Key Points
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Differences in susceptibility to disease can be seen at the level of individuals and populations. Genetic epidemiology data indicate that there might be major susceptibility genes that account for a significant proportion of the genetic contribution to disease susceptibility.
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Infectious diseases can influence the evolution of their hosts; the association between sickle-cell anaemia and reduced susceptibility to malaria is well known, and the prevalence of the sickle haemoglobin allele in malarial regions is considered to be a result of the selective pressure that malaria parasites exert on human populations.
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Several single-gene disorders have been implicated in altered susceptibility to many different infectious diseases; for example, individuals who carry mutations in the CD40 ligand are susceptible to opportunistic infections.
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Human leukocyte antigen (HLA) loci evolve very fast, probably as a result of selective pressure from pathogens, and polymorphisms in these loci have been associated with altered susceptibility to infectious diseases, such as leprosy and tuberculosis.
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Several non-HLA genes have also been linked with increased susceptibility to disease: tumour-necrosis factor-α with malaria; vitamin D receptor with tuberculosis; or a cytokine CD4 with HIV infection.
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Genome-wide linkage analysis and comparative genomics will be instrumental in the understanding of host–parasite genetic interactions, and are a prerequisite to developing effective vaccines and therapies.
Abstract
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.
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Glossary
- HERITABILITY
-
The proportion of the variation in a given characteristic or state that can be attributed to genetic factors.
- SIBLING RISK
-
The likelihood that a phenotype will recur in the sibling of an affected individual.
- SCHISTOSOMIASIS
-
Otherwise known as bilharzia; a parasitic infection contracted through infected fresh water.
- HAEMOLYSIS
-
Breakdown of red blood cells.
- SECRETOR STATUS
-
Individuals are secretors or non-secretors depending on whether blood-group antigens are secreted into mucosal fluids.
- POPULATION BOTTLENECK
-
A marked reduction in population size followed by the survival and expansion of a small random sample of the original population.
- MACROPHAGE
-
Phagocytic cell of the mononuclear lineage that internalizes and destroys infectious agents. Macrophages also function in antigen presentation.
- CD40 LIGAND
-
Member of the tumour-necrosis factor superfamily of molecules that are expressed on the surface of T cells. CD40–CD40 ligand interaction is crucial for the development of many aspects of the immune system.
- HYPER-IGM
-
The presence of unusually high levels of immunoglobulin M (IgM) in the blood.
- OPPORTUNISTIC INFECTION
-
An infection that is normally resisted by a healthy individual but takes hold in the setting of a compromised immune system.
- STAT FACTOR
-
(signal transducer and activator of transcription). Molecule that comprises one part of an intracellular pathway that mediates the effects of interferon-α and other cytokines.
- EPITOPE
-
The portion of an antigen that interfaces with the antigen-binding site of an antibody or T-cell receptor.
- POPULATION STRATIFICATION
-
A population that contains several sub-populations that differ in their genetic characteristics.
- LINKAGE DISEQUILIBRIUM
-
When the frequency of a particular haplotype for two loci is significantly greater than that expected from the product of the observed allelic frequencies at each locus.
- ROSETTING
-
Refers to the pathological process in malaria, in which uninfected red blood cells clump together with parasitized red blood cells.
- CYTOKINE
-
A soluble molecule, such as a growth factor, that mediates interactions between cells.
- CD36
-
Glycoprotein molecule that is expressed on leukocytes, endothelium and platelets and binds to parasitized erythrocytes.
- PHAGOLYSOSOME
-
Intracellular vesicle, which is the fused product of the phagosome and the lysosome. The phagosome contains the engulfed pathogen and the lysosome contains protein-digesting enzymes.
- LECTIN
-
A sugar-binding receptor of the innate immune system.
- INNATE IMMUNITY
-
That part of the immune response that is not adaptive (that is, does not change with repeated exposure to a pathogen).
- OPSONIZATION
-
The process whereby molecules that are deposited on the surface of pathogens (opsonins) aid uptake of these pathogens into the specialized cells of the immune system.
- INDOLENT
-
In medical terms, slow to develop or heal.
- COMMON ANCESTRY MAPPING
-
Method for finding genes for susceptibility to disease by identifying discrepancies in the time to most recent common ancestor in homologous regions from susceptible and non-susceptible individuals.
- ATOPY
-
Clinical manifestations of allergic immune responses; for example, eczema or asthma.
- ENDOTOXIN
-
Lipopolysaccharide that is found in the membrane of Gram-negative bacteria and that activates B cells and macrophages.
- BIOLOGICS
-
Agents of biological origin that are used to diagnose or treat disease.
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Cooke, G., Hill, A. Genetics of susceptibitlity to human infectious disease. Nat Rev Genet 2, 967–977 (2001). https://doi.org/10.1038/35103577
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DOI: https://doi.org/10.1038/35103577
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