has lead to the identification of at least one positional candidate. These findings are reviewed here.
Assuntos
Humanos , Animais , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Hanseníase/genética , Hanseníase/imunologia , Ligação Genética/genética , Ligação Genética/imunologia , Predisposição Genética para Doença/genéticaRESUMO
Before Robert Koch's work in the late nineteenth century, diseases such as tuberculosis and leprosy were widely believed to be inherited disorders. Heritability of susceptibility to several infectious diseases has been confirmed by studies in the twentieth century. Infectious diseases, old and new, continue to be an important cause of mortality worldwide. A greater understanding of disease processes is needed if more effective therapies and more useful vaccines are to be produced. As part of this effort, developments in genetics have allowed a more systematic study of the impact that the human genome and infectious disease have on each other.
Assuntos
Doenças Transmissíveis/genética , Predisposição Genética para Doença , Evolução Biológica , Ligação Genética , Antígenos HLA/genética , HumanosRESUMO
A genetic basis for interindividual variation in susceptibility to human infectious diseases has been indicated by twin, adoptee, pedigree, and candidate gene studies. This has led to the identification of a small number of strong genetic associations with common variants for malaria, HIV infection, and infectious prion diseases. Numerous other genes have shown less strong associations with these and some other infectious diseases, such as tuberculosis, leprosy, and persistent hepatitis viral infections. Many immunogenetic loci influence susceptibility to several infectious pathogens. Recent genetic linkage analyses of measures of infection as well as of infectious disease, including some genome-wide scans, have found convincing evidence of genetic linkage to chromosomal regions wherein susceptibility genes have yet to be identified. These studies indicate a highly polygenic basis for susceptibility to many common infectious diseases, with some emerging examples of interaction between variants of specific polymorphic host and pathogen genes.
Assuntos
Doenças Transmissíveis/genética , Predisposição Genética para Doença , Genética Médica , Genoma Humano , Ligação Genética , HumanosRESUMO
Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is prevalent in India, where about half of the world's estimated 800,000 cases occur. A role for the genetics of the host in variable susceptibility to leprosy has been indicated by familial clustering, twin studies, complex segregation analyses and human leukocyte antigen (HLA) association studies. We report here a genetic linkage scan of the genomes of 224 families from South India, containing 245 independent affected sibpairs with leprosy, mainly of the paucibacillary type. In a two-stage genome screen using 396 microsatellite markers, we found significant linkage (maximum lod score (MLS) = 4.09, P < 2x10-5) on chromosome 10p13 for a series of neighboring microsatellite markers, providing evidence for a major locus for this prevalent infectious disease. Thus, despite the polygenic nature of infectious disease susceptibility, some major, non-HLA-linked loci exist that may be mapped through obtainable numbers of affected sibling pairs.
Assuntos
Cromossomos Humanos Par 10 , Predisposição Genética para Doença , Hanseníase/genética , Mapeamento Cromossômico , Marcadores Genéticos , Antígenos HLA/genética , Humanos , Índia/epidemiologia , Hanseníase/epidemiologia , PrevalênciaRESUMO
Twin and family studies indicate that host genetic factors influence susceptibility to leprosy and, possibly, leprosy type. Murine studies have suggested a role for the natural resistance-associated macrophage protein 1 (Nramp1) gene, which can influence cellular immune responses to intracellular pathogens. We evaluated a variation in the human homolog, NRAMP1, recently associated with tuberculosis susceptibility in West Africa. A total of 273 patients with leprosy and 201 controls from Mali were genotyped for NRAMP1 polymorphisms previously associated with tuberculosis. No association was found with leprosy per se (P = 0.83), but the NRAMP1 3'-untranslated region 4-bp insertion/deletion polymorphism was associated with leprosy type (P = 0.007). Heterozygotes were more frequent among multibacillary than paucibacillary leprosy cases. Thus, variation in or near the NRAMP1 gene may exert an influence on the clinical presentation of leprosy, possibly by influencing cellular immune response type.
