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  • Review Article
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Genetics of susceptibitlity to human infectious disease

Key Points

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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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Figure 1: Global distribution of malaria and red-blood-cell disorders.
Figure 2: Life cycle of the malarial parasite Plasmodium falciparum.
Figure 3: Structural diagram of HLA B53 (class I) molecule.

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Correspondence to Adrian V. S. Hill.

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DATABASES

LocusLink 

CCR2

CCR5

CD4

CD36

CD40

CFTR

CXCR4

DARC

GATA1

HLA-DRB1

HLA-DR subtypes

ICAM1

IL4

IL9

IL10

IL13

IFNGR1

MASP1

MASP2

MBL2

NOD2

NRAMP1

NRAMP2

SDF1

STAT1

TLR4

TNF-α

VDR 

OMIM 

Crohn disease

cystic fibrosis

G6PD deficiency

HbS

immunodeficiency with hyper-IgM

thalassaemia

type I diabetes

FURTHER INFORMATION

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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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