Human genetic susceptibility to infectious disease

Key Points

  • Common and rare human genetic variation influences susceptibility to infectious disease.

  • Genome-wide association studies have identified various strong associations between genetic polymorphisms and susceptibility to common infectious disease phenotypes, such as HIV-1, hepatitis B and C viruses, dengue, malaria, tuberculosis, leprosy, meningococcal disease and prion disease.

  • Studies have confirmed an important role for human leukocyte antigen (HLA) variation in susceptibility to many, but not all, common infectious diseases.

  • Application of genome-wide approaches to African populations is challenging, which reflects in part the high levels of ethnic diversity in Africa and a lack of population-specific genotyping arrays.

  • An increasing number of rare, single-gene defects have been described in association with susceptibility to a narrow range of different pathogens in otherwise healthy individuals.

  • Examples of mutations associated with such 'selective' immunodeficiencies include: interleukin-12–interleukin-23–interferon-γ (IFNγ) pathway defects and susceptibility to mycobacterial disease; Toll-like receptor (TLR)–nuclear factor-κB pathway defects and invasive pneumococcal disease; and TLR3–IFNα–IFNβ pathway mutations and herpes simplex viral encephalitis.

  • Both common and rare variants in the same molecular pathway may underlie related infectious disease phenotypes.

  • The relative contributions of common and rare variants to infectious disease susceptibility at the individual and population level are currently unknown. The application of next-generation sequencing technology is likely to define the genetic architecture of infectious disease.


Recent genome-wide studies have reported novel associations between common polymorphisms and susceptibility to many major infectious diseases in humans. In parallel, an increasing number of rare mutations underlying susceptibility to specific phenotypes of infectious disease have been described. Together, these developments have highlighted a key role for host genetic variation in determining the susceptibility to infectious disease. They have also provided insights into the genetic architecture of infectious disease susceptibility and identified immune molecules and pathways that are directly relevant to the human host defence.

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Figure 1: Genetic variation in TLR signalling and susceptibility to infectious disease.


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Research in the authors' laboratory is funded by the Wellcome Trust, the UK Medical Research Council and the UK National Institute for Health Research (NIHR) Oxford Biomedical Research Centre.

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1000 Genomes Project

Nature Reviews Genetics series on Genome-wide association studies



The probability of correctly rejecting the null hypothesis when it is truly false. In genetic association studies, power is determined by the sample size, allele frequency, magnitude of effect and significance threshold, and can be considered as the probability that the study will correctly detect a genuine association.

Population stratification

The presence in a population of several subpopulations that differ in their genetic characteristics, reflecting their different ancestral histories. Such systematic ancestry differences between cases and controls can confound genetic association studies, causing spurious disease associations.

Multiple testing

An analysis in which multiple independent hypotheses are tested within a single data set. Performing multiple independent tests increases the likelihood of a type I error and requires adjustment of the threshold significance level (P value); for example, by using the Bonferroni correction.

Principal components analysis

A statistical method that is used to simplify a complex data set by transforming a series of correlated variables into a smaller number of uncorrelated variables called principal components. It is commonly used to correct for stratification in genome-wide association studies.

'Common disease, common variant' hypothesis

This hypothesis states that the genetic variants that underlie complex disease are themselves common.


The proportion of phenotypic variation in a given characteristic or state that is due to underlying genetic variation.

Human leukocyte antigens

(HLAs). Glycoproteins encoded by the major histocompatibility complex locus that are located on the surface of antigen-presenting cells and that present antigenic peptides to T cells.

Killer immunoglobulin-like receptors

Receptors expressed at the surface of natural killer (NK) cells that regulate NK cell cytotoxic activity through specific interactions with HLA class I molecules.

Viral-load set point

The HIV RNA level in the blood during the asymptomatic period of HIV-1 infection. It fluctuates around a steady set-point value, although it is variable both within patients over time and among patients. High viral-load set points correlate with rapid disease progression.

Linkage disequilibrium

(LD). The occurrence of alleles together at frequencies greater than are expected by chance alone.

Major histocompatibility complex

(MHC). A large complex of tightly linked genes on human chromosome 6, many of which are involved in the immune response. The HLA genes are located within the MHC.

HIV-1 nonprogression

HIV-1 disease progression may be assessed by a number of measures, which can be used to define subgroups of individuals with long-term nonprogression. It can be defined, for example, as asymptomatic HIV-1 infection and a stable CD4+ T cell count for ten or more years in the absence of treatment.

HIV-1 controllers

A small subgroup of individuals infected with HIV-1 who maintain very low or undetectable plasma HIV viral loads in the absence of antiviral therapy.


A statistical method that infers the genotype of untyped variants based on the known genotypes of a smaller number of nearby markers and the known linkage disequilibrium relationships in fully genotyped individuals (provided by HapMap reference data).

Hypovolaemic shock

A life-threatening condition in which fluid loss results in a reduction in the intravascular blood volume and inadequate tissue perfusion.

Conditional analysis

A form of statistical testing that considers the independent contributions of variants in a region of association containing multiple variants in linkage disequilibrium, in order to identify the most likely causal variant or variants.

Innate immunity

An immediate, non-specific and evolutionarily conserved ancient form of immune response to foreign infectious agents. It constitutes the first line of defence against invading organisms.

Crohn's disease

A type of inflammatory bowel disease characterized by granulomatous inflammation that may occur in any region of the gastrointestinal tract.


A complex protein cascade that is involved in both innate and adaptive immunity. Complement activation results in pathogen opsonization and cell lysis, and occurs through three different pathways: alternate, classical and lectin.

Respiratory burst

The rapid generation and release of reactive oxygen species that follows exposure of phagocytes (primarily neutrophils and macrophages) to microorganisms or inflammatory mediators.


The proportion of individuals with a given genotype who display a particular phenotype.

Odds ratio

A comparison of the odds of exposure to a susceptible genetic variant in cases versus controls.


A Gram-negative bacterial cell wall component that is recognized by Toll-like receptor 4 and triggers a pro-inflammatory host response.

'Pathway-based' sequencing strategies

Joint analysis of variants within a group of related genes in the same biological pathway, as opposed to analysis of individual markers.


The collection of protein-coding regions (exons) in the genome. It is widely presumed that most genetic variants that exert a large effect on disease susceptibility will be located in coding regions. Because these regions comprise only 1% of the human genome, whole-exome sequencing represents a potentially efficient strategy for the identification of rare, large-effect variants underlying disease.

Severe combined immunodeficiency

A range of primary immunodeficiencies due to severe defects in T cell (and often B cell) production and function and defective cytokine signalling that result in early-onset severe infections by a range of pathogens.

Chronic mucocutaneous candidiasis

Persistent or recurrent superficial infections of the skin, nails or mucous membranes by Candida species.

Hyper-IgE syndrome

A primary immunodeficiency characterized by eczema, greatly elevated serum levels of immunoglobulin E (IgE) and recurrent skin and pulmonary infections.

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Chapman, S., Hill, A. Human genetic susceptibility to infectious disease. Nat Rev Genet 13, 175–188 (2012).

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