Assuntos
População Negra/genética , Proteínas de Transporte de Cátions/genética , Predisposição Genética para Doença/genética , Hanseníase/genética , Adulto , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Hanseníase/classificação , Masculino , Mali , Pessoa de Meia-Idade , Polimorfismo GenéticoAssuntos
Alelos , Deleção de Sequência , Estudos de Casos e Controles , Frequência do Gene , Genótipo , Hanseníase Tuberculoide/genética , Hanseníase Tuberculoide/imunologia , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/imunologia , Hanseníase/genética , Hanseníase/imunologia , Imunogenética , Polimorfismo Genético , Primers do DNA/genética , Proteínas Precoces de Adenovirus , Proteínas de Membrana/genética , Proteínas de Transporte/genética , Receptores de Calcitriol/genética , Receptores de Calcitriol/imunologia , Sequência de Bases , Variação Genética , ÍndiaRESUMO
Host genetic factors including major histocompatibility complex (MHC) polymorphisms influence both susceptibility to leprosy per se and also to leprosy type. Non-MHC genes may play an important role, but such genes remain undefined. The influence of two non-MHC candidate genes was assessed in a case-control study of Bengali leprosy patients from Calcutta. Recent studies have implicated variation in the vitamin D receptor (VDR) gene in susceptibility to several diseases, including osteoporosis and pulmonary tuberculosis. In this population, homozygotes for the alternate alleles of the VDR polymorphism are associated, respectively, with lepromatous and tuberculoid leprosy. The NRAMP1 (natural resistance associated macrophage protein 1) gene may influence human mycobacterial disease susceptibility based on studies with the murine homologue Nramp1. However, no significant association was found between NRAMP1 and leprosy susceptibility. This study suggests that the VDR polymorphism may influence susceptibility to some diseases by affecting the type and the strength of the host immune response.
Assuntos
Proteínas de Transporte de Cátions , Hanseníase/genética , Receptores de Calcitriol/genética , Alelos , Sequência de Bases , Proteínas de Transporte/genética , Estudos de Casos e Controles , Primers do DNA/genética , Frequência do Gene , Variação Genética , Genótipo , Humanos , Imunogenética , Índia , Hanseníase/imunologia , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/imunologia , Hanseníase Tuberculoide/genética , Hanseníase Tuberculoide/imunologia , Proteínas de Membrana/genética , Polimorfismo Genético , Receptores de Calcitriol/imunologia , Deleção de SequênciaRESUMO
Twin and adoptee studies have indicated that host genetic factors are major determinants of susceptibility to infectious disease in humans. Twin studies have also found high heritabilities for many humoral and cellular immune responses to pathogen antigens, with most of the genetic component mapping outside of the major histocompatibility complex. Candidate gene studies have implicated several immunogenetic polymorphisms in human infectious diseases. HLA variation has been associated with susceptibility or resistance to malaria, tuberculosis, leprosy, AIDS, and hepatitis virus persistence. Variation in the tumor necrosis factor gene promoter has also been associated with several infectious diseases. Chemokine receptor polymorphism affects both susceptibility ot HIV-1 infection and the rate of progression to AIDS. Inactivating mutations of the gamma-interferon receptor lead to increased susceptibility to typical mycobacteria and disseminated BCG infection in homozygous children. The active form of vitamin D has immunomodulatory effects, and allelic variants of the vitamin D receptor appear to be associated with differential susceptibility to several infectious diseases. NRAMP1, a macrophage gene identified by positional cloning of its murine homologue, has been implicated in susceptibility to tuberculosis in Africans. Whole genome linkage analysis of multi-case families is now being used to map and identify new loci affecting susceptibility to infectious diseases. It is likely that susceptibility to most microorganisms is determined by a large number of polymorphic genes, and identification of these should provide insights into protective and pathogenic mechanisms in infectious diseases.
Assuntos
Imunogenética , Infecções/genética , Infecções/imunologia , Animais , Suscetibilidade a Doenças , Humanos , Estudos em Gêmeos como AssuntoRESUMO
Genetically determined differences in immune responses to environmental agents may underlie susceptibility to many autoimmune and infectious diseases. Leprosy provides an example of a polarity in the type of immune response made to an infectious agent, and there is evidence that the major histocompatibility complex is genetically linked to leprosy type. It was found that HLA-DR2 is associated with both tuberculoid and lepromatous types of leprosy; however, a variant at position -308 of the promoter of the neighboring tumor necrosis factor (TNF) gene was increased in frequency in lepromatous (odds ratio = 3.0, P = .02) but not tuberculoid leprosy. Some studies have found higher serum levels of TNF in lepromatous than tuberculoid leprosy, and high TNF levels are found in malaria and leishmaniasis, which are also associated with this TNF allele. It is speculated that this association reflects genetic variability in cytokine production, which influences the immune response to and clinical outcome of leprosy.